Belongs to the fatty acid desaturase type 1 family. DEGS subfamily.
Has sphingolipid-delta-4-desaturase activity. Converts D-erythro-sphinganine to D-erythro-sphingosine (E-sphing-4-enine) (By similarity). Catalyzes the equilibrium isomerization of retinols (By similarity).
Interacts with RLBP1; the interaction increases synthesis of chromophore-precursors by DEGS1.
Myristoylation can target the enzyme to the mitochondria leading to an increase in ceramide levels.
Belongs to the G-protein coupled receptor 1 family.
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.
Interacts with CHD8. Interacts with LLPH. Interacts with CENPE.
Sumoylated on Lys-74 and Lys-699; sumoylation of CTCF contributes to the repressive function of CTCF on the MYC P2 promoter.
Belongs to the intermediate filament family.
Expressed in the cortex and hippocampus. Expression decreases following acute and chronic corticosterone treatment.
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.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.
Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May also regulate the TOR signaling cascade (By similarity).
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.
Belongs to the poly(A) polymerase family.
Binds 2 magnesium ions. Also active with manganese.
Polymerase that creates the 3'-poly(A) tail of mRNA's.
Bridging factor that mediates the recruitment of CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis. 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). Required to activate the 'Met-1'- (linear) and 'Lys-63'-linked deubiquitinase activities of CYLD (By similarity). Controls the kinase activity of RIPK1 and TNF-alpha-induced necroptosis by promoting 'Met-1'-linked deubiquitination of RIPK1 by CYLD (By similarity).
During testicular development (from 2 to 45 days of age), expressed from 14 days and then increases steadily with an advancement of age.
Expressed in the testis and to a lesser extent in the brain, while skeletal muscle and kidney show weak expression.
Interacts (via the PIM motif) with RNF31/HOIP (via the PUB domain); the interaction is direct. Interacts (via the PUB domain) with CYLD; the interaction is direct.
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.
Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV4 sub-subfamily.
Expressed lung, spleen, kidney, testis, fat, and at very low levels in trigeminal ganglia.
Homotetramer. Interacts with calmodulin (By similarity). Interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, HCK, LCK and YES (By similarity). Interacts with CTNNB1 (By similarity). The TRPV4 and CTNNB1 complex can interact with CDH1 (By similarity). Part of a complex containing MLC1, AQP4, HEPACAM and ATP1B1 (By similarity). Interacts with PACSIN1, PACSIN2 and PACSIN3 (via SH3 domain) (PubMed:16627472). Interacts with ITPR3 (By similarity). Interacts with AQP5; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity (By similarity). Interacts with ANO1 (By similarity). Interacts (via C-terminus) with PKD2 (via C-terminus) (By similarity). Interacts with DDX3X; this interaction is decreased when the channel is activated (By similarity).
Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity (PubMed:11081638). Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification (PubMed:11081638). Also activated by heat, low pH, citrate and phorbol esters (By similarity). Increase of intracellular Ca(2+) potentiates currents (By similarity). Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes (By similarity). Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8 (By similarity). Together with PKD2, forms mechano- and thermosensitive channels in cilium (By similarity). Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to pro-inflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage (By similarity). In its inactive state, may sequester DDX3X at the plasma membrane. When activated, the interaction between both proteins is affected and DDX3X relocalizes to the nucleus (By similarity).
The ANK repeat region mediates interaction with Ca(2+)-calmodulin and ATP binding. The ANK repeat region mediates interaction with phosphatidylinositol-4,5-bisphosphate and related phosphatidylinositides.
Belongs to the aldo/keto reductase family.
Catalyzes the conversion of progesterone into 20-alpha-dihydroprogesterone (20 alpha-OHP).
Remains repressed throughout pregnancy and becomes highly and rapidly expressed before parturition.
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. 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. 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.
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with microtubules. Interacts with SMO. Interacts (via coiled-coil domains) with RAB3B (in GTP-bound form) (By similarity). Interacts with DRC7 (By similarity).
Expressed exclusively in Purkinje cells.
Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).
The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.
Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.
Transcriptional repressor of genes that require a bHLH protein for their transcription.
Belongs to the eukaryotic ribosomal protein eS26 family.
Calcium-dependent lectin involved in innate immune defense. 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 (By similarity).
Oligomeric complex of 3 or more homotrimers. Interacts with MASP1 and MASP2 (By similarity). Interacts with MEP1A and MEP1B and may inhibit their catalytic activity (By similarity).
The coiled-coil domain mediates trimerization.
Belongs to the bile acid:sodium symporter (BASS) (TC 2.A.28) family.
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. Also involved in the regulation of cellular calcium homeostasis. Does not show transport activity towards bile acids or steroid sulfates (including taurocholate, cholate, chenodeoxycholate, estrone-3-sulfate, dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate).
Strongly expressed in liver, adrenal gland, small intestine and colon. Moderately expressed in heart, lung, kidney and spleen. Weakly expressed in brain.
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:12176987). 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 (By similarity). 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:25043761). 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).
Belongs to the ABC transporter superfamily. ABCD family. Peroxisomal fatty acyl CoA transporter (TC 3.A.1.203) subfamily.
Can form homodimers and heterodimers with ABCD2 and ABCD3. Dimerization is necessary to form an active transporter (PubMed:12176987, PubMed:25043761, PubMed:28258215). The minimal functional unit is a homodimer but the major oligomeric form in peroxisomal membrane is a homotetramer. Forms heterotramers with ABCD2 (PubMed:28258215). Interacts with PEX19; facilitates ABCD1 insertion into the peroxisome membrane (By similarity).
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).
Belongs to the eukaryotic ribosomal protein eL38 family.
Component of the large ribosomal subunit.
Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
Contains 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.
Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production. Inhibits platelet aggregation and activation by agonists such as ADP and collagen-related peptide. 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. Appears to operate in a calcium-independent manner.
Interacts (via ITIM motif) with PTPN6 and PTPN11. Binds to heparin.
Belongs to the eukaryotic ribosomal protein eL39 family.
Component of the large ribosomal subunit (By similarity). Interacts with IMPACT (By similarity).
RNA-binding component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
This protein is the smallest and one of the most basic of the proteins in liver ribosomes.
Lacks conserved residue(s) required for the propagation of feature annotation.
Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells. Receptor for HDL, mediating selective uptake of cholesteryl ether and HDL-dependent cholesterol efflux. 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.
The six cysteines of the extracellular domain are all involved in intramolecular disulfide bonds.
May play a role in ubiquitination and subsequent proteasomal degradation of target proteins.
Phosphorylated at Ser-252 and Ser-302, 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 (By similarity).
The CS domain mediates interaction with HSP90.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE1 subfamily.
Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions, while site 2 has a preference for magnesium and/or manganese ions.
Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions.
Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium ions.
Cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a preference for cGMP as a substrate.
Type I PDE are activated by the binding of calmodulin in the presence of Ca(2+).
Interacts with ATRAID; the interaction promotes osteoblast cell differentiation and mineralization (By similarity). Homotrimer. Binds to PKC beta-1.
Plays a role in the control of cell growth and differentiation. Promotes osteoblast cell differentiation and terminal mineralization (By similarity).
Required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus.
Plays a role in mast cell degranulation.
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 (By similarity). 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).
Expressed throughout the kidney, including renal cortex, medulla, and glomeruli (PubMed:24694988). Expressed in glomeruli, tubular epithelial cells, and extraglomerular vascular endothelial cells (at protein level) (PubMed:24694988).
Interacts with NPC1L1; bridges NPC1L1 with MYO5B. Interacts with MYO5B; bridges MYO5B with NPC1L1 (By similarity). Interacts with PXN; this complex stabilizes actin dynamics. Interacts with F-actin and G-actin (By similarity).
Phosphorylation of the C-terminal region by MAPK1/MAPK3 reduces its association with F-actin and contributes to actin filament reorganization and enhanced cell motility.
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 endothelial cells of the lung at 12 dpc.
Expressed in lung (alveolar endothelial and bronchial epithelial cells), kidney (endothelium of peritubular capillaries), spleen, liver, adrenal (endothelial cells of the zona reticularis of the cortex and chromaffin cells in the medulla), pancreas (islets of Langerhans), testis (germ cells, interstitial cells in neonatal testis and spermatids), ovary (stromal endothelial, thecal layer of developing follicles, luteal cells within the corpus luteum), intestine (endothelium of capillaries of the intestinal villi) and pituitary (pituicyte cells in the neural lobe) (at protein level). Expressed in lung, kidney, spleen, liver, adrenal, testis, heart, muscle, pituitary, thyroid and ovary.
Belongs to the DHHC palmitoyltransferase family.
Golgi-localized palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates. 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 (By similarity). Palmitoylates ITGA6 and ITGB4, thereby regulating the alpha-6/beta-4 integrin localization, expression and function in cell adhesion to laminin (By similarity). Plays a role in the TRAIL-activated apoptotic signaling pathway most probably through the palmitoylation and localization to the plasma membrane of TNFRSF10A (By similarity). 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 (By similarity). Also constitutively palmitoylates DLG4 (PubMed:19596852). 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.
Monomer. Homooligomers. The monomeric form has a higher catalytic activity. Forms heterooligomers with ZDHHC7 (By similarity). Interacts with TNFRSF10A (By similarity).
Phosphorylation by FGFR1 and SRC probably regulates the palmitoyltransferase activity.
The DHHC domain is required for palmitoyltransferase activity.
Expressed in several tissues with the highest expression levels in heart, muscle, kidney and adrenal gland.
Important for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability. Possesses a dithiol-reducing activity.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.
Belongs to the short-chain dehydrogenases/reductases (SDR) family.
Belongs to the nuclear hormone receptor family. NR1 subfamily.
Forms a heterodimer with RXR. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner. Interacts (when sumoylated) with GPS2; interaction with GPS2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (By similarity). 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 (By similarity).
Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity (By similarity). 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. 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 (By similarity).
Sumoylated by SUMO2 at Lys-395 and Lys-433 during the hepatic acute phase response, leading to promote interaction with GPS2 and prevent N-Cor corepressor complex dissociation.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.1/KCNH2 sub-subfamily.
Highly expressed in brain and testis, slightly less so in heart, adrenal, retina and thymus. Detected at lower levels in lung, soleus, tibialis, and at very low levels in cornea and lens. A shorter transcript is detected in skeletal muscle. Found in pituitary.
Phosphorylated on serine and threonine residues.
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) (By similarity).
The potassium channel is probably composed of a homo- or heterotetrameric complex of pore-forming alpha subunits that can associate with modulating beta subunits (By similarity). Interacts with DNAJB12 and DNAJB14; chaperones DNAJB12 and DNAJB14 promote tetramerization (By similarity). Heteromultimer with KCNH6/ERG2 and KCNH7/ERG3 (PubMed:11212207). Interacts with ALG10B (PubMed:14525949). Heteromultimer with KCNE1 and KCNE2 (By similarity). Interacts with CANX (By similarity). The core-glycosylated, but not the fully glycosylated form interacts with RNF207 (By similarity). Interacts with NDFIP1 and NDFIP2 (By similarity).
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 G-protein coupled receptor 3 family. GABA-B receptor subfamily.
Widely expressed throughout the brain and is particularly dense in the olfactory tubercles, islands of Calleja, nucleus accumbens, piriform cortex and all fields of the hippocampus.
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.
Belongs to the protein-tyrosine phosphatase family. Receptor class 3 subfamily.
Receptor for neuropeptide Y and peptide YY.
Belongs to the fibrillar collagen family.
Contains 3-hydroxyproline at a few sites. This modification occurs on the first proline residue in the sequence motif Gly-Pro-Hyp, where Hyp is 4-hydroxyproline.
Contains mostly 4-hydroxyproline. Proline residues at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains.
Forms the fibrils of tendon, ligaments and bones. In bones the fibrils are mineralized with calcium hydroxyapatite.
Lysine residues at the third position of the tripeptide repeating unit (G-X-Y) are 5-hydroxylated in some or all of the chains.
O-glycosylated on hydroxylated lysine residues. The O-linked glycan consists of a Glc-Gal disaccharide.
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. Interacts with MRC2 (PubMed:15817460). Interacts with TRAM2. Interacts with MFAP4 in a Ca (2+)-dependent manner.
Type I collagen is a member of group I collagen (fibrillar forming collagen).
Belongs to the alpha-carbonic anhydrase family.
Allosterically regulated (By similarity); 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, and the hexamer is fully active for both enzyme activities. Up-regulated after PKC-dependent phosphorylation.
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. Required for normal sialylation in hematopoietic cells. Sialylation is implicated in cell adhesion, signal transduction, tumorigenicity and metastatic behavior of malignant cells. Plays an essential role in early development (By similarity).
Widely expressed. Highest expression is observed in liver.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Unc-104 subfamily.
Involved in the translocation of lysosomes from perinuclear regions to the cell periphery.
Isoform 1 is expressed in the brain with lower expression in testis and liver (at protein level). Isoform 1 is strongly expressed in the brain and ovary, with lower expression in lung, kidney, uterus, testis and liver. Isoform 2 is expressed in non-neuronal cells.
Mediates the transport of synaptic vesicles in neuronal cells.
Monomer (By similarity). Interacts with KIFBP (By similarity). Interacts (via C-terminus end of the kinesin-motor domain) with CHP1; the interaction occurs in a calcium-dependent manner (PubMed:12204119). Interacts with MADD (via death domain) (By similarity).
Motor for anterograde transport of mitochondria. Has a microtubule plus end-directed motility (By similarity).
Belongs to the G-alpha family. G(i/o/t/z) subfamily.
Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding (PubMed:19703466, PubMed:24596087, PubMed:25037222). The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal (PubMed:21158412). Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:21158412). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:19703466). 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:16870394). Required for cortical dynein-dynactin complex recruitment during metaphase (By similarity).
Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site (PubMed:8521505, PubMed:24596087, PubMed:25037222). Part of a spindle orientation complex at least composed of GNAI1, GPSM2 and NUMA1 (By similarity). Identified in complex with the beta subunit GNB1 and the gamma subunit GNG1 (PubMed:24596087). Identified in complex with the beta subunit GNB1 and the gamma subunit GNG2 (PubMed:8521505). GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Interacts (GDP-bound form) with GPSM1; this inhibits guanine nucleotide exchange and GTP binding (PubMed:11121039). Interacts (GDP-bound form) with GPSM2 (via GoLoco domains); this inhibits guanine nucleotide exchange (By similarity). Interacts with RGS10; this strongly enhances GTP hydrolysis. Interacts with RGS1 and RGS16 (By similarity). Interacts with RGS4 (PubMed:9108480). Interacts with RGS12 (PubMed:11387333). Interacts (via active GTP- or inactive GDP-bound forms) with RGS14 (via RGS and GoLoco domains) (PubMed:11387333, PubMed:16870394, PubMed:17635935, PubMed:21158412). Interacts with RGS3, RGS6, RGS7, RGS8, RGS17, RGS18 and RGS20 (in vitro) (By similarity). Interacts (GDP-bound form) with RIC8A (via C-terminus) (PubMed:21158412). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif); the interaction leads to activation of GNAI1 (PubMed:21653697). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI1 (By similarity). 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.
Belongs to the myelin P0 protein family.
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.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.
Forms an activin receptor complex with activin type II receptors such as ACVR1B. Interacts with VPS39. Interacts with DYNLT1. Interacts with BMP3. Interacts with BMP2.
Phosphorylated. Constitutive phosphorylation is in part catalyzed by its own kinase activity (By similarity).
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 (By similarity).
Homodimer, and heterodimer of GMEB1 and GMEB2. Interacts with the glucocorticoid receptor (NR3C1) and NCOA2/TIF2. May interact with HSP27 and CREB-binding protein (CBP). Interacts with TRIM63 (By similarity).
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 (By similarity).
Belongs to the bZIP family. Jun subfamily.
Heterodimer with either BATF3 or ATF7 (PubMed:9154808). Heterodimer with FOS (By similarity). Heterodimer with FOSB (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 (By similarity). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity. Interacts with MYBBP1A, SP1, SPIB and TCF20. Interacts with COPS5; indirectly leading to its phosphorylation. Interacts with DSIPI; this interaction inhibits the binding of active AP1 to its target DNA. Interacts with HIVEP3. Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site. The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta. 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 (By similarity). Component of an AP-1 transcription factor complex (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). Binds to HIPK3 (By similarity). Interacts with methylated RNF187 (PubMed:20852630). Interacts (when phosphorylated) with FBXW7 (By similarity). Interacts with PRR7 (PubMed:27458189). Found in a complex with PRR7 and FBXW7 (By similarity). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (By similarity). Interacts with RBM39 (By similarity). Interacts with PAGE4 (By similarity).
Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-246; this primes the protein for subsequent phosphorylation by GSK3B at Thr-242. Phosphorylated at Thr-242, Ser-246 and Ser-252 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity (By similarity).
Transcription factor that recognizes and binds to the AP-1 consensus motif 5'-TGA[GC]TCA-3' (By similarity). 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 (By similarity). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. Involved in activated KRAS-mediated transcriptional activation of USP28. Binds to the USP28 promoter (By similarity).
Ubiquitinated (PubMed:27458189). Ubiquitination by the SCF(FBXW7) is leading to its degradation (By similarity). Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7 (By similarity).
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.
Belongs to the CDP-alcohol phosphatidyltransferase class-I family.
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).
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. Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV), filoviridae: ebola virus (EBOV), arenaviridae: lassa virus (LASV), and rhabdoviridae: vesicular stomatitis virus (VSV). Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration. 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 (By similarity). Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells.
Parallel homodimer; disulfide-linked. May form homotetramers under reducing conditions. Dimerization is essential for its antiviral activity. Interacts with MMP14 (via C-terminal cytoplasmic tail) (By similarity). Interacts with LILRA4/ILT7 (By similarity). Interacts (via cytoplasmic domain) with ARHGAP44.
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.
Ubiquitously expressed, with highest levels in brain and liver. Present in liver (at protein level).
Belongs to the DEAD box helicase family. DEAH subfamily.
Identified in a complex with TFAM and SSBP1 (By similarity). Interacts (via N-terminus) with ZC3HAV1 (via N-terminal domain) in an RNA-independent manner. Found in a complex with GRSF1, DDX28, FASTKD2 and FASTKD5 (By similarity).
RNA-dependent helicase (By similarity). Plays an important role in the assembly of the mitochondrial large ribosomal subunit (By similarity). Associates with mitochondrial DNA (By similarity). Required for optimal function of the zinc-finger antiviral protein ZC3HAV1 (PubMed:21204022). Involved in nervous system development and differentiation through its involvement in the up-regulation of a number of genes which are required for neurogenesis, including GSC, NCAM1, neurogenin, and NEUROD (By similarity).
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 BMI1, or PCGF5, or PCGF6. Distinct PRC1-like complexes are composed of a RING1 subunit (RING1B or RING1A), one of the six PCGF proteins (PCGF1, PCGF2, PCGF3, BMI1, PCGF5 or PCGF6), one PHC protein (PHC1, PHC2 or PHC3) and one of the CBX proteins (CBX2, CBX4, CBX6, CBX7 or CBX8) (By similarity). 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. The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (By similarity). Part of a complex that contains PCGF5, RNF2 and UBE2D3. Part of a complex that contains AUTS2, PCGF5, RNF2, CSNK2B and RYBP (By similarity). Interacts with CBX6 and CBX8 (By similarity). Interacts with PHC1, PCGF2, RYBP, CBX7, CBX4, CBX2, RNF1/RING1, BMI1 and PHC2. 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 (By similarity). 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 (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 RYBP, HIP2 and TFCP2 (By similarity). Interacts with NUPR1 (By similarity).
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. 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. 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. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4. 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. Plays a role in the transcriptional repression of genes that are required for pluripotency in embryonic stem cells, thereby contributing to differentiation of the ectodermal and endodermal germ layers. 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. Also acts as a negative regulator of autophagy by mediating ubiquitination of AMBRA1, leading to its subsequent degradation.
Monoubiquitinated, by auto-ubiquitination (By similarity). Polyubiquitinated in the presence of UBE2D3 (in vitro) (By similarity).
Detected in heart, brain, lung, liver, skeletal muscle, kidney and testis.
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.
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).
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type II family.
Belongs to the glycosyltransferase 7 family.
Catalyzes the synthesis of lactosylceramide (LacCer) via the transfer of galactose from UDP-galactose to glucosylceramide (GlcCer) (PubMed:9593693). 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).
Highest expression in brain with lower levels found in lungs, heart, skeletal muscle and kidney. Lowest expression in testis, liver and spleen.
According to PubMed:11278534, 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.
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 activity toward Muc5Ac and EA2 peptide substrates.
Highly expressed in the sublingual gland, testis, small intestine, colon and ovary. Expressed at intermediate level in heart, brain, spleen, lung, stomach, cervix and uterus.
The ricin B-type lectin domain binds to GalNAc and contributes to the glycopeptide specificity.
There are two conserved domains in the glycosyltransferase region: the N-terminal domain (domain A, also called GT1 motif), which is probably involved in manganese coordination and substrate binding and the C-terminal domain (domain B, also called Gal/GalNAc-T motif), which is probably involved in catalytic reaction and UDP-Gal binding.
Was originally termed Galnt9/pp-GaNTase 9.
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 (By similarity).
Belongs to the gamma-glutamyltransferase family.
Cleaved by autocatalysis into a large and a small subunit.
Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione-S-conjugate. Converts leukotriene C4 (LTC4), a glutathione-S-conjugate, to leukotriene D4 (LTD4). Does not cleave gamma-glutamyl compounds such as gamma-glutamyl leucine. 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. Acts as a negative regulator of geranylgeranyl glutathione bioactivity by cleaving off its gamma-glutamyl group, playing a role in adaptive immune responses.
Heterodimer composed of the light and heavy chains. The active site is located in the light chain.
Widely expressed, but at low level, except in the airway epithelial cells. Detected in brain, heart, kidney, liver, lung, spleen, testis and trachea.
Belongs to the TRAPP small subunits family. BET3 subfamily.
A functional Walker motif (consensus sequence G-X-X-G-X-G-K-[ST]-T) is expected to bind ATP. The essential Lys in this region is not conserved in ABCG8 (G-S-S-G-C-R-A-S) and is not required for transport activity mediated by the heterodimer with ABCG5.
ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane. Plays an essential role in the selective transport of the dietary cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile. Required for normal sterol homeostasis. The heterodimer with ABCG5 has ATPase activity.
Belongs to the ABC transporter superfamily. ABCG family. Eye pigment precursor importer (TC 3.A.1.204) subfamily.
Highest expression in liver, with lower levels in small intestine and colon.
N-glycosylated. N-glycosylation is important for efficient export out of the endoplasmic reticulum.
Seems to have a defective ATP-binding region.
Binds two Mg(2+) per subunit. Required for catalysis and for stabilizing the dimer.
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. In brain, levels of ENO1 decrease around 10 dpc and then gradually increase to adult age. In embryonic heart, ENO1 levels decrease rapidly during cardiac development.
Expressed in flagella of epididymal sperm. 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.
Glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate. In addition to glycolysis, involved in various processes such as growth control, hypoxia tolerance and allergic responses. 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. Stimulates immunoglobulin production.
Lysine 2-hydroxyisobutyrylation (Khib) by p300/EP300 activates the phosphopyruvate hydratase activity.
Mammalian enolase is composed of 3 isozyme subunits, alpha, beta and gamma, which can form homodimers or heterodimers which are cell-type and development-specific (By similarity). ENO1 interacts with PLG in the neuronal plasma membrane and promotes its activation. The C-terminal lysine is required for this binding (PubMed:7964722). Interacts with ENO4 and PGAM2 (By similarity). Interacts with CMTM6 (By similarity).
Required for proper progression of late cytokinetic stages.
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 (By similarity). May promote CASP3 activation and TNF-stimulated apoptosis (PubMed:20193664).
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.
Component of the IFT complex A (IFT-A) complex. 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. Interacts directy with IFT122, ITF43 and TTC21B. Interacts with IFT43.
Expressed at high levels in testis and at lower levels in the brain (at protein level). Also present in other tissues, including heart, uterus, spinal cord, ovary, liver, kidney, lung, pancreas and stomach.
Phosphorylated and activated in vitro upon phosphorylation at Ser-74 by CSNK1D/CK1.
Phosphorylates the deoxyribonucleosides deoxycytidine, deoxyguanosine and deoxyadenosine.
Belongs to the immunoglobulin superfamily. Contactin family.
Contactins mediate cell surface interactions during nervous system development. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. May be involved in motor coordination.
Expressed at low level during embryogenesis. Highly expressed after birth.
Specifically expressed in neuronal cells. In brain, it is expressed in spinal cord, cerebrum and cerebellum. At 17 dpc, it is expressed in hippocampus, cerebellum, and the brain stem. Strongly expressed after birth with a maximum level between P1 and P21, which corresponds to the time frame of oligodendrogliogenesis.
Colocalized with E-24.11 in proximal tubules of juxtamedullary nephrons.
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).
N-glycosylated; contains GlcNAc, galactose, mannose and a small amount of fucose.
Activated by micromolar concentrations of calcium and inhibited by calpastatin.
Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves CTBP1 at 'Asn-364', 'Gly-377' and 'His-399'. Cleaves and activates caspase-7 (CASP7).
Forms a heterodimer with a small (regulatory) subunit CAPNS1.
Undergoes calcium-induced successive autoproteolytic cleavages that generate a membrane-bound 78 kDa active form and an intracellular 75 kDa active form. Calpastatin reduces with high efficiency the transition from 78 kDa to 75 kDa calpain forms (By similarity).
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 (By similarity). Interacts with and is activated by SCUBE3; this interaction does not affect TGFB1-binding to TGFBR2 (By similarity). Interacts with VPS39; this interaction is independent of the receptor kinase activity and of the presence of TGF-beta (By similarity). Interacts with CLU (By similarity).
Phosphorylated on a Ser/Thr residue in the cytoplasmic domain.
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 (By similarity).
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.
Belongs to the krueppel C2H2-type zinc-finger protein family.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family.
Associates with spliceosomes. Associates with U4/U5/U6 tri-snRNP and with U2 snRNP (By similarity).
Involved in spliceosome assembly (By similarity).
The Tudor domain mediates association with dimethylarginines, which are common in snRNP proteins.
Belongs to the immunoglobulin superfamily.
Interacts with the ninth PDZ domain of MPDZ. Interacts with the first PDZ domain of PARD3. The association between PARD3 and PARD6B probably disrupts this interaction. Interacts with ITGAL (via I-domain).
Seems to play a role in epithelial tight junction formation. Appears early in primordial forms of cell junctions and recruits PARD3. The association of the PARD6-PARD3 complex may prevent the interaction of PARD3 with JAM1, thereby preventing tight junction assembly. Plays a role in regulating monocyte transmigration involved in integrity of epithelial barrier. Ligand for integrin alpha-L/beta-2 involved in memory T-cell and neutrophil transmigration.
The Ig-like V-type 2 domain is necessary and sufficient for interaction with integrin alpha-L/beta-2.
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.
Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1. Interacts with PLK1. Interacts with DEPDC5 (via DEP domain); the interaction depends on amino acid availability. Interacts with YWHAE; required for the nuclear localization of KLHL22 upon amino acid starvation.
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. 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.
GAP activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid.
GTPase-activating protein (GAP) for ADP ribosylation factor 6 (ARF6).
GTPase-activating protein for the ADP ribosylation factor family.
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.
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.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.
Belongs to the two pore domain potassium channel (TC 1.A.1.8) family.
Highly expressed in the CNS and at lower levels in the colon, kidney, liver, lung, spleen, stomach and skeletal muscle. The highest expression was found in the olfactory nuclei, piriform cortex, cerebellum, antedorsal thalmic nucleus, pontine nucleus, dorsal raphe and several nuclei in the medulla. Shows a non-homogeneous distribution in the hippocampus. Expressed at highest levels in the lateral posterior and inferior portions and at medium levels in neocortex.
pH-dependent, voltage-insensitive, background potassium channel protein.
After bulbectomy or lesion of the olfactory bulb.
Belongs to the BPI/LBP/Plunc superfamily. Plunc family.
Detected in adult nasal epithelium, heart, lung, spleen, testis and salivary gland, and in embryonic nasal epithelium, lung, salivary gland and thymus.
Lipid-binding protein which shows high specificity for the surfactant phospholipid dipalmitoylphosphatidylcholine (DPPC). Plays a role in the innate immune responses of the upper airways. 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. 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. Plays a role in the airway inflammatory response after exposure to irritants. May attract macrophages and neutrophils.
Monomer. Interacts (via N-terminus) with SCNN1B, a subunit of the heterotrimeric epithelial sodium channel (ENaC); this inhibits proteolytic activation of ENaC (By similarity).
Reported to bind to bacterial lipopolysaccharide (LPS) in vitro. However, the in vivo significance of this is uncertain since other studies indicate little or no specificity for LPS.
Belongs to the class VI-like SAM-binding methyltransferase superfamily. PEMT/PEM2 methyltransferase family.
Catalyzes the three sequential steps of the methylation pathway for the biosynthesis of phosphatidylcholine, a critical and essential component for membrane structure (Probable) (PubMed:8344945). 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 (Probable) (PubMed:8344945).
Protein disulfide isomerase (By similarity). Promotes the localization of acetylcholine receptors (AChRs) to the plasma membrane (By similarity).
Belongs to the methyltransferase superfamily. RsmH family.
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). Also a component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, KIAA1429, RBM15, BCLAF1 and THRAP3 (By similarity).
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.
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. Positively regulates 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. Negatively regulates 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. Has no effect on ubiquitination.
Interacts with UBE2I/UBC9, NFKBIA, HIF1A and NCOA2.
The RWD domain is required for the sumoylation enhancement activity.
Adhesion molecule that accomplishes cell binding by presenting carbohydrate(s) to the lectin domain of L-selectin.
Lymph nodes. Associated with the lumenal surface of the high endothelial venules of peripheral lymph nodes.
Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC24A subfamily.
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).
The C-terminal half (AA 167-370) 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 tetraspanin (TM4SF) family.
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 (By similarity).
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 (By similarity).
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). 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 (By similarity).
Cell adhesion glycoprotein. Might be involved in osteoblast differentiation. It probably has a role in cell-extracellular matrix interactions (By similarity).
Interacts with LAMA2. Interacts with COL13A1 (By similarity). Interacts with EFEMP2 (By similarity).
Belongs to the universal ribosomal protein uS17 family.
Belongs to the AAA ATPase family. MSP1 subfamily.
Interacts with GRIA2 and GRIP1 in an ATP-dependent manner (PubMed:21496646). 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 (PubMed:21496646).
Outer mitochondrial translocase required to remove mislocalized tail-anchored transmembrane proteins on mitochondria (By similarity). 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 (PubMed:21496646). Required for NMDA-stimulated AMPAR internalization and inhibition of GRIA1 and GRIA2 recycling back to the plasma membrane; these activities are ATPase-dependent (PubMed:21496646).
Belongs to the DEAD box helicase family.
Interacts with DVL3 and FLII (By similarity). 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. In the presence of LPS, competes with FLII for MYD88-binding (By similarity).
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 (By similarity).
May play a role in Cajal bodies formation.
Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.
Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.
Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.
Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.
Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.
Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (PubMed:32273471).
Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.
Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.
Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.
Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.
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. Serine ADP-ribosylation at Ser-11 (H3S10ADPr) promotes recruitment of CHD1L. H3S10ADPr is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac).
Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (By similarity). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (By similarity).
Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes. It gives a specific tag for epigenetic transcription activation. Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with TONSL; CHAF1A; CHAF1B; MCM2 and DNAJC9 (By similarity).
This histone is only present in mammals.
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 by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity). Ubiquitinated in testes.
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.
Heterooligomer of a large alpha subunit and 2-3 smaller beta subunits. Heterooligomer with SCN2B or SCN4B; disulfide-linked. Interacts with NEDD4L (By similarity). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider beta/delta-theraphotoxin-Pre1a (PubMed:25784299, PubMed:28428547). Interacts with the spider RTX-VII toxin (AC P0DL75) (PubMed:25784299).
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 (By similarity). 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-1452 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.
G proteins are composed of 3 units; alpha, beta and gamma.
Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
Expressed in the neuronal fibers of the medial part of lateral habenula nucleus, thalamus, hypothalamus, stria terminalis, zona incerta, amygdaloid body and cingulum, olfactory bulb, hippocampus, cerebral cortex and cerebellum. In the cerebellum there is a predominant expression pattern in the granule layer of lobules VI-IX of the posterior lobe.
C-terminal Ser or Thr residues may be phosphorylated.
Interacts with MAS1 (By similarity). Interacts with ARRB1 (By similarity). Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA (By similarity).
Is expressed in the liver, kidney, aorta, lung, uterus, ovary, spleen, heart, and vascular smooth muscle cell. Expressed most abundantly in the adrenal gland.
Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney. The activated receptor in turn couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C.
Belongs to the THEM4/THEM5 thioesterase family.
Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays a role in mitochondrial fatty acid metabolism (By similarity). Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity (By similarity).
Homodimer and homotetramer (By similarity). Interacts with AKT1 in the cytosol (By similarity).
Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins.
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 (By similarity).
Belongs to the protein-tyrosine phosphatase family. Receptor class 1/6 subfamily.
Interacts with SKAP1. Interacts with DPP4; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes. Binds GANAB and PRKCSH (By similarity).
Isoform 1 and isoform 2 are found in thymocyte and lymph node. Isoform 4 and isoform 3 are found in the lymph nod.
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 (By similarity). Dephosphorylates LYN, and thereby modulates LYN activity (By similarity).
The cytoplasmic domain contains potential phosphorylation sites.
The first PTPase domain interacts with SKAP1.
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.
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. Forms a ternary complex with SQSTM1 and PRKCZ.
Belongs to the group II decarboxylase family.
Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine and L-5-hydroxytryptophan to serotonin.
Belongs to the snRNP core protein family.
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. Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes. Is also a component of the minor U12 spliceosome.
Interacts with GNPTAB; this interaction is important for proper localization of GNPTAB in Golgi stacks. Interacts with MBTPS1.
Required for mannose-6-phosphate-dependent trafficking of lysosomal enzymes. 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. LYSET is thus an essential factor for maturation and delivery of lysosomal hydrolases.
Catalyzes the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets (By similarity). 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 (By similarity). Transfers fatty acid from triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3-diacylglycerol from triglycerides (By similarity). Regulates adiposome size and may be involved in the degradation of adiposomes (By similarity). 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).
Increased by rosiglitazone in subcutaneous and visceral white adipose tissue.
Interacts with ABHD5; this association stimulates PNPLA2 triglyceride hydrolase activity (By similarity). Interacts with SERPINF1; this interaction stimulates the phospholipase A2 activity of PNPLA2 (By similarity). Despite a colocalization in lipid droplets, it probably does not interact with PLIN (By similarity). Interacts with PLIN5; prevents interaction with ABHD5 (PubMed:23408028, PubMed:24303154). Interacts with FAF2 (By similarity).
Phosphorylation at Ser-398 by PKA is increased during fasting and moderate intensity exercise, and moderately increases lipolytic activity.
Ubiquitinated by PEX2 in response to reactive oxygen species (ROS), leading to its degradation.
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 (By similarity). In addition to tyrosine, is able to catalyze the hydroxylation of phenylalanine and tryptophan but with lower specificity (PubMed:11922614, PubMed:10933781). Positively regulates the regression of retinal hyaloid vessels during postnatal development (By similarity).
Homotetramer (PubMed:9228951). 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 (By similarity).
Inhibited in feedback fashion by the catecholamine neurotransmitters, especially by dopamine in competition with tetrahydrobiopterin. Phosphorylation of several Ser/Thr residues in the N-terminus regulates the catalytic activity. Ser-31 and Ser-40 are readily phosphorylated to activate the catalytic activity. A cysteine modification induced by N-ethylmaleimide (NEM), inhibits tyrosine 3-monooxygenase activity through the modification of the Cys-177.
Phosphorylated on Ser-19, Ser-31 and Ser-40 by several protein kinases with different site specificities. Phosphorylation at Ser-31 and Ser-40 leads to an increase of TH activity. Phosphorylation at Ser-40 activates the enzyme and also counteracts the feedback inhibition of TH by catecholamines (By similarity). Phosphorylation of Ser-19 and Ser-31 triggers the proteasomal degradation of TH through the ubiquitin-proteasome pathway (PubMed:21392500). Phosphorylation at Ser-31 facilitates transport of TH from the soma to the nerve terminals via the microtubule network (By similarity). 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 (By similarity). Ser-19 increases the phosphorylation at Ser-40 in a hierarchical manner, leading to increased activity (PubMed:1672315, PubMed:11502746).
Belongs to the ribonuclease III family. Mitochondrion-specific ribosomal protein mL44 subfamily.
Endoplasmic reticulum-Golgi intermediate compartment membrane
Regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. May function as sterol isomerase.
Belongs to the cyclophilin-type PPIase family.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Belongs to the G-protein coupled receptor 2 family. LN-TM7 subfamily.
Interacts (via olfactomedin-like domain) with FLRT3 (via extracellular domain); the interaction is direct (PubMed:22405201). Identified in a complex with FLRT3 and UNC5B; does not interact with UNC5B by itself. Identified in a complex with FLRT3 and UNC5D; does not interact with UNC5D by itself (By similarity). Interacts (via olfactomedin-like domain) with FLRT1 (via extracellular domain). Interacts (via olfactomedin-like domain) with FLRT2 (via extracellular domain). Interacts (via extracellular domain) with TENM1. Interacts (via extracellular domain) with TENM3 (By similarity).
O-glycosylated (major) and N-glycosylated.
Plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3 that are expressed at the surface of adjacent cells. Plays a role in the development of glutamatergic synapses in the cortex. Important in determining the connectivity rates between the principal neurons in the cortex.
Predominantly expressed in brain, followed by heart, placenta, pancreas, kidney and testis.
Proteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit.
The Olfactomedin-like domain is required for the synapse-promoting function and the interaction with FLRT3. The Olfactomedin-like and the SUEL-type lectin domains are required for the interaction with TENM1 (By similarity).
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.
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.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.
Detected in retina (at protein level) (PubMed:21504899). Retina-specific. Expressed in rod and cone photoreceptor cells.
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).
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 (By similarity). 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).
Belongs to the MICOS complex subunit Mic10 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 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 (By similarity). This complex was also known under the names MINOS or MitOS complex (By similarity). 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 (By similarity). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with IMMT/MIC60 and MICOS13/MIC13 (By similarity). Interacts with APOO/MIC23/MIC26 and APOOL/MIC27 (By similarity). Interacts with ARMC1 (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA2 subfamily.
Detected at low levels in newborns. Levels increase strongly and are highest in hippocampus from 8 to 14 day old animals. Detected at intermediate levels at day 42 (at protein level).
Detected in forebrain. Detected in dendrites of neuronal cells. Expressed in the pyramidal cell layers of CA1 and CA3 and in the granule cell layer of the dentate gyrus (PubMed:12657670).
Down-regulated in the pyramidal cell layer of CA1 in the hippocampus by global ischemia.
Fully edited in the brain. Heteromerically expressed edited GLUR2 (R) receptor complexes are impermeable to calcium, whereas the unedited (Q) forms are highly permeable to divalent ions (By similarity).
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 (By similarity). 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 NSF via its C-terminus. Interacts with CACNG2, PRKCABP and GRIP2 (PubMed:27756895). Part of a complex containing GRIA2, NSF and NAPA and/or NAPB. Interacts with PICK1 (via PDZ domain) (By similarity). Interacts with GRIA1 and SYNDIG1. 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 LRFN1. Found in a complex with GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5. 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, GRIA2 and STX12; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (PubMed:16037816). Interacts with IQSEC1; the interaction is required for ARF6 activation (PubMed:20547133).
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).
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 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. 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 (PubMed:16037816).
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.
Ubiquitinated by RNF167, leading to its degradation.
Detected in brain, heart, liver and skeletal muscle.
Heterodimer with PPIH. Interacts with PRPF4 and with the spliceosome. Part of a complex containing U4/U6 snRNPs (By similarity). Also detected in the cytoplasm.
Participates in the second step of pre-mRNA splicing (By similarity). Down-regulates the expression of potassium channel subunits.
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.
Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.
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 (By similarity).
After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-347 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). Requires the presence of the other members of the gamma-secretase complex for protease activity. 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. 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). Under conditions of apoptosis or calcium influx, cleaves CDH1. 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 (By similarity). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (By similarity). 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. Involved in the regulation of neurite outgrowth (By similarity). 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 (PubMed:30429473).
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 or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity. Other components which are associated with the complex include SLC25A64, SLC5A7 and PHB. As part of the gamma-secretase complex, interacts with CRB2 (via transmembrane domain) (By similarity). Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment. Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Associates with NOTCH1. Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2. Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation. Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane. Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL. Interacts through its N-terminus with GFAP (isoform 2) (By similarity). Interacts with DOCK3 (By similarity). Interacts with UBQLN1 (By similarity).
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 play a role in cell differentiation in the intestinal epithelium.
Interacts with ZMYND10 (By similarity). Interacts with STUB1 (By similarity). Interacts with ESR1 and ESR2. Interacts with DNAAF2 (By similarity). Interacts with CCT3, CCT4, CCT5 and CCT8 (By similarity). Interacts with DNAAF6/PIH1D3 (By similarity).
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. Axonemal dynein assembly factor required for ciliary motility (By similarity).
Pore-forming subunit of a voltage-gated ion channel.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-Tu/EF-1A subfamily.
Heterotetramer of two type I and two type II keratins. Heterodimer with KRT1 (By similarity). Two heterodimers of KRT1 and KRT10 form a heterotetramer (By similarity). The KRT10 subunit in the heterotetramer is probably disulfide-linked (By similarity).
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).
There are two types of cytoskeletal and microfibrillar keratin: I (acidic; 40-55 kDa) and II (neutral to basic; 56-70 kDa).
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 NDUFA1 subunit family.
Complex I is composed of 45 different subunits.
Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.
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.
Predominantly in small intestine, colon, and stomach, with much lower levels in skeletal muscle, kidney, brain, testis, uterus, heart and lung.
PubMed:8595899 sequence was originally thought to originate from human.
The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.
ATP-binding induces a conformation change.
Activated by ATP, other nucleotide triphosphates and small peptides (PubMed:14527953, PubMed:21731629, PubMed:22049080). Inhibited by bacitracin (PubMed:12941771).
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:1836994, PubMed:1445854, PubMed:10684867, PubMed:12941771, PubMed:14527953, PubMed:22049080). Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin (By similarity). 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:10684867). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP (By similarity). Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients (By similarity). 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.
Belongs to the universal ribosomal protein uS10 family.
Component of the 40S small ribosomal subunit.
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.
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.
SAP is a precursor of amyloid component P which is found in basement membrane and associated with amyloid deposits.
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. Upon phosphorylation of ITIM motif KLRG1 associates with the two phosphatases, PTPN11 and INPP5D.
Forms a monomer and homodimer; disulfide-linked. Interacts (via ITIM motif) with PTPN11 and INPP5D (By similarity).
Phosphorylated in response to monoclonal antibody G63 binding and antigenic stimulation.
Plays an inhibitory role on natural killer (NK) cells and T-cell functions upon binding to their non-MHC ligands. May mediate missing self recognition by binding to a highly conserved site on classical cadherins, enabling it to monitor expression of E-cadherin/CDH1, N-cadherin/CDH2 and R-cadherin/CDH4 on target cells (By similarity).
Belongs to the major facilitator (TC 2.A.1) superfamily. Organic cation transporter (TC 2.A.1.19) family.
Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions (PubMed:21074513). Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid (PubMed:21074513). Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-) (PubMed:21074513). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate (By similarity). 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. Orotate transport is Cl(-)-dependent (By similarity).
Expressed in the proximal tubular epithelial cells in kidney.
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). 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. Also functions as deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3 and TSHZ3. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (By similarity). 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. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (By similarity).
Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core complex associates with MTA2, MBD2, 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. 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. Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2. Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3. Component of a RCOR/GFI/KDM1A/HDAC complex. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2. The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. Associates with the 9-1-1 complex; interacts with HUS1. Found in a complex with DNMT3A and HDAC7. Interacts with the non-histone region of MACROH2A1. Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation. Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity. Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity. In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter. Interacts with TSHZ3 (via N-terminus); the interaction is direct. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21. Interacts with CDKN1A/p21. Interacts with CDK5 complexed to CDK5R1 (p25). Interacts directly with GFI1 and GFI1B. Interacts with NR1D2 (via C-terminus). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity. Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, DNMT1, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541. Interacts with KDM5A; this interaction impairs histone deacetylation (By similarity). Interacts with DNTTIP1. 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. Interacts with CCAR2. Interacts with PPHLN1. Found in a complex with YY1, SIN3A and GON4L. Interacts with CHD4. Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SIN3A. Interacts with DHX36; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with ZBTB7A (By similarity). Interacts with SMAD4; positively regulated by ZBTB7A (By similarity). Interacts with PACS2 (By similarity). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (By similarity). Interacts with ZNF638 (By similarity). Interacts with SPHK2 (By similarity). Interacts with ERCC6 (By similarity). Interacts with NSD2 (By similarity). Interacts with SMYD4 (via MYND-type zinc finger) (By similarity). Interacts with PWWP2A in a MTA1-dependent manner (By similarity). Interacts with PWWP2B (By similarity). Interacts with ZNF516 and BRCC3; these interactions are enhanced in the presence of PWWP2B (By similarity). Interacts with SANBR (via the BTB domain) (By similarity). Interacts with ZNHIT1 (By similarity).
Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.
Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.
Ubiquitinated by CHFR and KCTD11, leading to its degradation by the proteasome.
In the C-terminal section; belongs to the sulfate adenylyltransferase family.
In the N-terminal section; belongs to the APS kinase family.
Belongs to the protein kinase superfamily. Tyr protein kinase family. ROR subfamily.
Cytoskeletal protein that may act as an adapter that brings other proteins (like kinases) to the cytoskeleton (By similarity). 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 (PubMed:22659164).
Expressed most abundantly in heart, lung and liver, moderately in spleen and skeletal muscle, and at extremely low levels (if at all) in testis and brain tissues.
Interacts with ACTN1 (PubMed:22659164). Interacts with ACTN2 and ACTN4 (By similarity). Interacts with PDLIM4 (PubMed:22659164).
Expressed in olfactory bulb, cerebellum and neuronal layers in hippocampus.
Inhibits neuronal cell proliferation by negative regulation of the cell cycle transition. Promotes pituitary gonadotrope cell proliferation, migration and invasion, when overexpressed. May play a role in cell pituitary tumor development (By similarity).
Belongs to the SLC13A/DASS transporter (TC 2.A.47) family. NADC subfamily.
Expressed in large and small intestine and in the kidney proximal tubules.
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:9691021, PubMed:9694847). Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic (PubMed:9691021, PubMed:9694847). Citrate is transported in protonated form as a divalent anion, rather than the trivalent form which is normally found in blood (PubMed:9694847). Has a critical role in renal dicarboxylate transport (By similarity).
Higher expression in neonates than in adult.
Receptor for apelin receptor early endogenous ligand (APELA) and apelin (APLN) hormones coupled to G proteins that inhibit adenylate cyclase activity (PubMed:11359874). Plays a key role in early development such as gastrulation, blood vessels formation and heart morphogenesis by acting as a receptor for APELA hormone. May promote angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis. Promotes sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel development. Also plays a role in various processes in adults such as regulation of blood vessel formation, blood pressure, heart contractility and heart failure (By similarity).
Widely expressed. Highest expression in the lung, lower in the heart, placenta, ovary, skeletal muscle, mammary gland, kidney and several structures in the brain as the hypothalamus (supraoptic and periventricular nuclei), pituitary, olfactory bulb and pineal gland.
Catalyzes the synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs.
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 (PubMed:27133463). The L-glutamate transport activity is allosterically activated by lumenal H(+) and Cl(-) (PubMed:27133463, PubMed:32439795). The allosteric requirement for H(+) efficiently prevents non-vesicular efflux across the plasma membrane (PubMed:27133463). The L-glutamate uniporter activity exhibits a biphasic dependence on chloride concentration (PubMed:11502256, PubMed:17046815).
Expressed in brain (at protein level). Expressed in brainstem, deep nuclei, septal nuclei, nuclei of the diagonal band, frontal cortex, hypothalamus, midbrain, parietal cortex and temporal cortex. Also expressed in pineal gland and islets of Langerhans.
Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, proton, potassium, sodium and phosphate (PubMed:18080752, PubMed:11551935, PubMed:11698619, PubMed:11502256, PubMed:29642010, PubMed:17046815, PubMed:32439795, PubMed:27133463, PubMed:25433636). 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:18080752, PubMed:11698619, PubMed:11551935, PubMed:11502256, PubMed:29642010, PubMed:17046815, PubMed:32439795, PubMed:27133463). 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:11551935, PubMed:11698619, PubMed:11502256, PubMed:17046815, PubMed:32439795, PubMed:29642010). In addition, functions as a chloride channel that allows a chloride permeation through the synaptic vesicle membrane therefore affects the proton electrochemical gradient and promotes synaptic vesicles acidification (PubMed:27133463). Moreover, functions as a vesicular K(+)/H(+) antiport allowing to maintain the electrical gradient and to decrease chemical gradient and therefore sustain vesicular L-glutamate uptake (PubMed:25433636). The vesicular H(+)/H(+) antiport activity is electroneutral (PubMed:25433636). 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:17046815, PubMed:29642010). The symporter activity is driven by an inside negative membrane potential and is electrogenic (PubMed:29642010, PubMed:17046815). Also involved in the regulation of retinal hyaloid vessel regression during postnatal development (By similarity). May also play a role in the endocrine L-glutamatergic system of other tissues such as pineal gland and pancreas (PubMed:11551935).
Belongs to the peptidase S1 family. Kallikrein subfamily.
High levels in pancreas, submaxillary and parotid glands, spleen, and kidney.
Belongs to the IL-1 family. Highly divergent.
Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines. Also involved in activation of mast cells, basophils, eosinophils and natural killer cells. Acts as a chemoattractant for Th2 cells, and may function as an 'alarmin', that amplifies immune responses during tissue injury (By similarity).
Forms a 1:1:1 heterotrimeric complex with its primary high-affinity receptor IL1RL1 and the coreceptor IL1RAP. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.
In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets. This form is rapidely lost upon angiogenic or pro-inflammatory activation (By similarity).
The full-length protein can be released from cells and is able to signal via the IL1RL1/ST2 receptor. However, proteolytic processing by CSTG/cathepsin G and ELANE/neutrophil elastase produces C-terminal peptides that are more active than the unprocessed full-length protein. May also be proteolytically processed by calpains. Proteolytic cleavage mediated by apoptotic caspases including CASP3 and CASP7 results in IL33 inactivation. In vitro proteolytic cleavage by CASP1 was reported but could not be confirmed in vivo suggesting that IL33 is probably not a direct substrate for that caspase (By similarity).
The homeodomain-like HTH domain mediates nuclear localization and heterochromatin association.
Belongs to the aldolase class II family. Adducin subfamily.
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. Interacts with APAF1. May interact with CASP1.
Adopts an atypical protein kinase-like fold: while it adopts a core fold similar to that of well-characterized protein kinase-like domains. The KxGQ motif completely occludes the typical substrate binding pocket. Nucleotide-binding opens the substrate binding pocket and flips the active site from inside the hydrophobic core into a catalytically competent, solvent-exposed posture.
Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration. Its substrate specificity is unclear: does not show any protein kinase activity. Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway. Required for podocyte migration.
Belongs to the protein kinase superfamily. ADCK protein kinase family.
Homodimer; homodimerizes via its transmembrane region. Interacts with COQ6 and COQ7. Interacts with the multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9.
In the kidney, expressed in glomeruli, predominantly in podocyte foot precesses, as well as in proximal tubules and collecting ducts (at protein level).
Interacts with RAC1 (GTP-bound form preferentially).
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. AIG1/Toc34/Toc159-like paraseptin GTPase family. IAN subfamily.
Exerts an anti-apoptotic effect in the immune system and is involved in responses to infections.
Spleen, thymus and T-cells. Greatly reduced in T-cells from lymphopenic rats.
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:6477520, PubMed:12513690, PubMed:24187134). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (PubMed:6477520). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues (By similarity). 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 (By similarity). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:6477520, PubMed:12513690).
Expression is restricted to the liver and pancreatic islets (at protein level).
Monomer (By similarity). 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, PubMed:16542652).
Subject to allosteric regulation (By similarity). Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus (PubMed:10456334).
Belongs to the adenylate kinase family. AK3 subfamily.
Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon GTP/ATP binding. Assembling and dissambling the active center during each catalytic cycle provides an effective means to prevent GTP/ATP hydrolysis.
Expressed in the central nervous system in a region-specific manner from the middle stage of embryogenesis to the adulthood in the rodent.
Expressed in the pyramidal cells in the hippocampus.
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates (By similarity). Efficiently phosphorylates AMP and dAMP using ATP as phosphate donor, but phosphorylates only AMP when using GTP as phosphate donor (By similarity). Also displays broad nucleoside diphosphate kinase activity (By similarity). Plays a role in controlling cellular ATP levels by regulating phosphorylation and activation of the energy sensor protein kinase AMPK (By similarity). Plays a protective role in the cellular response to oxidative stress (By similarity).
Monomer (By similarity). Interacts with SLC25A5/ANT2 (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. NNMT/PNMT/TEMT family.
Catalyzes the transmethylation of nonepinephrine (noradrenaline) to form epinephrine (adrenaline), using S-adenosyl-L-methionine as the methyl donor (By similarity). Other substrates include phenylethanolamine, octopamine and normetanephrine (PubMed:13863458, PubMed:683413).
Expressed in the adrenal medulla and brain.
Inhibited by 3-methyl-l,2,3,4-tetrahydro[1]benzothieno[3,2-c]pyridine hydrochloride.
Belongs to the integrin beta chain family.
Belongs to the eukaryotic ribosomal protein eL8 family.
Identified in the spliceosome B 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, WDR57, SNRNP40, DDX23, CD2BP2, PPIH, NHP2L1, EFTUD2, SART1 and USP39. Interacts with RAD17 and PRPF31. The complex formed by SNU13 and PRPF31 binds U4 snRNA. The complex formed by SNU13 and PRPF31 binds also U4atac snRNA, a characteristic component of specific, less abundant spliceosomal complexes.
Involved in pre-mRNA splicing as component of the spliceosome. Binds to the 5'-stem-loop of U4 snRNA and thereby contributes to spliceosome assembly. The protein undergoes a conformational change upon RNA-binding.
Belongs to the type II cytokine receptor family.
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 mannose-6-phosphate isomerase type 1 family.
Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.
May have a role in sperm development and fertilization.
Belongs to the protein-tyrosine phosphatase family. Receptor class 2A subfamily.
Interacts with GRIP1. Interacts with PPFIA1, PPFIA2 and PPFIA3. Interacts with PTPRF.
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.
Galactose (Gal) transferase involved in the synthesis of terminal N-acetyllactosamine (LacNac) unit present on glycan chains of glycoproteins and glycosphingolipids. Catalyzes the transfer of Gal residue via a beta1->4 linkage from UDP-Gal to the non-reducing terminal N-acetyl glucosamine 6-O-sulfate (6-O-sulfoGlcNAc) in the linearly growing chain of both N- and O-linked keratan sulfate proteoglycans. Cooperates with B3GNT7 N-acetyl glucosamine transferase and CHST6 and CHST1 sulfotransferases to construct and elongate mono- and disulfated disaccharide units [->3Galbeta1->4(6-sulfoGlcNAcbeta)1->] and [->3(6-sulfoGalbeta)1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer. Transfers Gal residue via a beta1->4 linkage to terminal 6-O-sulfoGlcNAc within the LacNac unit of core 2 O-glycans forming 6-sulfo-sialyl-Lewis X (sLex). May contribute to the generation of sLex epitope on mucin-type glycoproteins that serve as ligands for SELL/L-selectin, a major regulator of leukocyte migration. In the biosynthesis pathway of neolacto-series glycosphingolipids, transfers Gal residue via a beta1->4 linkage to terminal GlcNAc of a lactotriaosylceramide (Lc3Cer) acceptor to form a neolactotetraosylceramide.
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 (PubMed:9660828). 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.
During the embryonic stages, high expressed in the brain, spinal cord, sensory ganglia (dorsal root and trigeminal ganglia), and thymus. In brain found throughout the ventricular and marginal zones.
Expressed in heart, brain, spleen, lung, liver, kidney and testis. Not expressed in skeletal muscle. Expressed in fetal as heterodimer and adult brain as homodimer. In neural cells, expressed in granule cells, astroglial cells, and oligodendrocytes (PubMed:9660828).
Forms a catalytic dimer which is either homodimer (alpha2/alpha2 homodimer) or heterodimer with PAFAH1B3 (alpha2/alpha1 heterodimer) (PubMed:9660828). Component of the cytosolic (PAF-AH (I)) heterotetrameric enzyme, which is composed of PAFAH1B1 (beta), PAFAH1B2 (alpha2) and PAFAH1B3 (alpha1) subunits (PubMed:9660828). 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 (By similarity). 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) (By similarity). Now these subunits have been renamed beta (PAFAH1B1), alpha2 (PAFAH1B2) and alpha1 (PAFAH1B3) respectively (By similarity).
Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1 (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type C (BoNT/C), which hydrolyzes the 252-Lys-|-Ala-253 bond (PubMed:7737992). Cleavage inhibits neurotransmitter release (PubMed:7901002).
Cerebral cortex, hippocampus, cerebellum, and adrenal medulla.
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 (PubMed:7901002). May mediate Ca(2+)-regulation of exocytosis acrosomal reaction in sperm (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 (By similarity).
Belongs to the DHHC palmitoyltransferase family. ERF2/ZDHHC9 subfamily.
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:2831537). Preferentially oxidizes aromatic aldehyde substrates (PubMed:2831537). 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).
Belongs to the aldehyde dehydrogenase family.
This protein can be induced by a number of chemical carcinogens during rat hepatocarcinogenesis.
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.
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 (By similarity). Interacts with LIG3 (By similarity).
Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA (By similarity).
Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA.
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:10085103). 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 (PubMed:10085103). Has a marked selectivity for phospholipids with short acyl chains at the sn-2 position (PubMed:10085103).
Interacts with IFNAR1; this interaction prevents association of IFNAR1 with TYK2.
Autophosphorylation at Ser-1070 negatively regulates the phosphatidylinositol-4,5-bisphosphate 3-kinase activity.
Belongs to the PI3/PI4-kinase family. Type III PI4K subfamily.
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 (By similarity). Part of a complex with PIK3R1 and PTEN (By similarity). Binding to PTEN may antagonize the lipid kinase activity under normal growth conditions (By similarity). 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 (PI) derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and 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. 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.
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 (By similarity).
Potential calcium-dependent cell-adhesion protein. May be involved in the establishment and maintenance of specific neuronal connections in the brain.
Belongs to the metallo-dependent hydrolases superfamily. Hydantoinase/dihydropyrimidinase family.
Highly expressed in embryonic and early postnatal brain and spinal cord.
Homotetramer, and heterotetramer with other DPYS-like proteins. Interacts with DPYSL2, DPYSL3 and DPYSL4 (By similarity). Interacts with MAP2 and TUBB3 (By similarity).
Involved in the negative regulation of dendrite outgrowth.
Lacks most of the conserved residues that are essential for binding the metal cofactor and hence for dihydropyrimidinase activity. Its enzyme activity is therefore unsure.
Activated by phosphorylation on Thr-189 by STK11/LKB1.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.
Mainly present in brain. Present in presynaptic nerve terminals (at protein level).
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. May be autophosphorylated.
Protein synthesis is inhibited by the TSC1-TSC2 complex acting through TORC1 in neurons, leading to regulate neuron polarization.
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-523' and 'Ser-573'. Also regulates neuron polarization by mediating phosphorylation of WEE1 at 'Ser-642' in postmitotic neurons, leading to down-regulate WEE1 activity in polarized neurons. 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 (By similarity). In neurons, localizes to synaptic vesicles and plays a role in neurotransmitter release, possibly by phosphorylating RIMS1.
Belongs to the PDK/BCKDK protein kinase family.
Homodimer. Interacts with the pyruvate dehydrogenase complex subunit DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3) (By similarity).
Kinase that plays a key role in regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.
Ubiquitous; highest levels of expression in heart and skeletal muscle.
Up-regulated by exercise, starvation, glucocorticoids, thyroid hormone and epinephrine. Down-regulated by insulin.
Belongs to the LDH/MDH superfamily. LDH family.
Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.
Expressed in adipose tissue, lung and spleen.
At least expressed in the lung and trachea.
Belongs to the intercrine alpha (chemokine CxC) family.
By lipopolysaccharide (LPS) and inflammation; in lung.
Chemotactic for human polymorphonuclear leukocytes but does not induce chemokinesis or an oxidative burst. Contributes to neutrophil activation during inflammation.
Belongs to the dynein intermediate chain family.
Belongs to the peptidase M24A family. Methionine aminopeptidase type 1 subfamily.
Binds 2 divalent metal cations per subunit. Has a high-affinity and a low affinity metal-binding site. The true nature of the physiological cofactor is under debate. The enzyme is active with 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.
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).
Belongs to the cytochrome c oxidase subunit 6B family.
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I, COX5A, COX5B, COX6A, COX6B, COX6C, COX7A, COX7B, COX7C, COX8 and NDUFA4, which are encoded in the nuclear genome. The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)).
Component of the cytochrome c oxidase, 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.
Contaminating sequence. Sequence of unknown origin in the N-terminal part.
Down-regulated in small intestine upon fasting.
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.
Monomer and homooligomer; most probably hexameric. Interacts with GP2. According to PubMed:10753942 interaction with syntaxins shown in PubMed:9244306 is physiologically questionable.
Specifically expressed in pancreas and also detected in secretory granules of parotid gland (at protein level). Expressed in pancreas, spleen, small intestine, lung and neutrophilic granulocytes (at protein level). Expressed by epithelial cells in duodenum and colon.
Syncollin comes from the Greek word meaning to glue together.
Belongs to the SLC33A transporter family.
Expressed in brain at all developmental stages. Detected in hippocampus, hypothalamus, cerebellum, cortex, olfactory bulb, and the ventral and dorsal anterior olfactory nucleus.
Probable acetyl-CoA transporter necessary for O-acetylation of gangliosides. Negatively regulates BMP signaling (By similarity).
Acetylation is essential for its transcriptional coactivator activity.
Induced by dexamethasone and, in pancreas, by treatment with the proteinase inhibitor FOY-305 which binds to activated trypsin and induces release of cholecystokinin.
Isoform 1 abundant in testis and expressed at low levels in brain, heart, lung, liver, and kidney. Isoform 2 abundant in adrenal gland, brain, colon, heart, liver, lung, muscle, prostate, stomach, testis, and thymus and expressed at low levels in duodenum, kidney, pancreas, parotid, and spleen.
Isoform 1 is a component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD). Interacts with HDAC1 and ITGB3BP/CENPR. Binds to CSNK1G2 in the cytoplasm. Isoform 2 interacts with amylase. 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 PWWP2A and PWWP2B (By similarity).
Phosphorylation by CSNK1G2/CK1 triggered by estrogen enhances corepression of estrogen receptor (ER).
Produced by alternative splicing and alternative initiation at Met-465 of isoform 1.
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 (By similarity).
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. 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 (By similarity). Isoform 2 may be involved in the sorting of amylase during zymogen granule formation in the pancreas. 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.
Belongs to the dynactin subunits 5/6 family. Dynactin subunit 6 subfamily.
May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway.
Highly expressed in liver and kidney. Weakly expressed in other tissues.
Interacts with PEX5, probably required to target it into peroxisomes.
Participates in chain elongation of fatty acids. Catalyzes the reduction of trans-2-enoyl-CoAs of varying chain lengths from 6:1 to 16:1, having maximum activity with 10:1 CoA. Has no 2,4-dienoyl-CoA reductase activity.
Binds directly to lamin B1 and chromosomes in a mitotic phosphorylation-regulated manner. May play an important role in nuclear envelope reassembly at the end of mitosis and/or anchoring of the nuclear lamina and interphase chromosomes to the nuclear envelope.
Has two structurally independent, non-interacting domains: LEM-like (also called LAP2-N or LEM-D) and LEM (also called LAP2-C or LEM-B). LEM-like binds DNA while LEM interacts with BANF1 (By similarity).
Interacts with LMNB1, LMNB2, BANF1, AKAP8L, GMCL and chromosomes.
Mitosis-specific phosphorylation specifically abolishes its binding to lamin B and chromosomes.
Belongs to the peptidase S1 family. Granzyme subfamily.
This enzyme is necessary for target cell lysis in cell-mediated immune responses.
In vitro binds long double-stranded RNA (dsRNA) (500 and 700 base pairs), but not dsRNA shorter than 300 bp. Not involved in RNA autophagy, a process in which RNA is directly imported into lysosomes in an ATP-dependent manner, and degraded.
May function as a growth factor receptor.
RNA-binding protein that regulates alternative splicing events.
Belongs to the sphingomyelin synthase family.
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).
Belongs to the glycosyltransferase 31 family.
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. However, recent studies show that it is not directly involved in apoptosis regulation but in the protection of COX from oxidatively induced degradation.
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.
N-terminal mitochondrial targeting sequence is cleaved from the mature protein once in the mitochondrion.
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.
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 FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBXW7) complex. 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.
Interacts with ZNF304. Interacts with PRKD1. Interacts with TP53BP1. Interacts with FBXW7; following DNA damage, dissociates from FBXW7 leading to degradation of MYC.
Phosphorylated upon DNA damage at Ser-67 and Ser-720, by ATM or ATR. Phosphorylated by PRKD1.
High expression in liver and kidney. Lower expression in brain.
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.
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 (By similarity).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A6 subfamily.
Mediates sodium- and chloride-dependent transport of taurine (PubMed:1435737, PubMed:18501699, PubMed:22896705). Mediates transport of gamma-aminobutyric acid (GABA) (PubMed:18501699). Can also mediate transport of beta-alanine and hypotaurine (By similarity).
Taurine transport activity is down-regulated upon Ser-322 phosphorylation.
Taurine transport activity is inhibited by beta-alanine and gamma-aminobutyric acid (GABA) (PubMed:1435737). GABA transport activity is inhibited by taurine and beta-alanine (PubMed:18501699).
Forms a heterodimer with TMPRSS7. Interacts with VTN. Binds LRP1B; binding is followed by internalization and degradation. Interacts with PPP1CB. In complex with PLAU/uPA, interacts with PLAUR/uPAR (By similarity). Interacts with SORL1 and LRP1, either alone or in complex with PLAU; these interactions are abolished in the presence of LRPAP1/RAP (By similarity). The ternary complex composed of PLAUR-PLAU-PAI1 also interacts with SORL1 (By similarity). Also interacts with SORL1, when complexed to PLAT/tPA (By similarity).
Serine protease inhibitor. Inhibits TMPRSS7. 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. As PLAU inhibitor, it is involved in the regulation of cell adhesion and spreading. Acts as a regulator of cell migration, independently of its role as protease inhibitor. It is required for stimulation of keratinocyte migration during cutaneous injury repair. It is involved in cellular and replicative senescence (By similarity). 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 (By similarity).
Highly expressed in brain and at lower levels in other tissues.
Homodimer. Can also form heterodimers. Interacts with PRKN (By similarity). Interacts (via C2 2 domain) with AGO2 and SND1; the interaction with SND1 is direct (PubMed:24882364). Interacts with KIF1A; the interaction increases in presence of calcium (PubMed:30021165).
Synaptotagmin family member involved in vesicular and membrane trafficking which does not bind Ca(2+) (PubMed:9162066). Inhibits clathrin-mediated and bulk endocytosis in neurons, functions to ensure precision in vesicle retrieval (PubMed:29311685, PubMed:26589353). Plays an important role in dopamine transmission by regulating endocytosis and the vesicle-recycling process (PubMed:29311685). 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 (By similarity).
The second C2 domain/C2B is required for the inhibitory role in both clathrin-mediated and bulk endocytosis (PubMed:26589353, PubMed:29311685). The transmembrane domain and the first C2 domain/C2A are critical for the inhibitory role in clathrin-mediated endocytosis or bulk endocytosis, respectively (PubMed:26589353).
Ubiquitinated, at least by PRKN, and targeted to the proteasome complex for degradation (PubMed:29311685). Ubiquitination is inhibited by ATP13A2 (By similarity).
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.
Appears in pancreatic juice after induction of pancreatic inflammation. Secreted also by pituitary cells; the secretion there is stimulated by GH-releasing hormone and inhibited by somatostatin.
Bactericidal C-type lectin which acts against several intestinal Gram-positive bacteria and Gram-negative bacteria. Lacks antibacterial activity against S.typhimurium. May play a role in protection against infection with S.enteritidis by inhibiting its translocation from the gut lumen into intestinal tissues and further extraintestinal tissues (By similarity).
Overexpressed during the acute phase of pancreatitis.
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.
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids. Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long-chain fatty acids (PubMed:10620324, PubMed:3027069, PubMed:10362749). Acts as a major omega-hydroxylase for dodecanoic (lauric) acid in liver (PubMed:3027069). In kidney, may play an important role 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:10362749, PubMed:10620324, PubMed:16212878). Also participates in the formation of anti-inflammatory hydroxyepoxyeicosatrienoic acids (HEETs) in kidney by converting 8,9-epoxyeicosatrienoic acid (EET) to 20,8,9-HEET, an activator of PPARA (PubMed:14742258). Displays substantially lower fatty acid omega-1 hydroxylase activity (PubMed:10362749, PubMed:10620324). 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:10620324, PubMed:3027069, PubMed:10362749).
Expressed in liver (at protein level) and kidney (at protein level).
Detected in the brain at 12 dpc with increasing level reaching a peak within 2 weeks after birth.
Expressed in the brain in neuronal cells of the hypothalamus, thalamus, cerebral cortex, amygdala, and cerebellum.
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.
Belongs to the G-protein coupled receptor T2R family.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in 15% taste bud cells in circumvallate and foliate papillae but only in 2% in fungiform papillae.
Gustducin-coupled receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5.
Several bitter taste receptors are expressed in a single taste receptor cell.
Binds to the Fc region of immunoglobulins gamma. Low affinity receptor. By binding to IgG it initiates cellular responses against pathogens and soluble antigens.
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.
Phosphorylated by SRC-type Tyr-kinases such as LYN, BLK, FYN and SYK.
In the C-terminal section; belongs to the OMP decarboxylase family.
In the N-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.
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.
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. 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).
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.
Binds anionic lipids and gangliosides at acidic pH.
N-glycosylated; the glycan contains mannose-6-phosphate moieties.
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.
GTPase tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis (By similarity).
Interacts with ZFYVE27 (By similarity). Interacts with REEP5 (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. Interacts with PTPN23. Interacts (via UBA domains) with ubiquitinated proteins.
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). Plays a role in the proteasomal degradation of ubiquitinated cell-surface proteins, such as EGFR and BST2.
The UMA domain mediates association with the ESCRT-I complex.
Converts proline to delta-1-pyrroline-5-carboxylate.
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 with GAS2L2 (By similarity).
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 class-I pyridoxal-phosphate-dependent aminotransferase family.
Belongs to the V-ATPase C subunit family.
Lung, kidney and testis. Expressed in both bronchiolar and alveolar lung epithelial cells. Isoform 1 is predominantly expressed in the lung while isoform 2 is strongly expressed in the kidney and testis.
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 (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).
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.
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.
Heterodimer of DFFA and DFFB (By similarity). Interacts with H1-1 (By similarity).
Nuclease that induces DNA fragmentation and chromatin condensation during apoptosis. Degrades naked DNA and induces apoptotic morphology.
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.
Detected just before birth in Schwann cells and after birth in oligodendrocytes of brainstem and spinal cord.
Exclusively expressed in white and gray matter oligodendrocytes in the CNS and in myelinating Schwann cells in peripheral nerves. Higher levels are found in the PNS than in the CNS or spinal cord, in the gray matter than in the white. Weak expression also found in spleen and kidney.
By trimethyltin (TMT), a trialkyltin compound which is a potent neurotoxic agent that selectively damages specific brain regions.
High level of expression in spleen, followed by brain and kidney.
Plays a role in the toxic effects of organotins (PubMed:1635553). Plays a role in endosomal maturation (By similarity).
Interacts with CTTN/cortactin SH3 domain. Interacts with STRN, STRN4/zinedin and MOB4/phocein; this interaction may regulate dendritic spine distribution of STRN and STRN4 in hippocampal neurons. Activation of glutamate receptors weakens the interaction with STRN and STRN4.
Regulates the dendritic spine distribution of CTTN/cortactin in hippocampal neurons, and thus controls dendritic spinogenesis and dendritic spine maintenance.
Belongs to the sirtuin family. Class IV subfamily.
Interacts with UBTF and the RNA polymerase I complex. Interacts with components of the B-WICH complex, such as MYBBP1A, SMARCA5/SNF2H and BAZ1B/WSTF. Interacts with ELK4, leading to stabilization at target promoters for H3K18Ac deacetylation. Interacts with histone H2A and/or histone H2B (By similarity). Interacts with DNMT1. Interacts with SIRT1 (By similarity).
Methylation at Arg-390 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. Histone deacetylase activity is activated by DNA. Protein-lysine deacylase activity is activated by RNA. H3K18Ac histone deacetylase activity is inhibited by methylation at Arg-390. H3K18Ac histone deacetylase activity is inhibited by deubiquitination by USP7.
NAD-dependent protein-lysine deacylase that can act both as a deacetylase or deacylase (desuccinylase, depropionylase and deglutarylase), depending on the context. Specifically mediates deacetylation of histone H3 at 'Lys-18' (H3K18Ac). In contrast to other histone deacetylases, displays strong preference for a specific histone mark, H3K18Ac, directly linked to control of gene expression. 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. Moreover, H3K18 hypoacetylation has been reported as a marker of malignancy in various cancers and seems to maintain the transformed phenotype of cancer cells. Also able to mediate deacetylation of histone H3 at 'Lys-36' (H3K36Ac) in the context of nucleosomes. Also mediates deacetylation of non-histone proteins, such as ATM, CDK9, DDX21, DDB1, FBL, FKBP5/FKBP51, GABPB1, RAN, RRP9/U3-55K and POLR1E/PAF53. Enriched in nucleolus where it stimulates transcription activity of the RNA polymerase I complex. 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. In response to metabolic stress, SIRT7 is released from nucleoli leading to hyperacetylation of POLR1E/PAF53 and decreased RNA polymerase I transcription. Required to restore the transcription of ribosomal RNA (rRNA) at the exit from mitosis. 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. Mediates 'Lys-37' deacetylation of Ran, thereby regulating the nuclear export of NF-kappa-B subunit RELA/p65. 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. 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). 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. Deacetylates FBL, promoting histone-glutamine methyltransferase activity of FBL (By similarity). Acts as a regulator of mitochondrial function by catalyzing deacetylation of GABPB1 (By similarity). Regulates Akt/AKT1 activity by mediating deacetylation of FKBP5/FKBP51. 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. In addition to protein deacetylase activity, also acts as protein-lysine deacylase (By similarity). 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. 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 (By similarity). Also promotes DSB repair by promoting H3K18Ac deacetylation, regulating non-homologous end joining (NHEJ). 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. Required to stabilize ribosomal DNA (rDNA) heterochromatin and prevent cellular senescence induced by rDNA instability (By similarity). Acts as a negative regulator of SIRT1 by preventing autodeacetylation of SIRT1, restricting SIRT1 deacetylase activity (By similarity).
Ubiquitinated via 'Lys-63'-linked ubiquitin chains. Deubiquitinated by USP7, inhibiting the H3K18Ac histone deacetylase activity and regulating gluconeogenesis.
Belongs to the FARP (FMRFamide related peptide) family.
Isoform 1 is expressed at high levels in the hypothalamus and eye. Isoform 2 is specifically expressed in a region between the dorsomedial hypothalamic and ventromedial hypothalamic nuclei.
Neuropeptide RFRP-1 acts as a potent negative regulator of gonadotropin synthesis and secretion. Neuropeptides NPSF and NPVF efficiently inhibit forskolin-induced production of cAMP (By similarity). Neuropeptide NPVF blocks morphine-induced analgesia.
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.
Costa, costicartilage, femur, calvaria, trachea, aorta and brain. Predominantly in the cerebellum.
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.
At embryonic day 19, both maternal and embryonic kidneys express isoform 1 almost exclusively. In the postpartum female and neonate, expression of isoform 2 increases.
Expressed predominantly in kidney. Also detected in lung and small intestine.
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. Interacts (via cytoplasmic domain) with USH1C and MYO7B; required for proper localization of CDHR5 to microvilli tips and its function in brush border differentiation.
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 (By similarity).
Phosphorylation mediates agonist-mediated desensitization by promoting cytoplasmic retention.
Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. Has a relaxing effect on smooth muscle. May play an important role in regulating renal hemodynamics, intestinal epithelial transport, adrenal aldosterone secretion, and uterine function.
Was originally designated as the EP2 subtype.
Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.2/KCND2 sub-subfamily.
Detected in brain cortex, hippocampus, dentate gyrus, thalamus and cerebellum (PubMed:16123112). Detected in neurons from the primary visual cortex (PubMed:16207878). Detected in the supraoptic nucleus in hypothalamus, in hippocampus and the habenular nucleus of the thalamus (PubMed:9070739). Detected in the bed nucleus of the stria terminalis (PubMed:24037673). Detected in dendritic fields in the hippocampus CA1 layer, in stratum radiatum, stratum oriens, stratum lacunosum-moleculare and stratum pyramidale (PubMed:10676964, PubMed:22098631). Detected in dendritic fields in the hippocampus CA3 layer and in dentate gyrus (PubMed:10676964). Detected in the cerebellum granule cell layer, where it localizes at synapses (PubMed:11102480, PubMed:10676964, PubMed:15736227). Detected in the main olfactory bulb, especially in the granule cell layer and the external plexiform layer, but also the mitral layer (PubMed:18371079). Detected in heart atrium and ventricle (PubMed:10860776). Detected in heart left ventricle (at protein level) (PubMed:24793047). Highly expressed in heart and throughout the brain, with similar levels in cortex and hypothalamus, and much higher levels in hippocampus, dentate gyrus and the habenular nucleus of the thalamus. Detected in brain, and at lower levels in heart atrium and ventricle (PubMed:1705709). Detected in neurons from the bed nucleus of the stria terminalis (PubMed:24037673). Detected in aorta, cardiac and smooth muscle.
Down-regulated in response to hypoxia lasting about 15 min, a treatment that leads to spontaneous convulsive seizures in these pups.
Homotetramer or heterotetramer with KCND1 or KCND3 (PubMed:12754210, PubMed:15485870, PubMed:20224290, PubMed:25352783). Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4 (PubMed:10676964, PubMed:12451113, PubMed:11847232, PubMed:11805342, PubMed:15485870, PubMed:15356203, PubMed:15452711, PubMed:16820361, PubMed:20045463, PubMed:24811166, PubMed:14980206). Interacts with DPP6, DPP10, DLG4 and DLG1 (PubMed:11923279, PubMed:12575952, PubMed:14559911, PubMed:15671030, PubMed:19213956). In vivo, probably exists as heteromeric complex containing variable proportions of KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (PubMed:16123112, PubMed:19901547). The tetrameric channel can associate with up to four regulatory subunits, such as KCNIP2 or KCNIP4 (By similarity). Interaction with KCNIP3 promotes tetramerization and formation of a functional potassium channel (PubMed:15485870). Interaction with four KCNIP4 chains does not reduce interaction with DPP10 (By similarity). Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (By similarity). Interacts with FLNA and FLNC (PubMed:11102480). Interacts with NCS1/FREQ (By similarity). Identified in a complex with cAMP-dependent protein kinase (PKA), CAV3, AKAP6 and KCND3 in cardiac myocytes (PubMed:20224290).
Inhibited by 5 mM 4-aminopyridine (4-AP) (PubMed:1840649, PubMed:1722463, PubMed:9093524). Not inhibited by dendrotoxins and by tetraethylammonium (TEA) (PubMed:1722463). Inhibited by 10 mM flecainide and 20 mM quinidine (PubMed:9093524). Inhibited by the heteropodatoxins HpTx(1), HpTx(2), and HpTx(3) (PubMed:9058605).
Is specifically and reversibly inhibited by the scorpion toxin Ts8 (AC P69940).
Phosphorylation at Ser-438 in response to MAPK activation is increased in stimulated dendrites (PubMed:24404150). Interaction with KCNIP2 and DPP6 propomtes phosphorylation by PKA at Ser-552 (PubMed:19441798). Phosphorylation at Ser-552 has no effect on interaction with KCNIP3, but is required for the regulation of channel activity by KCNIP3 (PubMed:12451113). Phosphorylation at Ser-552 leads to KCND2 internalization (PubMed:17582333). 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. It is required for interaction with KCNIP2, and probably other family members as well.
The N-terminal cytoplasmic region can mediate N-type inactivation by physically blocking the channel (PubMed:15452711). This probably does not happen in vivo, where the N-terminal region mediates interaction with regulatory subunits, such as KCNIP1 and KCNIP2 (PubMed:16820361, PubMed:18357523, PubMed:14980206). The zinc binding sites in the N-terminal domain are important for tetramerization and assembly of a functional channel complex (PubMed:12754210). 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.
The transmembrane segment S4 functions as voltage-sensor and is characterized by a series of positively charged amino acids at every third position. Channel opening and closing is effected by a conformation change that affects the position and orientation of the voltage-sensor paddle formed by S3 and S4 within the membrane. A transmembrane electric field that is positive inside would push the positively charged S4 segment outwards, thereby opening the pore, while a field that is negative inside would pull the S4 segment inwards and close the pore. Changes in the position and orientation of S4 are then transmitted to the activation gate formed by the inner helix bundle via the S4-S5 linker region.
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in rodent heart (PubMed:1840649, PubMed:1722463, PubMed:9093524, PubMed:9058605, PubMed:10676964, PubMed:12592409, PubMed:12754210, PubMed:16207878, PubMed:16123112, PubMed:19279261, PubMed:25352783, PubMed:14980206). Mediates the major part of the dendritic A-type current I(SA) in brain neurons (PubMed:16207878, PubMed:17026528). 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 (PubMed:9093524, PubMed:9058605). 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:1840649, PubMed:1722463, PubMed:9093524, PubMed:10676964, PubMed:12451113, PubMed:12592409, PubMed:12754210, PubMed:15452711, PubMed:16207878, PubMed:16820361, PubMed:25352783, PubMed:14980206). 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 (PubMed:25352783). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes (PubMed:12451113, PubMed:16123112). 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:12451113, PubMed:15452711, PubMed:16123112, PubMed:16820361, PubMed:20045463, PubMed:14980206). Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (PubMed:15671030, PubMed:16123112, PubMed:19441798, PubMed:19901547, PubMed:19279261).
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.
Belongs to the inositol phosphokinase (IPK) family.
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.
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 (By similarity). Interacts with alpha-actinin. Identified in a complex composed of ACTA1, COBL, GSN AND TMSB4X (By similarity). Interacts with TTID. Interacts (via its C-terminus) with USP25 (By similarity).
May be involved in fusion of ER-derived transport vesicles with the Golgi complex.
Belongs to the ATPase delta chain family.
Expressed by the principal cells of the epididymis. Detected in flagella of epididymal sperm (at protein level).
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 ATP5MPL.
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.
Belongs to the tumor necrosis factor family.
Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. 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.
Highly expressed in thymus and bone tissues.
Homotrimer. Interacts with TNFRSF11A and TNFRSF11B. Interacts with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner. Interacts with TNFAIP6 (via both Link and CUB domains).
The soluble form derives from the membrane form by proteolytic processing.
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. 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. Interacts (via N-terminus) with the NDC80 complex. Heterodimer with CENPW; this dimer coassembles with CENPS-CENPX heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex.
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 during the cell cycle. Phosphorylated 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.
Accessory component of the DNA polymerase epsilon complex (By similarity). 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 (By similarity). Does not enhance nucleosome sliding activity of the ACF-5 ISWI chromatin remodeling complex (By similarity).
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 (By similarity). 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 (By similarity). 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 (By similarity). Within the complex, the heterodimer with CHRAC1 interacts with BAZ1A/ACF1; the interactions are direct (By similarity).
Belongs to the nucleoporin Nup133 family.
Involved in trophoblast cell proliferation and differentiation probably by affecting mitotic cell cycle progression. Proteolytic activity and nuclear localization are essential for its role in cell cycle progression (By similarity).
Acyl-CoA dehydrogenase, that exhibits maximal activity towards saturated C22-CoA. 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.
Belongs to the acyl-CoA dehydrogenase family.
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:8719777). Involved in the regulation of TNF-induced transcriptional activity of NF-kappa-B (By similarity). Required for normal osteoclastogenesis (By similarity).
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 (By similarity).
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 (By similarity).
Belongs to the calcineurin regulatory subunit family. CHP subfamily.
Calcium-binding protein involved in different processes such as regulation of vesicular trafficking, plasma membrane Na(+)/H(+) exchanger and gene transcription. Involved in the constitutive exocytic membrane traffic. Mediates the association between microtubules and membrane-bound organelles of the endoplasmic reticulum and Golgi apparatus and is also required for the targeting and fusion of transcytotic vesicles (TCV) with the plasma membrane. Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Affects the pH sensitivity of SLC9A1/NHE1 by increasing its sensitivity at acidic pH. Required for the stabilization and localization of SLC9A1/NHE1 at the plasma membrane. Inhibits serum- and GTPase-stimulated Na(+)/H(+) exchange. Plays a role as an inhibitor of ribosomal RNA transcription by repressing the nucleolar UBF1 transcriptional activity. May sequester UBF1 in the nucleoplasm and limit its translocation to the nucleolus. Associates to the ribosomal gene promoter. Acts as a negative regulator of the calcineurin/NFAT signaling pathway. Inhibits NFAT nuclear translocation and transcriptional activity by suppressing the calcium-dependent calcineurin phosphatase activity. Also negatively regulates the kinase activity of the apoptosis-induced kinase STK17B. Inhibits both STK17B auto- and substrate-phosphorylations in a calcium-dependent manner.
Endoplasmic reticulum-Golgi intermediate compartment
Expressed in liver and kidney (at protein level). Ubiquitously expressed. Expressed in the brain, lung, testes, kidney, spleen and heart.
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 (By similarity). 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.
N-myristoylation is required for its association with microtubules and interaction with GAPDH, but not for the constitutive association to membranes. Both N-myristoylation and calcium-mediated conformational changes are essential in exocytic traffic.
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 (By similarity).
Binds 3 Ca(2+) ions per subunit. The ions are bound to the C2 domains.
Brain, various endocrine tissues and hormone-secreting clonal cells.
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 (PubMed:11823420, PubMed:18508778). Plays a role in dendrite formation by melanocytes (By similarity).
Homodimer; disulfide-linked via the cysteine motif. Can also form heterodimers with SYT6, SYT9 and SYT10.
The cysteine motif mediates homo- or heterodimer formation via formation of disulfide bonds.
The first C2 domain mediates Ca(2+)-dependent phospholipid binding.
Belongs to the Mediator complex subunit 20 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 (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 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.
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 PPARG (By similarity).
Belongs to the archaeal rpoM/eukaryotic RPA12/RPB9/RPC11 RNA polymerase family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
Acts as receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex). Recognizes and mediates the translocation of mitochondrial preproteins from the cytosol into the mitochondria in a chaperone dependent manner (PubMed:11956321, PubMed:19401463). Mediates TBK1 and IRF3 activation induced by MAVS in response to Sendai virus infection and promotes host antiviral responses during virus infection (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) (By similarity). Interacts with CAPN8 (By similarity). Interacts with TRADD, TRAF6 and STING. Interacts with MAVS. Interacts with HSPA8 and HSP90AA1; both interactions are required for preprotein mitochondrial import. The interaction with HSP90AA1 is direct and mediates the association of TOMM70 with IRF3 and TBK1 (By similarity).
Affects the rate of fibrils formation. May have a primary role in collagen fibrillogenesis (By similarity).
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class II subfamily.
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.
High-molecular-weight caldesmon (h-caldesmon) is predominantly expressed in smooth muscles, whereas low-molecular-weight caldesmon (l-caldesmon) is 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.
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 negative regulator of osteoclast differentiation in basal and inflammatory conditions by regulating TNFSF11-induced Ca (2+) fluxes, thereby controlling the induction of NFATC1.
Component of the MLL-HCF complex, at least composed of KMT2A/MLL1, MEN1, ASH2L, RBBP5, DPY30, WDR5, HCFC1 and HCFC2 (By similarity). Component of the menin-associated histone methyltransferase complex, at least composed of KMT2B/MLL4, MEN1, ASH2L, RBBP5, DPY30 and WDR5 (By similarity). Interacts with POLR2B (By similarity). Interacts with POLR2A phosphorylated at 'Ser-5', but not with the unphosphorylated, nor 'Ser-2' phosphorylated POLR2A forms (By similarity). Interacts with FANCD2 and DBF4 (By similarity). Interacts with SMAD3, but not with SMAD2, nor SMAD4 (PubMed:11274402). Directly interacts with NFKB1, NFKB2 and RELA (By similarity). Interacts with JUND (via MBM motif); inhibits the interaction of JUND with MAPK10 and the phosphorylation of JUND by MAP kinases MAPK8 and MAPK10 (By similarity). Interacts with KMT2A (via MBM motif) (By similarity). The KMT2A-MEN1 complex interacts with PSIP1 with a greater affinity as MEN1 enhances interaction of KMT2A with PSIP1 (By similarity).
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. 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. May be involved in DNA repair (By similarity). Plays a role in TGFB1-mediated inhibition of cell-proliferation, possibly regulating SMAD3 transcriptional activity.
In the brain, highest expression at 16 dpc to 18 dpc. Expression decreases from 20 dpc onward.
Widely expressed, including in the pituitary, brain, large intestine, spleen, kidney, adrenal gland, ovary, testis, thymus, lung, epididymis, bone marrow, pancreatic islets and placenta.
Belongs to the universal ribosomal protein uL2 family.
Component of the large ribosomal subunit (By similarity). Interacts with CRY1 (By similarity).
Hydroxylated on His-216 by RIOX1. The modification is impaired by hypoxia.
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. Also mediates ubiquitination of SMURF2 and WWP2 (By similarity). Required for bone mass maintenance.
Belongs to the snRNP Sm proteins family. SmF/LSm6 subfamily.
Ca(2+) sensor specifically required for the Ca(2+)-dependent exocytosis of secretory vesicles containing IGF1 in neurons of the olfactory bulb. Exocytosis of IGF1 is required for sensory perception of smell. Not involved in Ca(2+)-dependent synaptic vesicle exocytosis (By similarity). Acts 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 (PubMed:18508778).
Homodimer; disulfide-linked via the cysteine motif. Can also form heterodimers with SYT3, SYT6, SYT7 and SYT9.
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 (By similarity) (PubMed:22820017, PubMed:25152401). Plays an important role in ascorbic acid biosynthesis by catalyzing the reduction of D-glucuronic acid and D-glucurono-gamma-lactone (PubMed:22820017). 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 (PubMed:8500767, PubMed:25152401). Involved also in the detoxification of lipid-derived aldehydes like acrolein (PubMed:25152401). Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs (By similarity). Displays no reductase activity towards retinoids (By similarity).
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.
Part of the tectonic-like complex (also named B9 complex).
By hypertension. Up-regulated by shear stress, lipopolysaccharide and TNF-alpha in cultured vascular endothelial cells.
Homodimer; disulfide-linked. May form a hexamer composed of 3 homodimers. Interacts with HSP70 (By similarity).
Predominantly expressed in lung and at lower level in kidney. Expressed in macrophages but not in vascular smooth muscle cells.
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 Neck region contains 3 internal repeats that are only found in rodents.
The cytoplasmic region is required for subcellular sorting on the cell surface.
May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.
Interacts with PRKCABP, and disrupts the interaction between GRIA2 and PRKCABP, leading to the internalization of GRIA2 (PubMed:11931741). Found in a complex with VAMP8 (PubMed:9614193). Component of a SNARE-like complex that contains at least ZW10, USE1L, RINT1, STX18 and NAPA/SNAP-alpha (By similarity). Interacts with VTI1A (By similarity). Interacts with STX12 (PubMed:9507000). Interacts with GNA12 (via N-terminus); the interaction promotes CDH5 localization to plasma membrane (By similarity).
Required for vesicular transport between the endoplasmic reticulum and the Golgi apparatus. Together with GNA12 promotes CDH5 localization to plasma membrane.
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 (By similarity). Interacts with DLEC1 (By similarity).
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 (By similarity).
Belongs to the glycerophosphoryl diester phosphodiesterase family.
May interact with target proteins during translocation into the lumen of the endoplasmic reticulum. May protect unfolded target proteins against degradation and facilitate correct glycosylation.
G-proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with ADGRB2 (By similarity).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.
Belongs to the mitochondrial carrier (TC 2.A.29) family.
Expressed in the liver (at protein level).
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. 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:9359400, PubMed:10417335). Lysine and arginine are also transported by the antiport mechanism (By similarity). In addition, catalyzes an electroneutral exchange of ornithine or lysine for H(+), a reaction driven by the pH gradient across the inner membrane (PubMed:10417335).
Belongs to the GST superfamily. Mu family.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.
Expressed in testis and brain. Very low expression in liver, kidney, heart and lung.
Belongs to the cation diffusion facilitator (CDF) transporter (TC 2.A.4) family. SLC30A subfamily.
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.
Expressed in endocrine pancreatic islet alpha and beta cells. May be more abundant in beta cells than in alpha cells. Expressed in cubical epithelium lining thyroid follicles (at protein level). In the adrenal gland, detected in the cortex, but not in the medulla (at protein level).
Proton-coupled zinc ion antiporter mediating the entry of zinc into the lumen of pancreatic beta cell secretory granules, thereby regulating insulin secretion.
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. Interacts with AP2A1 (via its alpha-appendage domain). Interacts (via N-terminus) with VAMP2; VAMP3; VAMP7 and VAMP8 (Via N-terminus). Interacts with LC3/MAP1LC3A.
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. Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. 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. In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors. Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF).
Isoform 2 was found in most tissues examined. Isoform 1 has an overlapping expression pattern but is absent from lung, heart and pancreas. Both isoforms are widely expressed in the brain, higher levels are seen in hippocampus, dentate gyrus, medial habenula nucleus and cerebellar granule cells.
Belongs to the metallothionein superfamily. Type 1 family.
Metallothioneins have a high content of cysteine residues that bind various heavy metals.
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.
Efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein (By similarity). Interacts with CEBPA, the interaction produces a transcriptional synergy. Interacts with LMNA (By similarity).
Expressed predominantly in brown adipose tissue.
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 (By similarity). Has a role in the nutritional regulation of fatty acids and triglycerides in lipogenic organs such as the liver. 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 (By similarity). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3') (PubMed:7739539). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3') (By similarity). Regulates the promoters of genes involved in cholesterol biosynthesis and the LDL receptor (LDLR) pathway of sterol regulation (By similarity).
Phosphorylated by AMPK, leading to suppress protein processing and nuclear translocation, and repress target gene expression. Phosphorylation at Ser-395 by SIK1 represses activity possibly by inhibiting DNA-binding.
Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 1), which is embedded in the endoplasmic reticulum membrane (By similarity). 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 (By similarity). Strongly activates global lipid synthesis in rapidly growing cells (By similarity).
Processed in the Golgi apparatus, releasing the protein from the membrane. At low cholesterol the SCAP-SREBP complex is recruited into COPII vesicles for export from the endoplasmic reticulum. In the Golgi, complex SREBPs are cleaved sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) proteases. 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.
The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.
Ubiquitinated; the nuclear form has a rapid turnover and is rapidly ubiquitinated and degraded by the proteasome in the nucleus.
Belongs to the peptidase C19 family. USP14/UBP6 subfamily.
Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes.
Homodimer (Potential). Associates with the 26S proteasome. Interacts with FANCC, CXCR4 and ERN1. Interacts with TRIM14; this interaction recruits USP14 to cleave ubiquitin chains of CGAS.
Transcription elongation factor implicated in the maintenance of proper chromatin structure in actively transcribed regions.
Belongs to the enoyl-CoA hydratase/isomerase family.
Converts unsaturated trans-2-enoyl-CoA species ((2E)-enoyl-CoA) to the corresponding 3(S)-3-hydroxyacyl-CoA species through addition of a water molecule to the double bond (PubMed:7883013, PubMed:10074351). Catalyzes the hydration of medium- and short-chained fatty enoyl-CoA thioesters from 4 carbons long (C4) up to C16 (PubMed:7883013, PubMed:10074351). 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). Can bind tiglyl-CoA (2-methylcrotonoyl-CoA), but hydrates only a small amount of this substrate (By similarity). Plays a key role in the beta-oxidation spiral of short- and medium-chain fatty acid oxidation (PubMed:7883013). 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) (PubMed:10074351).
Belongs to the helicase family. SKI2 subfamily.
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.
Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM11 methyltransferase family.
Catalytic subunit of an S-adenosyl-L-methionine-dependent tRNA methyltransferase complex that mediates the methylation of the guanosine nucleotide at position 10 (m2G10) in tRNAs.
Belongs to the complex I NDUFS6 subunit family.
Mammalian complex I is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme.
Thr-195 is present instead of the conserved Ser which is expected to be an active site residue. It is therefore unsure if this protein has kept its catalytic activity.
Activated by guanine nucleotide-exchange factors (GEF) EPAC and EPAC2 in a cAMP-dependent manner, and GFR.
Belongs to the small GTPase superfamily. Ras family.
Found in a complex, at least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (active GTP-bound form preferentially) with KRIT1 (via C-terminus FERM domain); the interaction does not induce the opening conformation of KRIT1. In its GTP-bound form interacts with PLCE1 and RADIL. Interacts with SGSM1, SGSM2 and SGSM3. Interacts (via GTP-bound active form) with RAPGEF2 (via Ras-associating domain) (By similarity). Interacts with TBC1D21 (By similarity). Interacts with RAP1GDS1 (By similarity).
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 (By similarity). 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.
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 (By similarity).
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.
Important role in the capacity of milk to transport calcium phosphate.
Belongs to the L-aspartate dehydrogenase family.
Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in binding dynein to membranous organelles or chromosomes.
Belongs to the dynein light intermediate chain family.
Homodimer (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.
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).
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.
Belongs to the ZIP transporter (TC 2.A.5) family.
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. Interacts with PTGER4 (By similarity). Interacts with NFKB1; the interaction is direct (By similarity).
Phosphorylated; highly phosphorylated in myoblasts and myotubes. Phosphorylation at Ser-108 and Ser-608 promote PGE2-EP4-mediated inhibition of inflammation. Dephosphorylated by protein phosphatase 2A (PP2A).
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. 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. 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 (By similarity). Involved in PGE2-EP4-mediated inhibition of inflammation of macrophages via interaction with NFKB1 and PTGER4. Promotes inflammation in brain microglia through MAP2K4/MKK4-mediated signaling (By similarity).
Belongs to the DNA polymerase type-B family.
DNA polymerase II participates in chromosomal DNA replication.
Belongs to the protein kinase superfamily. Tyr protein kinase family. SYK/ZAP-70 subfamily.
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 (By similarity).
Binds NTRK1, FGFR1, NGFR, GRB2, PTPN11 and ERK2.
Phosphorylated on tyrosine residues upon stimulation by BFGF or NGFB.
Belongs to the inner dynein arm light chain family.
Interacts with CFAP45 (By similarity). Interacts with DYNC1H1 (By similarity).
May play a dynamic role in flagellar motility.
Expressed in the cortex, cerebellum, striatum, midbrain, brainstem and thalamus of the brain (at protein level). Expressed in neurons (at protein level). Expressed in brain and testis. Expressed in the dentate gyrus of the hippocampus.
Phosphorylated on tyrosine residues by FYN. Tyrosine phosphorylated by PTK6 and SRC (By similarity). Tyrosine phosphorylated by SRC during mitosis (By similarity).
RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Its phosphorylation by FYN inhibits its ability to regulate splice site selection. Induces an increased concentration-dependent incorporation of exon in CD44 pre-mRNA by direct binding to purine-rich exonic enhancer. May function as an adapter protein for Src kinases during mitosis (By similarity). Binds both poly(A) and poly(U) homopolymers (By similarity). Phosphorylation by PTK6 inhibits its RNA-binding ability (By similarity).
Self-associates to form homooligomers. Interacts with SAFB, SFRS9 and YTHDC1. Found in a complex with KHDRBS1, KHDRBS2 and KHDRBS3. Interacts with RBMX (By similarity). Interacts with the SH3 domains of FYN and PLCG1 (By similarity). Interacts with the SH2 domains of FYN, GRAP2, PLCG1 and RASA1 (By similarity). Interacts with RBMX.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family.
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 (By similarity).
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. Homodimer, and heterodimer with EID2. Interacts with the C-terminal region of CREBBP (By similarity).
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 (By similarity).
Belongs to the protein-tyrosine phosphatase family. Non-receptor class subfamily.
May act at junctions between the membrane and the cytoskeleton.
Belongs to the kinesin light chain family.
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.
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.
Belongs to the activator 1 small subunits family.
Belongs to the DOK family. Type B subfamily.
Belongs to the eukaryotic ribosomal protein eL13 family.
Component of the 60S large ribosomal subunit (LSU).
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the LSU, it is probably required for its formation and the maturation of rRNAs. Plays a role in bone development.
Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces (PubMed:15897609, PubMed:16478722). Required for the assembly and secretion of plasma lipoproteins that contain apolipoprotein B (By similarity). May be involved in regulating cholesteryl ester biosynthesis in cells that produce lipoproteins (By similarity).
Heterodimer; heterodimerizes with the protein disulfide isomerase (P4HB/PDI) (By similarity). Interacts with APOB (By similarity). Interacts with PRAP1 (By similarity).
Probably involved in neuronal development.
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.
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. Hydrolyze 1-acyl-2-lyso-sn-glycero-3-phosphocholine (lyso-PC) and 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine (lyso-platelet-activating factor).
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 (By similarity). 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 (By similarity). Isoform 2 increases water and sodium absorption in the intestine and gall-bladder.
Expressed in brain; found in synapses in cerebellum.
Interacts with ABL1/c-Abl, ABL2/v-Abl/Arg, ACTN, CBL and PALLD (By similarity). Interacts with ABL, CBL, DNM1, DNM2, FLOT1, AFDN, PTK2B/PYK2, SAPAP, SPTAN1, SYNJ1, SYNJ2, VCL/vinculin and WASF. 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.
Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5'-phosphate as cofactor.
Expressed in brain and pancreatic islets.
Belongs to the glycosyl hydrolase 85 family.
Belongs to the eIF-2B gamma/epsilon subunits family.
Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.
Complex of five different subunits; alpha, beta, gamma, delta and epsilon. Interacts with RGS2 (By similarity).
Phosphorylated on serine and threonine residues by GSK3B; phosphorylation inhibits its function (By similarity). Phosphorylated at Ser-539 by DYRK2; this is required for subsequent phosphorylation by GSK3B.
Belongs to the DNA mismatch repair MutS family.
Component of the post-replicative DNA mismatch repair system (MMR).
Interacts with lamins A and C, BANF1, GMCL, BCLAF1 and YTHDC1/YT521. Interacts with TMEM43; the interaction retains emerin in the inner nuclear membrane. Interacts with ACTB, SPTAN1, F-actin, CTNNB1 and beta-tubulin. Interacts with SUN1 and SUN2. Interacts with TMEM201 (By similarity). Interacts with NEMP1 (By similarity).
Stabilizes and promotes the formation of a nuclear actin cortical network. Stimulates actin polymerization in vitro by binding and stabilizing the pointed end of growing filaments. Inhibits beta-catenin activity by preventing its accumulation in the nucleus. Acts by influencing the nuclear accumulation of beta-catenin through a CRM1-dependent export pathway. Links centrosomes to the nuclear envelope via a microtubule association. Required for proper localization of non-farnesylated prelamin-A/C. Together with NEMP1, contributes to nuclear envelope stiffness in germ cells.
Belongs to the small GTPase superfamily. Rab family.
Interacts (in GTP-bound form) with ZFYVE1 (By similarity). Interacts with ZW10 and this interaction is enhanced in the presence of ZFYVE1 (By similarity). Interacts with BSCL2 (By similarity).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (By similarity). 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 (By similarity). 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 (By similarity). Also required for maintaining endoplasmic reticulum structure (By similarity). Plays a role in apical endocytosis/recycling (By similarity). Plays a key role in eye and brain development and neurodegeneration (By similarity).
Belongs to the POU transcription factor family. Class-3 subfamily.
Expressed from embryonic day 11.5 into adulthood.
Transcription factor that acts synergistically with SOX11 and SOX4. Plays a role in neuronal development. Is implicated in an enhancer activity at the embryonic met-mesencephalic junction; the enhancer element contains the octamer motif (5'-ATTTGCAT-3') (By similarity).
Belongs to the anion exchanger (TC 2.A.31) family.
Down-regulated after cadmium-intoxication and sodium or bicarbonate loading (at protein level). Down-regulated by HCO3[-] loading.
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.
Expression is first detected at 17 dpc in spinal cord and starts in forebrain at birth. Higher expression in brain is detected at postnatal day 15 and persists throughout adulthood.
Homodimer. Interacts with CA2/carbonic anhydrase 2 and CA4/carbonic anhydrase 4 which may regulate transporter activity. Isoform 1 but not isoform 2 interacts with AHCYL1 (via PEST domain when phosphorylated); the interaction increases SLC4A4 isoform 1 activity. Interacts with AHCYL2.
Inhibited by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS).
N-glycosylation is not 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. Phosphorylated in presence of STK39 and dephosphorylated in presence of PP1 phosphatase; phosphorylation seems to inhibit SLC4A4 activity.
Specifically expressed in kidney and to a lower extent in liver, lung, spleen, brain, skeletal muscle and heart. In kidney, expressed in proximal tubules at the corticomedullary junction. Isoform 2 is specifically expressed in kidney. Isoform 1 is expressed in kidney and pancreas while isoform 3 is specifically expressed in brain (at protein level). In brain, isoform 1 is expressed in astrocytes while isoform 3 is expressed in neurons (at protein level). In the eye, isoform 1 is expressed in cornea, conjunctiva, lens epithelium, ciliary bodies and retina while isoform 2 is detected only in the conjunctiva.
Anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) and protein kinase C (PKC).
Binds to dimeric RII-alpha regulatory subunit of PKC.
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 (By similarity). 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 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. Interacts with MYC; competitive with NOP53. Interacts with NOP53; the interaction is direct and competitive with MYC (By similarity). Interacts with LRRC34 (By similarity). Interacts with RRP1B. Interacts with NPM3. Interacts with ALKBH2 (By similarity). Interacts with TTF1 (via C-terminal region) (By similarity).
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. In complex with MYC enhances the transcription of MYC target genes (By similarity). May act as chaperonin or cotransporter in the nucleolar localization of transcription termination factor TTF1 (By similarity).
May be ubiquitinated. Ubiquitination leads to proteasomal degradation. Deubiquitinated by USP36 (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-198. Phosphorylation at Thr-198 may trigger initiation of centrosome duplication. Phosphorylated by CDK1 at Thr-198, Thr-217, Thr-232 and Thr-235 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-198 phosphorylated form has higher affinity for ROCK2 (By similarity).
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 (By similarity). Interacts with CNPY3; this interaction is disrupted in the presence of ATP. Interacts with TLR4, TLR9 and TLR11, but not with TLR3 (By similarity). Interacts with MZB1 in a calcium-dependent manner (By similarity). Interacts with METTL23 (By similarity). Interacts with IL1B; the interaction facilitates cargo translocation into the ERGIC (By similarity).
Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors. Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity. 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 (By similarity).
Glycopeptide transferase involved in O-linked oligosaccharide biosynthesis, which catalyzes the transfer of an N-acetyl-D-galactosamine residue to an already glycosylated peptide. In contrast to other proteins of the family, it does not act as a peptide transferase that transfers GalNAc onto serine or threonine residue on the protein receptor, but instead requires the prior addition of a GalNAc on a peptide before adding additional GalNAc moieties. Some peptide transferase activity is however not excluded, considering that its appropriate peptide substrate may remain unidentified.
Highly expressed in sublingual gland. Expressed at lower level in stomach, small intestiine and colon.
Was originally termed Galnt6/pp-GaNTase 6.
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 (By similarity).
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 (By similarity). Interacts with STX17; the interaction is direct.
N-linked glycosylated containing high mannose.
Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
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.
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.
P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.
Belongs to the nuclear hormone receptor family. NR3 subfamily.
Binds DNA as a monomer (By similarity). 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).
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 (By similarity). 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 (By similarity). Plays a role as transcription factor repressor of NFE2L2 transcriptional activity and ESR1 transcriptional activity (By similarity). 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).
Was originally (PubMed:3267207) thought to originate from human but was later shown (PubMed:10072763) to be derived from rat.
GTPase-activating protein (GAP) for ADP ribosylation factor 1 (ARF1). May regulate coatomer-mediated protein transport from the Golgi complex to the endoplasmic reticulum. Hydrolysis of ARF1-bound GTP may lead to dissociation of coatomer from Golgi-derived membranes to allow fusion with target membranes (By similarity).
Interacts with the coatomer complex. Interacts with the C-terminal appendage domain of COPG1 (By similarity).
Functions as a cellular zinc transporter.
Expressed by podocytes in kidney glomeruli (at protein level).
Interacts (non-phosphorylated form) with NCOA1; NCOA2 AND NCOA3 (By similarity). Interacts with AIFM1 (By similarity). 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 (By similarity).
Involved in transcription regulation by sequestering in the cytoplasm nuclear receptor coactivators such as NCOA1, NCOA2 and NCOA3 (By similarity). Involved in regulation of caspase-independent apoptosis by sequestering the proapoptotic factor AIFM1 in mitochondria (By similarity). Pro-apoptotic stimuli can induce its proteasomal degradation allowing the translocation of AIFM1 to the nucleus to induce apoptosis (By similarity). Involved in the negative control of vitamin D receptor signaling pathway (By similarity). Involved in actin stress fibers formation through its interaction with ARHGDIA and the regulation of the Rho signaling pathway (By similarity). May thereby play a role in cell adhesion and migration, regulating for instance podocytes migration during development of the kidney (By similarity). Through the Rho signaling pathway may also regulate cell proliferation (By similarity).
Phosphorylated by casein kinase II upon estrogen stimulation (By similarity). Phosphorylation induces the release by KANK2 of NCOA1 and its translocation to the nucleus where NCOA1 can activate gene transcription (By similarity).
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.
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 (By similarity).
5 rat isozymes encoded by different genes have been described. ACSL6 corresponds to isozyme 2 (ACS2).
Belongs to the ATP-dependent AMP-binding enzyme family.
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:28209804). ACSL5 may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL at the villus tip of the crypt-villus axis of the small intestine (By similarity). May have a role in the survival of glioma cells (By similarity). May activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage. It was suggested that it may also stimulate fatty acid oxidation. Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids.
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 most abundantly in the small intestine, and to a much lesser extent in the lung, liver, adrenal gland, adipose tissue and kidney.
Expression decreases in response to fast and increases after high sucrose diet.
Belongs to the VPS10-related sortilin family. SORCS subfamily.
Belongs to the JHDM3 histone demethylase family.
Belongs to the eukaryotic ribosomal protein eL24 family.
Mono-ADP-ribosylation at Glu-4 by PARP16 inhibits polysome assembly and mRNA loading, thereby inhibiting protein translation.
Belongs to the pyrroline-5-carboxylate reductase family.
Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Has high activity on the succinyl- (suc-) peptide-4-methylcoumaryl-7-amide (MCA) substrates suc-Gly-Pro-Leu-Gly-Pro-MCA, suc-Gly-Pro-MCA and suc-Ala-Ala-Ala-MCA.
Expressed in all tissues tested: uterus, kidney, heart, lung, small intestine, smooth muscle, liver, spleen, thymus, adrenal, pituitary and whole brain.
In the estrous cycle, expression and activity are highest in the luteal phase.
Inhibited by DFP, Z-Pro-prolinal and poststatin, but not by PMSF, SBTI, EDTA, leupeptin, E-64 and pepstatin.
Belongs to the eukaryotic RPB7/RPC8 RNA polymerase subunit family.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. RPB4 and RPB7 form a subcomplex that protrudes from the 10-subunit Pol II core complex.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB7 is part of a subcomplex with RPB4 that binds to a pocket formed by RPB1, RPB2 and RPB6 at the base of the clamp element. The 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. Binds RNA (By similarity).
Expressed in flagella of epididymal sperm.
Interacts with PRKAR1A and PRKAR2A. Interacts with ENO4.
Major structural component of sperm fibrous sheath. May play a role in sperm motility (By similarity).
RI-alpha binding site, predicted to form an amphipathic helix that is required for binding to Prkar1a.
Negatively regulates nitric oxide production by inducing NOS1 and NOS3 translocation to actin cytoskeleton and inhibiting their enzymatic activity.
Interacts with RIMS1 and RIMS2 (PubMed:10748113) (By similarity). Interacts with Rabphilin-3A/RPH3A and Rab effector Noc2/RPH3AL (PubMed:10025402) (By similarity). Interacts with SYTL4 (By similarity). Interacts with RAB3IP (PubMed:7532276). Interacts with SGSM1 and SGSM3 (By similarity). Interacts with SYT1 (PubMed:28057568). Interacts with MYH9; this interaction is essential for lysosome exocytosis and plasma membrane repair (By similarity). Interacts with STXBP1; this interaction promotes RAB3A dissociation from the vesicle membrane (PubMed:21689256). Interacts with SNCA (By similarity). Interacts with GDI1, GDI2 and CHM; phosphorylation at Thr-86 disrupts these interactions (By similarity).
Phosphorylation of Thr-86 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM and RAB GDP dissociation inhibitors GDI1 and GDI2.
Small GTP-binding protein that plays a central role in regulated exocytosis and secretion. Controls the recruitment, tethering and docking of secretory vesicles to the plasma membrane (PubMed:21689256). Upon stimulation, switches to its active GTP-bound form, cycles to vesicles and recruits effectors such as RIMS1, RIMS2, Rabphilin-3A/RPH3A, RPH3AL or SYTL4 to help the docking of vesicules onto the plasma membrane (PubMed:18407218). Upon GTP hydrolysis by GTPase-activating protein, dissociates from the vesicle membrane allowing the exocytosis to proceed (PubMed:17149709). Stimulates insulin secretion through interaction with RIMS2 and RPH3AL effectors in pancreatic beta cells (By similarity). Regulates calcium-dependent lysosome exocytosis and plasma membrane repair (PMR) via the interaction with 2 effectors, SYTL4 and myosin-9/MYH9 (By similarity). Acts as a positive regulator of acrosome content secretion in sperm cells by interacting with RIMS1 (By similarity). Plays a role in the regulation of dopamine release by interacting with synaptotagmin I/SYT (PubMed:28057568). Interacts with MADD (via uDENN domain); the GTP-bound form is preferred for interaction (By similarity).
Channel activity inhibited by ATP via ABCB8/MITOSUR subunit.
Mitochondrial potassium channel located in the mitochondrial inner membrane. 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). May contribute to the homeostatic control of cellular metabolism under stress conditions by regulating the mitochondrial matrix volume.
The mitochondrial potassium channel (mitoK(ATP)) forms a heteromultimer.
Belongs to the major facilitator superfamily. Organophosphate:Pi antiporter (OPA) (TC 2.A.1.4) family.
Calcium-dependent mitochondrial solute carrier. Mitochondrial solute carriers shuttle metabolites, nucleotides, and cofactors through the mitochondrial inner membrane. 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 (By similarity).
In the liver, expression is higher in the adult stage than in the fetal stage.
Mainly present in the liver and the skeletal muscle (at protein level).
Up-regulated in dexamethasone-treated cells before the expression of albumin.
Belongs to the mitochondrion-specific ribosomal protein mL42 family.
Component of the mitochondrial ribosome large subunit (39S) which comprises a 16S rRNA and about 50 distinct proteins. Component of the mitochondrial ribosome small subunit (28S) which comprises a 12S rRNA and about 30 distinct proteins.
Has been found in the mitochondrial ribosome large and small subunits.
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. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex. The IKK complex associates with TERF2IP/RAP1, leading to promote IKK-mediated phosphorylation of RELA/p65. Part of a complex composed of NCOA2, NCOA3, CHUK/IKKA, IKBKB, IKBKG and CREBBP. Part of a 70-90 kDa complex at least consisting of CHUK/IKKA, IKBKB, NFKBIA, RELA, ELP1 and MAP3K14. Found in a membrane raft complex, at least composed of BCL10, CARD11, DPP4 and IKBKB (By similarity). Interacts with SQSTM1 through PRKCZ or PRKCI (PubMed:16079148). Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 (PubMed:16079148). May interact with MAVS/IPS1. Interacts with NALP2. Interacts with TICAM1. Interacts with FAF1; the interaction disrupts the IKK complex formation. Interacts with ATM. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with TRIM21. Interacts with NLRC5; prevents IKBKB phosphorylation and kinase activity. Interacts with PDPK1. Interacts with EIF2AK2/PKR. The phosphorylated form interacts with PPM1A and PPM1B. Interacts with ZNF268 isoform 2; the interaction is further increased in a TNF-alpha-dependent manner. Interacts with IKBKE. Interacts with NAA10, leading to NAA10 degradation. Interacts with FOXO3. Interacts with ZC3H12A (By similarity). Interacts with AKAP13 (PubMed:23090968). 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 (By similarity). Interacts with SASH1 (By similarity). Interacts with ARFIP2 (By similarity). Interacts with FKBP5 (By similarity).
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. 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 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. 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. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation (By similarity). 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 (By similarity).
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 (By similarity).
Ubiquitinated. Monoubiquitination involves TRIM21 that leads to inhibition of Tax-induced NF-kappa-B signaling. 'Ser-163' may not serve as a monoubiquitination site. Ubiquitination on 'Ser-163' may modulate 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.
Protects the body from potent vasoactive and inflammatory peptides containing C-terminal Arg or Lys (such as kinins or anaphylatoxins) which are released into the circulation.
Tetramer of two catalytic chains and two glycosylated inactive chains.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa1.1/KCNMA1 sub-subfamily.
Ethanol and carbon monoxide-bound heme increase channel activation. Heme inhibits channel activation.
Homotetramer; which constitutes the calcium-activated potassium channel. Interacts with 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. Interacts with RAB11B (By similarity).
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 (By similarity).
Phosphorylated (Probable). Phosphorylation by kinases such as PKA and/or PKG. In smooth muscles, phosphorylation affects its activity (By similarity).
Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). 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 (By similarity).
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 (By similarity).
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 contains binding sites for Ca(2+) and Mg(2+).
Activated by Triton X-100, insensitive to inhibition by adenosine and inhibited by wortmannin (PubMed:8662589). The PI4K complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (By similarity). Interaction with TMEM150A regulates PtdIns(4)P synthesis (By similarity).
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). Interacts with TMEM150A; regulating recruitment to the plasma membrane. Interacts with TTC7A.
Detected in the brain, kidney and lung. Less intensely expressed in the small intestine, uterus, adrenal gland, heart, skeletal muscle, thymus, spleen and testis.
In brain of prenatal day 18 embryos, the expression is detected throughout the mantle zone of fore-, mid-, and hind brain. In the cerebrum, the expression is intense in the cortical plate and weak in the ventricular zone. At P49, expressed in the gray matter of the entire brain by hippocampal pyramidal cells, dentate granule cells, and cerebellar granule cells and to a lower extent by olfactory mitral and granule cells and the cerebral cortex. Weakly expressed in the diencephalon and brain stem and not detected in the cerebellar medulla. Expression is much higher in the fetal brain than the adult brain, especially in the brain stem.
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.
Interacts with EF1A1, facilitates EF1A1 distribution to the membrane periphery and ruffles upon growth factor stimulation and suppresses cell migration.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1. Ubiquitinates STUB1-associated HSP90AB1 in vitro. Lacks inherent specificity for any particular lysine residue of ubiquitin. Essential for viral activation of IRF3. Mediates polyubiquitination of CYP3A4 (By similarity). Mediates ubiquitination of PEX5.
Belongs to the ubiquitin-conjugating enzyme family.
Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with RNF11.
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 (By similarity). Interacts with MAF and MAFB. Interacts with PAX5; the interaction alters DNA-binding properties (By similarity). Interacts with DAXX. Interacts with UBE2I. Interacts with SP100; the interaction is direct and modulates ETS1 transcriptional activity (By similarity).
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. Directly controls the expression of cytokine and chemokine genes in a wide variety of different cellular contexts. May control the differentiation, survival and proliferation of lymphoid cells. May also regulate angiogenesis through regulation of expression of genes controlling endothelial cell migration and invasion.
Ubiquitinated; which induces proteasomal degradation.
Defects in Slc11a2 are the cause of microcytic anemia (Belgrade or b). Homozygous b/b rats have hypochromic microcytic anemia due to severe defects in intestinal iron absorption and erythroid iron utilization.
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. Interacts with ARRDC4; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism.
May serve to import iron into the mitochondria (By similarity). Important in metal transport, in particular iron. Can also transport zinc, manganese, cobalt, cadmium, copper, nickel 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.
Interacts with RAC1. Binds to F-actin. Interacts with FASLG (By similarity).
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 (By similarity).
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).
Interacts with CAMSAP3 (By similarity). Interacts with KATNA1 and KATNB1; leading to regulate the length of CAMSAP2-decorated microtubule stretches. Interacts with a complex formed by AKAP9 and PDE4DIP; this interaction, which is PDE4DIP isoform-specific, recruits CAMSAP2 to the Golgi. Interacts with MAPRE1/EB1 (By similarity).
Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization (PubMed:24908486). Specifically recognizes growing microtubule minus-ends and autonomously decorates and stabilizes microtubule lattice formed by microtubule minus-end polymerization (By similarity). Acts on free microtubule minus-ends that are not capped by microtubule-nucleating proteins or other factors and protects microtubule minus-ends from depolymerization (By similarity). In addition, it also reduces the velocity of microtubule polymerization (By similarity). Through the microtubule cytoskeleton, also regulates the organization of cellular organelles including the Golgi and the early endosomes (By similarity). Essential for the tethering, but not for nucleation of non-centrosomal microtubules at the Golgi: together with Golgi-associated proteins AKAP9 and PDE4DIP, required to tether non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (By similarity). Also acts as a regulator of neuronal polarity and development: localizes to non-centrosomal microtubule minus-ends in neurons and stabilizes non-centrosomal microtubules, which is required for neuronal polarity, axon specification and dendritic branch formation (PubMed:24908486). Through the microtubule cytoskeleton, regulates the autophagosome transport (By similarity).
Present in the soma, axon, and dendritic shaft of hippocampal neurons (at protein level) (PubMed:24908486).
The CKK domain binds microtubules and specifically recognizes the minus-end of microtubules.
The MBD (microtubule-binding domain) region can recognize some features of the microtubule lattice, which might contribute to the specific decoration of growing microtubule minus-ends by CAMSAP2.
Belongs to the archaeal Rpo6/eukaryotic RPB6 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 polymerases catalyze the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2F/RPB6 is part of the clamp element and together with parts of RPB1 and RPB2 forms a pocket to which the RPB4-RPB7 subcomplex binds (By similarity).
Putative taste receptor which may play a role in the perception of bitterness.
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. Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with MCM9; the interaction recruits MLH1 to chromatin. Interacts MCM8. Interacts with PMS2. Interacts with MBD4. Interacts with EXO1. Interacts with MTMR15/FAN1.
Heterodimerizes with Pms2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (Msh2-Msh6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of Pms2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (Mlh1-Pms2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with Mlh3 to form MutL gamma which plays a role in meiosis (By similarity).
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 (By similarity). Shows a small preference for NADPH over NADP(+) (By similarity). Represses translation and promotes degradation of target mRNA molecules (By similarity). 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 (By similarity). Was subsequently shown to act as a phosphatase (By similarity).
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation (By similarity).
Interacts with CLIC6 (PubMed:14499480). Interacts with GRK4. Interacts with PALM. Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA (By similarity).
In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family.
In the N-terminal section; belongs to the ubiquitin family.
May be signaling molecules that resemble neuropeptides.
Belongs to the glycosyl hydrolase 13 family.
Detected in early embryonic stage as early as 15 dpc, gradually increased throughout early development, peaked at approximately between postnatal days P6 and P8, then slightly decreased and remained relatively stable in the adult.
Expressed in brain, testis and retina. In brain highly expressed in the olfactory bulb, cortex and hippocampus and lower level in thalamus, cerebellum and spinal cord. In brain it is found in the perikaryon, dendrites, dendritic shafts, dendritic spines and, excitatory and inhibitory synapses of neurons. In retina, it is most abundant in the plexiform layers than in perikarya.
Interacts with EFNB1, EPHA7, EPHB2, EFNB3, KIF5A, KIF5C, KIF5B and the C-terminal tail of PRLHR. Forms a ternary complex with GRIA2 and CSPG4 (By similarity). Can form homomultimers or heteromultimers with GRIP2. Interacts with GRIA2, GRIA3, GRIPAP1/GRASP1, PPFIA1, PPFIA4, FRAS1, PLCD4, PTPRF and liprins-alpha. Interacts with ATAD1 in an ATP-dependent manner. ATAD1-catalyzed ATP hydrolysis disrupts binding to ATAD1 and to GRIA2 and leads to AMPAR complex disassembly. Interacts with SLC30A9 (By similarity). Interacts with BUD23 (By similarity). Forms a complex with NSG1, GRIA2 and STX12; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (PubMed:16037816). Interacts with NSG1 (PubMed:16037816).
May play a role as a localized scaffold for the assembly of a multiprotein signaling complex and as mediator of the trafficking of its binding partners at specific subcellular location in neurons (PubMed:9069286). Through complex formation with NSG1, GRIA2 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (PubMed:16037816).
PDZ 6 mediates interaction with the PDZ recognition motif of EFNB1 and EPHB2 and with the C-terminus of PPFIA1 and PPFIA4. PDZ 4 and PDZ 5 mediate interaction with PRLHR (By similarity). PDZ 4 and PDZ 5 mediate interaction with the C-terminus of GRIA2 and GRIA3. PDZ 4, PDZ 5 and PDZ 6 mediate homomultimers. PDZ 7 mediates interaction with PDZ domain of GRASP1. PDZ 7 domain binds CSPG4. PDZ 6 mediates interaction with the C-terminus of liprins-alpha. PDZ 1, PDZ 2 and PDZ 3 mediate interaction with the PDZ-binding motif of FRAS1.
Belongs to the glycine N-acyltransferase family.
Belongs to the cytochrome c oxidase VIII family.
Increased levels in liver during prenatal development.
Belongs to the UDP-glycosyltransferase family.
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.
Belongs to the eutherian X-chromosome-specific Armcx family.
May regulate the dynamics and distribution of mitochondria in neural cells.
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 a critical role in the assembly of N-DRC and also stabilizes the assembly of multiple inner dynein arms and radial spokes. Coassembles with CCDC65/DRC2 to form a central scaffold needed for assembly of the N-DRC and its attachment to the outer doublet microtubules.
Component of the nexin-dynein regulatory complex (N-DRC).
Putative pheromone receptor implicated in the regulation of social as well as reproductive behavior.
Catalyzes the final step of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway, the ATP-dependent amidation of deamido-NAD using L-glutamine as a nitrogen source.
In the C-terminal section; belongs to the NAD synthetase family.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIC subfamily.
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.
Binds 1 myo-inositol hexakisphosphate (IP6) per subunit.
Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2 and GRIK2) and serotonin (HTR2C), GABA receptor (GABRA3) and potassium voltage-gated channel (KCNA1). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alter their functional activities. Edits GRIA2 at both the Q/R and R/G sites efficiently but converts the adenosine in hotspot1 much less efficiently (By similarity). Can inhibit cell proliferation and migration and can stimulate exocytosis.
Homodimer. Homodimerization is essential for its catalytic activity (By similarity).
Belongs to the calycin superfamily. Lipocalin family.
Detected in blood plasma (at protein level).
Interacts with TTR (PubMed:4708098). Interaction with TTR prevents its loss by filtration through the kidney glomeruli (Probable). Interacts with STRA6 (By similarity).
Retinol-binding protein that mediates retinol transport in blood plasma.
Retinol-binding protein that mediates retinol transport in blood plasma. Delivers retinol from the liver stores to the peripheral tissues (PubMed:4708098). Transfers the bound all-trans retinol to STRA6, that then facilitates retinol transport across the cell membrane (By similarity).
Forms dimers and possibly higher-order oligomers.
N-glycosylated, but not all potential glycosylation sites may be used. Contains high-mannose type oligosaccharides.
Nucleoporin essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity.
Phosphorylated at Ser-1880 in mitosis specifically; not phosphorylated in interphase.
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. Possible crucial role in the regulation of tissue concentration of AdoMet and of metabolism of methionine.
Inhibited by 5-methyltetrahydrofolate monoglutamate and by 5-methyltetrahydrofolate pentaglutamate, inhibition is much more effective by the pentaglutamate form than by the monoglutamate form (PubMed:3838667). 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.
Expressed in the trachea (at protein level).
Plays a role in motile cilium function, possibly by acting on outer dynein arm assembly. Seems to be important for initiation rather than maintenance of cilium motility. Required for correct positioning of cilia at the apical cell surface, suggesting an additional role in the planar cell polarity (PCP) pathway. May suppress canonical Wnt signaling activity.
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 (By similarity).
The RNase H2 complex is a heterotrimer composed of the catalytic subunit RNASEH2A and the non-catalytic subunits RNASEH2B and RNASEH2C.
Forms homodimers and heterodimers with SOX6.
Transcription factor involved in chondrocytes differentiation and cartilage formation (By similarity). Specifically binds the 5'-AACAAT-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes, such as COL2A1 and AGC1 (By similarity). 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 (PubMed:26150426). Not involved in precartilaginous condensation, the first step in chondrogenesis, during which skeletal progenitors differentiate into prechondrocytes (By similarity). Together with SOX6, required to form and maintain a pool of highly proliferating chondroblasts between epiphyses and metaphyses, to form columnar chondroblasts, delay chondrocyte prehypertrophy but promote hypertrophy, and to delay terminal differentiation of chondrocytes on contact with ossification fronts (By similarity). Binds to the proximal promoter region of the myelin protein MPZ gene (By similarity).
Hydrolyzes bioactive fatty-acid esters of hydroxy-fatty acids (FAHFAs), but not other major classes of lipids (By similarity). Shows a preference for FAHFAs with branching distal from the carboxylate head group of the lipids (By similarity). Regulates the expression and the cell-associated anticoagulant activity of the inhibitor TFPI in endothelial cells (in vitro) (By similarity).
Belongs to the ATP synthase subunit s family.
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.
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.
Expressed in various tissues. At the highest level in liver and at the second highest in heart. The amount is higher in heart than in lung.
Acetylation modifies enzyme activity in response to alterations of extracellular nutrient availability. Acetylation increased with trichostin A (TSA) or with nicotinamide (NAM). Glucose increases acetylation by about a factor of 3 with decreasing enzyme activity. Acetylation on Lys-288 is decreased on the addition of extra amino acids resulting in activation of enzyme activity.
Belongs to the lyase 1 family. Argininosuccinate lyase subfamily.
Catalyzes the reversible cleavage of L-argininosuccinate to fumarate and L-arginine, an intermediate step reaction in the urea cycle mostly providing for hepatic nitrogen detoxification into excretable urea as well as de novo L-arginine synthesis in nonhepatic tissues (By similarity). Essential regulator of intracellular and extracellular L-arginine pools. As part of citrulline-nitric oxide cycle, forms tissue-specific multiprotein complexes with argininosuccinate synthase ASS1, transport protein SLC7A1 and nitric oxide synthase NOS1, NOS2 or NOS3, allowing for cell-autonomous L-arginine synthesis while channeling extracellular L-arginine to nitric oxide synthesis pathway (By similarity).
Enzyme activity is regulated by acetylation.
Homotetramer (By similarity). Forms tissue-specific complexes with ASS1, SLC7A1, HSP90AA1 and nitric oxide synthase NOS1, NOS2 or NOS3; the complex maintenance is independent of ASL catalytic function (By similarity).
Expressed in most tissues. Bcl-X(beta) is specifically expressed in cerebellum, heart, and thymus. In the ovary, the predominant form is Bcl-X(L), with a small but detectable level of Bcl-X(S).
Forms heterodimers with BAX, BAK or BCL2; heterodimerization with BAX does not seem to be required for anti-apoptotic activity (By similarity). Interacts with isoform 1 of SIVA1; the interaction inhibits the anti-apoptotic activity (By similarity). Interacts with IKZF3 (By similarity). Interacts with RTL10/BOP (By similarity). 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:18250306, 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 (By similarity). Interacts with BECN1 (By similarity).
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 (PubMed:21926988). Interacts with VDAC1 (By similarity). Interacts with BCL2L11 (via BH3) (By similarity). Interacts with RNF183 (By similarity). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (By similarity). 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 (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
The BH4 motif is required for anti-apoptotic activity. The BH1 and BH2 motifs are required for both heterodimerization with other Bcl-2 family members and for repression of cell death.
The loop between motifs BH4 and BH3 is required for the interaction with NLRP1.
Ubiquitinated by RNF183 during prolonged ER stress, leading to degradation by the proteosome.
Interacts (via LRR repeats) with TLR2, TLR3, TLR4, TLR9 and probably other Toll-like receptors (By similarity). Interacts with CYBB/NOX2; the interaction is direct. 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 (By similarity).
Key regulator of transforming growth factor beta-1 (TGFB1) specifically required for microglia function in the nervous system. 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. 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. 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.
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:24896179). Preferentially cleaves 'Lys-6'- and 'Lys-11'-linked polyubiquitin chains, 2 types of linkage that participate in mitophagic signaling. Does not cleave efficiently polyubiquitin phosphorylated at 'Ser-65' (By similarity). Acts as negative regulator of mitochondrial fusion by mediating deubiquitination of MFN1 and MFN2 (By similarity).
Inhibited by the diterpenoid derivative 15-oxospiramilactone (S3).
Ubiquitinated by parkin (PRKN) at Lys-235 and Lys-289, leading to its degradation.
Probable C-mannosyltransferase that mediates C-mannosylation of tryptophan residues on target proteins.
Belongs to the RIN (Ras interaction/interference) family.
Interacts with PLCE1 (By similarity). Interacts (active GTP-bound form preferentially) with RGS14 (PubMed:19319189). Interacts with OSBPL3 (By similarity). Interacts with ZDHHC19 (By similarity).
Regulates the organization of the actin cytoskeleton. With OSPBL3, modulates integrin beta-1 (ITGB1) activity.
S-palmitoylated by ZDHHC19, leading to increased association with membranes and with rafts/caveolae as well as enhanced cell viability.
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).
Belongs to the G-protein coupled receptor 2 family.
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.
Present in the pancreas as well as the gut, adipose tissue, heart, pituitary, and inner layers of the adrenal cortex, whereas it is not found in kidney, spleen, or liver. It is also expressed in several brain regions, including the cerebral cortex, hippocampus, and olfactory bulb.
This is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Belongs to the amino acid-polyamine-organocation (APC) superfamily. Cationic amino acid transporter (CAT) (TC 2.A.3.3) family.
Acts as a co-chaperone for HSP90AA1 (By similarity). Mediates the association of the molecular chaperones HSPA8/HSC70 and HSP90 (PubMed:9528774).
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (By similarity). Forms a complex with HSPA8/HSC70, HSPCA/HSP-86 and HSPCB/HSP-84. Interacts with PACRG. Interacts with EEF1AKMT3 (By similarity). Interacts with HSP90/HSP90AA1; the interaction dissociates the PPP5C:HSP90AA1 interaction. Interacts with FLCN, FNIP1 and FNIP2 (By similarity). Interacts with HSPA8/HSC70 (PubMed:9528774). Interacts with HSP90AB1; upon SMYD2-dependent HSP90AB1 methylation (By similarity).
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 (By similarity).
Belongs to the RNA polymerase beta chain 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. 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.
Belongs to the eukaryotic mitochondrial porin family.
Consists mainly of a membrane-spanning beta-barrel formed by 19 beta-strands. The helical N-terminus folds back into the pore opening and plays a role in voltage-gated channel activity.
Forms a channel through the mitochondrial outer membrane and also the plasma membrane (By similarity). 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 (By similarity). It 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 (PubMed:25628567). Binds various signaling molecules, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterol cholesterol (By similarity). 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 (By similarity). May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis (By similarity). May mediate ATP export from cells (By similarity).
Homodimer and homotrimer; in response to cyclic AMP or calcium. Interacts with hexokinases including HK1. The HK1-VDAC1 complex interacts with ATF2. Interacts with BCL2L1. Interacts with BAK1. Interacts with RTL10/BOP (via BH3 domain). Interacts with amyloid-beta and APP; induces VDAC1 dephosphorylation. Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF. Interacts with SPG7, NIPSNAP2 and SLC25A30. Interacts with TMEM41B. Interacts with BCAP31.
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. Undergoes monoubiquitination and polyubiquitination by PRKN; monoubiquitination at Lys-274 inhibits apoptosis, whereas polyubiquitination leads to its degradation and promotes mitophagy. Deubiquitinated by USP30.
Widely expressed. High levels in heart and kidney with lower levels in brain and ascitic tumor. Very low levels in liver.
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.
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.
Down-regulated by theophylline (THP) and up-regulated by 1,3-dinitrobenzene (DNB), two reprotoxic agents thought to induce infertility.
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. Directly interacts with POMP. Interacts with ABCB1 and TAP1.
Inhibits neuronal cell proliferation by negative regulation of the cell cycle transition.
Plays a role into cellular response to oxidative stress. Decreases cell proliferation (By similarity).
Belongs to the glycosyl hydrolase 31 family.
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.
Belongs to the amino acid/polyamine transporter 2 family.
Expressed predominantly in liver, and at lower level in skeletal muscle.
Symporter that cotransports neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane (PubMed:11118514). The transport is electrogenic, pH dependent and partially tolerates substitution of Na(+) by Li(+) (PubMed:11118514). 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:11118514).
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 (By similarity). While Hatanaka et al. shown that SLC38A4 may mediate sodium-independent transport of cationic amino acids, such as L-arginine and L-lysine (By similarity). Recent studies by Fairweather et al., using quantitative LC-MS analysis, shown any transport activity of cationic amino acids, such as L-arginine and L-lysine (By similarity).
Belongs to the round spermatid basic protein 1 family.
Homodimer; disulfide-linked (By similarity). Interacts directly with ACVR2B. Interacts directly with ACVR2A. Interacts with ACVR1B, TGFBR1 and ACVR1C in an ACVR2B-dependent manner (By similarity). Interacts with FST isoform 2/FS288 (By similarity).
Secreted signal that acts globally to regulate anterior/posterior axial patterning during development. May play critical roles in patterning both mesodermal and neural tissues. It is required for proper vertebral patterning and orofacial development. Signals through activin receptors type-2, ACVR2A and ACVR2B, and activin receptors type-1, ACVR1B, ACVR1C and TGFBR1 leading to the phosphorylation of SMAD2 and SMAD3.
Synthesized as large precursor molecule that undergoes proteolytic cleavage by furin-like proteases. This produces an inactive form consisting of the mature C-terminal portion non-covalently bound to its cleaved N-terminal propeptide. Activation of the mature form requires additional cleavage of the propeptide by a tolloid-like metalloproteinase.
Dephosphorylates CDKN1B at 'Thr-187', thus removing a signal for proteasomal degradation.
Methylated in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation (By similarity).
Monomer (By similarity). Homodimer (By similarity). Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (By similarity). Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins (By similarity). MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer (By similarity). Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (By similarity). Interacts with LZTR1 (By similarity). Interacts with Ras proteins; the interaction is antagonized by RIN1 (By similarity). Weakly interacts with RIT1 (By similarity). Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity (By similarity). Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') (By similarity). Interacts with MAP3K5/ASF1 (via N-terminus) and this interaction inhibits the proapoptotic function of MAP3K5/ASK1 (By similarity). Interacts with PAK1 (via kinase domain) (By similarity). The phosphorylated form interacts with PIN1 (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2 (By similarity). Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (By similarity). Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin (By similarity). Interacts with ROCK2 (By similarity). 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 (PubMed:19319189, PubMed:19878719). 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 (By similarity). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (PubMed:7565670). In its active form, interacts with PRMT5 (By similarity). Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (By similarity). Interacts with PDE8A; the interaction promotes RAF1 activity (By similarity). Interacts with MFHAS1 (By similarity). Interacts with GLS (By similarity). Interacts with YWHAZ. Interacts with NEK10 and MAP2K1; the interaction is direct with NEK10 and required for ERK1/2-signaling pathway activation in response to UV irradiation (By similarity).
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 (By similarity). 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 a decreased of activity (By similarity).
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 (By similarity).
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. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation (By similarity). Phosphorylates TNNT2/cardiac muscle troponin T.
Interacts with PIP5K1A; the interaction inhibits PIP5K1A kinase activity.
Phosphatidylinositol 5-phosphate 4-kinase with low enzymatic activity (PubMed:9685379). May be a GTP sensor, has higher GTP-dependent kinase activity than ATP-dependent kinase activity (By similarity). 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 (By similarity).
Phosphorylated, phosphorylation is induced by EGF.
Widely expressed, with the most abundant expression in kidney.
Homodimer; disulfide-linked (By similarity). Interacts with GFRAL; ligand of GFRAL which mediates GDF15 internalization and cellular signaling through interaction with RET (By similarity).
Regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses. Binds to its receptor, GFRAL, and activates GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem. 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 (Probable). On hepatocytes, inhibits growth hormone signaling (By similarity).
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. 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. The complex binds a box H/ACA small nucleolar RNA (snoRNA), which may target the specific site of modification within the RNA substrate. 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. 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. 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). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1.
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 (By similarity).
Belongs to the eukaryotic RPC7 RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex.
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.
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. Participates in the U6 snRNA 3' end processing that prevents U6 snRNA degradation. In addition also removes uridines from the 3' end of U6atac snRNA and possibly the vault RNA VTRNA1-1.
Belongs to the 2H phosphoesterase superfamily. USB1 family.
Expressed at low levels in the brain in early embryonic stages. Levels increase to a maximum before or just after birth, and are lower in adult brain (PubMed:1768439). At 16 dpc intensely expressed in the matrix of the developing cartilage and persists in the matrix of the mineralized cartilage at 20 dpc (at protein level). Localized within the unmineralized cartilage matrix (at mRNA level) (PubMed:9817766).
Expressed in brain (PubMed:2170351). Hardly expressed in bone. Abundantly expressed in the growth plate. Intensely expressed in the cartilage matrix that forms the hollow for the secondary ossification center. Is expressed selectively by the osteocytes of the lamellar bone, whereas it is hardly expressed by those of the woven bone. Is detected in the matrix surrounding the osteocytes and in the canaliculi of the osteocytes. Is distributed on the surface of lamellar bone (PubMed:9817766).
Interacts with ALK and NEK6 (By similarity). Interacts with PTPRZ1 (via chondroitin sulfate groups); promotes formation of homooligomers; oligomerization impairs tyrosine phosphatase activity (PubMed:16814777). Forms a complex with PTPRZ1 and CTNNB1; this complex inactivates PTPRZ1 protein tyrosine phosphatase activity through PTN interaction and stimulates tyrosine phosphorylation of CTNNB1. Interacts with ITGB3 and ITGA5. Forms a complex with PTPRZ1 and integrin alpha-V/beta-3 (ITGAV:ITGB3) that stimulates endothelial cell migration through ITGB3 'Tyr-773' phosphorylation (By similarity). 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 (PubMed:8175719, PubMed:9817766). 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 (PubMed:27671118).
Secreted growth factor that mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors (PubMed:16814777, PubMed:27671118, PubMed:9817766). Binds cell-surface proteoglycan receptor via their chondroitin sulfate (CS) groups (By similarity). Thereby regulates many processes like cell proliferation, cell survival, cell growth, cell differentiation and cell migration in several tissues namely neuron and bone (PubMed:27671118, PubMed:9817766). 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 or AFAP1L2 in order to activate the PI3K-AKT pathway (PubMed:16814777). Through PTPRZ1 binding, regulates endothelial cell migration and controls oligodendrocyte precursor cell differentiation (By similarity). 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 (By similarity). 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 (PubMed:27671118). Binds SDC3 and mediates bone formation by recruiting and attaching osteoblasts/osteoblast precursors to the sites for new bone deposition (PubMed:9817766). Binds ALK and promotes cell survival and cell proliferation through MAPK pathway activation (By similarity). 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).
Chaperone protein which promotes assembly of the 20S proteasome as part of a heterodimer with PSMG1.
Belongs to the HAD-like hydrolase superfamily. NANP family.
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.
Autophosphorylated, leading to regulate its activity. Leptin promotes phosphorylation on tyrosine residues, including phosphorylation on Tyr-813. Autophosphorylation on Tyr-119 in response to EPO down-regulates its kinase activity. Autophosphorylation on Tyr-868, Tyr-966 and Tyr-972 in response to growth hormone (GH) are required for maximal kinase activity. Also phosphorylated by TEC (By similarity). Phosphorylated on tyrosine residues in response to interferon gamma signaling. Phosphorylated on tyrosine residues in response to a signaling cascade that is activated by increased cellular retinol (By similarity).
Belongs to the protein kinase superfamily. Tyr protein kinase family. JAK subfamily.
Interacts with IL23R, SKB1 and STAM2 (By similarity). Interacts with EPOR. Interacts with LYN. Interacts with SIRPA. Interacts with SH2B1. Interacts with TEC (By similarity). Interacts with IFNGR2 (via intracellular domain) (By similarity). Interacts with LEPR (Isoform B) (By similarity). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner. Interacts with STRA6 (By similarity). Interacts with ASB2; the interaction targets JAK2 for Notch-induced proteasomal degradation (By similarity).
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. 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, 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). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. 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.
Regulated by autophosphorylation, can both activate or decrease activity. Heme regulates its activity by enhancing the phosphorylation on Tyr-1007 and Tyr-1008.
The N-terminal domain of JAKs mediates their interaction with cytokine/interferon/growth hormone receptors. 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).
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.
ATP-binding RNA helicase which 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. 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.
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 (By similarity). Interacts with IFIT1 and IFIT2 (By similarity). Interacts with BZW2/5MP1 (By similarity).
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. Required for nonsense-mediated mRNA decay (NMD); may act in conjunction with UPF2 to divert mRNAs from translation to the NMD pathway. May interact with MCM7 and EPAS1 and regulate the proteasome-mediated degradation of these proteins.
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. 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 (PubMed:22632720). Interacts with intersectin 1/ITSN1 (PubMed:26797119). Interacts with SNARE complex components, including SNAP25, STX1A, SYT1 and SYT2; this interaction may inhibit SNARE complex formation (By similarity).
Neuron-specific expression throughout the brain, including hippocampus (at protein level).
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity), preferentially releasing fatty acyl groups with a low degree of unsaturation such as oleoyl (C18:1) and linoleoyl (C18:2) groups (By similarity). Hydrolyzes low-density lipoprotein (LDL) phospholipids releasing unsaturated fatty acids that drive macrophage polarization toward an M2 phenotype (By similarity). May act in an autocrine and paracrine manner. Contributes to lipid remodeling of cellular membranes at different subcellular locations and generation of lipid mediators involved in pathogen clearance. Cleaves sn-2 fatty acyl chains of cardiolipin, a major component of the inner membrane of mitochondria and bacterial membranes. Promotes phagocytosis of bacteria in macrophages through production of lysophosphatidylethanolamines. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane (By similarity). Promotes phagocytosis and killing of ingested fungi likely through controlling phagosome-lysosome fusion and phagosome maturation (By similarity). Plays a role in biosynthesis of cysteinyl leukotrienes (CysLTs) in myeloid cells. In eosinophils, triggers perinuclear arachidonate release and LTC4 synthesis in a PLA2G4A-independent way. In neutrophils, amplifies CysLTs biosynthesis initiated by PLA2G4A (By similarity). Promotes immune complex clearance in macrophages via stimulating synthesis of CysLTs, which act through CYSLTR1 to trigger phagocytosis. May regulate antigen processing in antigen-presenting cells. In pulmonary macrophages regulates IL33 production required for activation of group 2 innate lymphoid cells (By similarity). May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines (By similarity).
This enzyme lacks one of the seven disulfide bonds found in similar PA2 proteins.
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).
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. Has lipid phosphatase activity and inactivates lysophosphatidic acid in seminal plasma.
Belongs to the histidine acid phosphatase family.
Expressed in prostate epithelium. Also expressed in the pelvic nerve and sacral spinal cord. Localizes in peptidergic and non-peptidergic nociceptive (pain-sensing) neurons.
Homodimer; dimer formation is required for phosphatase activity.
In addition to its tyrosine phosphatase activity, also has ecto-5'-nucleotidase activity in dorsal root ganglion (DRG) neurons. Generates adenosine from AMP. This extracellular adenosine leads to a decrease in chronic pain by activating A1R in nociceptive neurons.
May interact with UPF2 (By similarity). Component of the small ribosomal subunit, ribosomal RNA processing complex (SSU RRP complex) (By similarity).
May play a role in mRNA degradation (By similarity). Endonuclease required for processing of 20S pre-rRNA precursor and biogenesis of 40S ribosomal subunits (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mL52 family.
Belongs to the integrin alpha chain family.
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.
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 (By similarity). 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 (By similarity). 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.
Homodimer. Interacts with ATG3 and ATG12. The complex, composed of ATG3 and ATG7, plays a role in the conjugation of ATG12 to ATG5. Forms intermediate conjugates with ATG8 family proteins such as GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, or GABARAPL1. Interacts with EP300 acetyltransferase and FOXO1 (By similarity).
The C-terminal part of the protein is essential for the dimerization and interaction with ATG3 and ATG12.
The N-terminal FAP motif (residues 11 to 13) is essential for the formation of the ATG89-PE and ATG5-ATG12 conjugates.
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 to the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
Interacts with 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 (By similarity). In association with BSCL2/seipin, defines the sites of LD formation in the endoplasmic reticulum (By similarity).
Component of some chromatin repressor complex. Interacts with SNAI1. Interacts with TAF10. Interacts with HSPA5. Interacts with EFEMP2 (By similarity).
Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine).
Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine). Acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation. 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). 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. LOXL2-mediated deamination of TAF10 results in transcriptional repression of genes required for embryonic stem cell pluripotency including POU5F1/OCT4, NANOG, KLF4 and SOX2. 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. During EMT, involved with SNAI1 in negatively regulating pericentromeric heterochromatin transcription. 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. 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. 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. Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding. Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation.
N-glycosylated. N-glycosylation on Asn-458 and Asn-646 may be essential for proper folding and secretion; may be composed of a fucosylated carbohydrates attached to a trimannose N-linked glycan core.
Specifically inhibited by a mouse monoclonal antibody AB0023, inhibition occurs in a non-competitive manner.
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.
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)) (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 purine/pyrimidine phosphoribosyltransferase family.
Binds 2 magnesium ions per subunit. The magnesium ions are essentially bound to the substrate and have few direct interactions with the protein.
Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate. Transfers the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate onto the purine. Plays a central role in the generation of purine nucleotides through the purine salvage pathway (By similarity).
Expression increases steadily during postnatal rat brain development.
Forms heteromeric complexes with LRFN2, LRFN4 and LRFN5; binding to LRFN2 and LRFN5 may be weaker than that to LRFN4. Also interacts with LRFN3 (By similarity). Forms homomeric complexes, but not across cell junctions (By similarity). Interacts with DLG1, DLG2 and DLG4, but not with MAGI2, not CASK. Interacts with DLG3 (By similarity). Interacts with 2 AMPA receptor subunits GRIA1 and GRIA2 and NMDA receptor subunit GRIN1.
Mainly expressed in brain (at protein level) and testis. In brain, found in cerebral cortex (including pyramidal neurons), hippocampus (including CA3 and CA1 neurons), dentate gyrus, cerebellum (including Purkinje neurons) (at protein level) (at protein level). Also expressed in the olfactory bulb.
Promotes neurite outgrowth in hippocampal neurons (By similarity). Involved in the regulation of the differentiation and maintenance of excitatory synapses. Induces the clustering of excitatory postsynaptic proteins, including DLG4, DLGAP1, GRIA1 and GRIN1.
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 calycin superfamily. Fatty-acid binding protein (FABP) family.
May play a role in lipid transport protein in Schwann cells. May bind cholesterol.
Specifically binds 5-hydroxymethylcytosine (5hmC), suggesting that it acts as a specific reader of 5hmC.
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.
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. Has a high affinity for both cAMP and cGMP (PubMed:7568196). 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 (By similarity).
Highly expressed in olfactory epithelium and at moderate levels, in cerebellum, as well as weakly in forebrain, testis, heart and lung (PubMed:7568196). In the olfactory epithelium, expressed by sensory neurons, but not epithelial cells (PubMed:7568196).
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.
Critical regulator of endosomal recycling of numerous surface proteins, including integrins, signaling receptor and channels. Binds to NPxY sequences in the cytoplasmic tails of target cargos. 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. Also required for maintenance of normal cell surface levels of APP and LRP1. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)).
Monomer (By similarity). Interacts with APP (via cytoplasmic YXNPXY motif). Interacts with KIF1B (By similarity). Interacts with the C-termini of P-selectin, PTC, LDLR, VLDLR, LRP1 and LRP8. Interacts with KRIT1 (via N-terminus). Interacts with HRAS. Interacts with ITGB1 and ITGB5 (via NPxY motif). Interacts with CCDC22, CCDC93, VPS26C and VPS35L; the interaction with VPS26C is direct and associates SNX17 with the retriever and CCC complexes (By similarity).
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.
Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily.
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 (By similarity).
Interacts with FYN (By similarity). Interacts with RALA (By similarity). Interacts with DGKQ (By similarity).
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.
The C1 domain, containing the phorbol ester/DAG-type region 1 (C1A) and 2 (C1B), is the diacylglycerol sensor and the C2 domain is a non-calcium binding domain.
Interacts with 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 thought to be a lin-10 homolog.
A connexon is composed of a hexamer of connexins.
Belongs to the connexin family. Beta-type (group I) 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.
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.
Belongs to the isocitrate and isopropylmalate dehydrogenases family.
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.
Expressed in brown adipose tissue (BAT).
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.
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.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RsmB/NOP family.
Expressed in developing nervous system and in highly plastic areas of the adult brain. Also expressed in neuroendocrine cells, where it concentrates at the tip of neurites. Expressed in developing muscle and is concentrated at the neuromuscular junction (NMS). SNTA1 can regulate its localization in the NMS.
Expressed in postmitotic neurons during the stage of development in which extensive axon pathfinding is occurring. At 14 dpc, expressed in both spinal cord and dorsal root ganglia. Present on the sarcolemma in postnstal day 1 (P1) gastrocnemius muscle. By P8, becomes more concentrated at the junctional sites and by P21, colocalizes with acetylcholine receptor clusters.
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 (PubMed:17724123). Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation (PubMed:17724123). Isoform 2 interacts (via C-terminal domain) with MAGI2 isoform 1 (via PDZ domain) (PubMed:17724123). Interacts with NTRK1, NTRK2, NTRK3, ERKL and NGFR (PubMed:11150334, PubMed:15167895, PubMed:15378608). Can form a ternary complex with NGFR and NTRK1 and this complex is affected by the expression levels of KIDINS220/ARMS (PubMed:15378608). An increase in KIDINS220/ARMS expression leads to a decreased association of NGFR and NTRK1 (PubMed:15378608). Interacts (via PDZ-binding motif) with SNTA1 and SNTB2 (via PDZ domains) (PubMed:15939763). Interacts with EPHA4 and PRKD1 (PubMed:10998417, PubMed:15939763).
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.
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).
Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C. Activated by inositol 1,4,5-triphosphate receptors (ITPR) with bound IP3. May be activated by internal calcium store depletion. Inhibited by intracellular Ca(2+).
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC3 sub-subfamily.
Forms a receptor-activated non-selective calcium permeant cation channel. May be operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors.
Homotetramer. Interacts with ITPR1, ITPR3, MX1 and RNF24. Interacts with JPH2; the interaction is involved in maintaining Ca(2+) homeostasis in skeletal muscle and is mediated by JPH2 'Ser-165' phosphorylation.
The cytoplasmic portion of the protein is required for channel assembly and gating.
Belongs to the somatotropin/prolactin family.
Expressed in mast cells (at protein level).
Homodimer (By similarity). Interacts with FYN (By similarity). Interacts with PTPRC (By similarity). Interacts with GRB2 when phosphorylated on Tyr-267 (By similarity). Interacts with FYB1, which is required for SKAP2 protein stability (By similarity). Interacts with FYB1, which is required for SKAP2 protein stability (By similarity). Part of a complex consisting of SKAP1, FYB1 and CLNK (PubMed:12681493). Interacts with RASGRP1 (By similarity). Interacts with FYB2 (By similarity).
Phosphorylated on tyrosines. Phosphorylation by FYN on Tyr-267 is required for GRB2 interaction (By similarity). Phosphorylation by FYN on Tyr-290 abolishes interaction with FYB1. Tyr-236 is dephosphorylated by PTPRC (By similarity).
Positively regulates T-cell receptor signaling by enhancing the MAP kinase pathway (By similarity). Required for optimal conjugation between T-cells and antigen-presenting cells by promoting the clustering of integrin ITGAL on the surface of T-cells (By similarity). May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells (PubMed:12681493).
Belongs to the protein disulfide isomerase family.
Belongs to the protein kinase superfamily.
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.
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).
Detected in adult heart, kidney, skin and cochlea, where it is detected in spiral ganglion, stria vascularis, spiral limbus and spiral ligament (at protein level).
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).
Forms homodimers or heterodimers with ARFIP2. Interacts with non-myristoylated GTP-bound ARF3, but not to GDP-bound ARF3. Interacts with ARF1. Binds with lower affinity to ARF5 and with very little affinity to ARF6. Interacts with ARL1. Interacts with ATG9A.
Plays a role in controlling biogenesis of secretory granules at the trans-Golgi network. Mechanisitically, binds ARF-GTP at the neck of a growing secretory granule precursor and forms a protective scaffold. Once the granule precursor has been completely loaded, active PRKD1 phosphorylates ARFIP1 and releases it from ARFs. In turn, ARFs induce fission. Through this mechanism, ensures proper secretory granule formation at the Golgi of pancreatic beta cells.
Binding to PMPCA is required for catalytic activity.
Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins (PubMed:12433926) (Probable). Preferentially, cleaves after an arginine at position P2 (PubMed:12433926). Required for PINK1 turnover by coupling PINK1 mitochondrial import and cleavage, which results in subsequent PINK1 proteolysis (PubMed:22354088).
Heterodimer of PMPCA (alpha) and PMPCB (beta) subunits, forming the mitochondrial processing protease (MPP) in which PMPCA is involved in substrate recognition and binding and PMPCB is the catalytic subunit.
Belongs to the synaptophysin/synaptobrevin family.
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.
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.
Belongs to the SLC12A transporter family.
Detected in thalamus, but not in hippocampus and neocortex at 20 dpc. At birth barely detectable in hippocampus. Expression increases steeply from day 5 to day 9 and then stabilizes at adult levels.
Highly expressed in brain. Not detected in other tissues. Highly expressed in pyramidal neurons and in neurons throughout the cortex, hippocampus, the granular layer of the cerebellum and in groups of neurons throughout the brainstem. Barely detectable in dorsal-root ganglions.
Homomultimer and heteromultimer with other K-Cl cotransporters (Probable). Interacts with AP2A1 (By similarity).
Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis (PubMed:11551954). 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 (PubMed:9930699). Involved in the regulation of dendritic spine formation and maturation (PubMed:22345354).
Belongs to the protein-tyrosine phosphatase family. Non-receptor class dual specificity subfamily.
Interacts with NRAP. Part of a complex that contains CUL3, RBX1 and KLHL41. Interacts with LASP1.
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.
Primarily expressed in skeletal muscle. Also found in heart and lung.
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 transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM2 sub-subfamily.
Detected in pancreas beta-cells (PubMed:16601673). Detected in fetal brain cortex neurons (at protein level) (PubMed:16651700).
Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels (PubMed:16651700, PubMed:16260005, PubMed:11804595, PubMed:16601673, PubMed:19454650). Functions as ligand-gated ion channel. 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. Extracellular calcium passes through the channel and increases channel activity (By similarity). Also 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). 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:16260005, PubMed:16601673, PubMed:25562606). The precise physiological activators are under debate; the true, physiological activators may be ADP-ribose and ADP-ribose-2'-phosphate. Activation by ADP-ribose and beta-NAD is strongly increased by moderate heat (35 to 40 degrees Celsius) (By similarity). Likewise, reactive oxygen species lower the threshold for activation by moderate heat (37 degrees Celsius). 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 (PubMed:16601673). 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 function in increasing cytoplasmic Ca(2+) and Zn(2+) levels (By similarity). Confers susceptibility to cell death following oxidative stress (PubMed:16651700, PubMed:11804595, PubMed:19454650, PubMed:25562606).
The cytosolic nudix box binds ADP-ribose and is required for channel activation by ADP-ribose.
Belongs to the myelin proteolipid protein family.
By hypercapnic stimulation (CO2 inhalation) in ventral medullary surface neurons but not in the cerebral cortex.
Highly expressed in the ventral medullary surface, moderately in the cerebral cortex and cerebellum, poorly in lung and kidney, and not at all in heart, skeletal muscle, liver, stomach or stomach.
In the developing brain, expression begins by at least embryonic day 20, increases gradually through postnatal day 2 and day 50 and decreases by postnatal day 300.
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.
Required for biogenesis of the 60S ribosomal subunit.
Expressed as a 3.0 kb transcript, in whole brain, hippocampus, striatum, frontal cortex, thalamus, pons and hypothalamus. A lower molecular weight transcript was detected in all regions examined, except the hypothalamus.
Orphan receptor. Possible candidate for amine-like G-protein coupled receptor (By similarity).
Belongs to the eukaryotic RPB4 RNA polymerase subunit family.
Belongs to the DOK family. Type A subfamily.
Constitutively tyrosine-phosphorylated (By similarity). Phosphorylated by TEC. Phosphorylated by LYN (By similarity). Phosphorylated on tyrosine residues by the insulin receptor kinase. Results in the negative regulation of the insulin signaling pathway (By similarity). Phosphorylated on tyrosine residues by SRMS (By similarity).
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 (By similarity).
Interacts with RasGAP and INPP5D/SHIP1. Interacts directly with phosphorylated ITGB3 (By similarity). Interacts with SRMS (via the SH2 and SH3 domains) (By similarity).
The PTB domain mediates receptor interaction.
In the C-terminal section; belongs to the formate--tetrahydrofolate ligase family.
In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
Constitutes the precursor of the Nlrp1a 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.
Interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) in absence of pathogens and other damage-associated signals.
Interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus) in absence of pathogens and other damage-associated signals (By similarity). Homomultimer; forms the Nlrp1a inflammasome polymeric complex, a filament composed of homopolymers of this form in response to pathogens and other damage-associated signals (By similarity). The Nlrp1a inflammasome polymeric complex directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC (By similarity). Interacts (via CARD domain) with CASP1 (via CARD domain); leading to CASP1 activation.
Regulatory part that prevents formation of the Nlrp1a inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), preventing activation of the Nlrp1a inflammasome. 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 Nlrp1a inflammasome.
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. 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.
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.
Belongs to the small GTPase superfamily. Arf family.
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.
Belongs to the actin-binding proteins ADF family.
Monomer, and homodimer. Interacts (via BIR3 domain) with DIABLO/SMAC; the interaction inhibits apoptotic suppressor activity (By similarity). Interacts with HTRA2/PRSS25; the interaction inhibits apoptotic suppressor activity. Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with DIABLO/SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts (via BIR3 domain) with SEPTIN4 (By similarity). Interacts with RIP1, RIP2, RIP3, RIP4, CCS and USP19. Interacts (via BIR 2 domain and BIR 3 domain) with HAX1 (via C-terminus) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with the monomeric form of BIRC5/survivin (By similarity). Interacts with TLE3 and TCF7L2/TCF4 (By similarity). Interacts (via BIR 3 and RING domains) with PDCL3 (By similarity).
Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitination of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitination of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinating COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nod-like receptors (NLRs). 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. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program (By similarity).
S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity.
The first BIR domain is involved in interaction with TAB1/MAP3K7IP1 and is important for dimerization. The second BIR domain is sufficient to inhibit caspase-3 and caspase-7, while the third BIR is involved in caspase-9 inhibition. The interactions with DIABLO/SMAC and HTRA2/PRSS25 are mediated by the second and third BIR domains (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 (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.
Interacts with the ligand binding domain of the thyroid receptor (TR) (in vitro). Requires the presence of thyroid hormone for its interaction. Interacts with transcriptional regulator SEHBP. Interacts with nucleosomes.
Expressed at low levels in the developing embryo (PubMed:10051670). Expressed at high levels in the lung and adult central nervous system, including the dorsal root ganglia (PubMed:10051670).
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 (PubMed:21945643). Has growth cone collapse activity against retinal ganglion-cell axons (PubMed:10051670).
Functions as an adapter recruiting ubiquitin-protein ligases to their specific substrates. Through an ubiquitination-dependent mechanism plays for instance a role in the incorporation of SLC11A2 into extracellular vesicles. More generally, plays a role in the extracellular transport of proteins between cells through the release in the extracellular space of microvesicles. By participating in the ITCH-mediated ubiquitination and subsequent degradation of NOTCH1, negatively regulates the NOTCH signaling pathway.
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 (By similarity). Interacts with ARRB1 and ARRB2; the interaction is direct (PubMed:23886940). Interacts with TSG101; may recruit TSG101 to the plasma membrane. Interacts (via PPxY motifs) with WWP2 (via WW domains); ubiquitinates ARRDC1. Interacts with SLC11A2; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism. Interacts with WWP1 (via WW domains). Interacts with NEDD4 (via WW domains). Interacts with PDCD6IP (By similarity).
The PPxY motifs mediate interaction with WW domain-containing ubiquitin-protein ligases.
Ubiquitinated. Ubiquitination by WWP2; promotes localization to extracellular microvesicles. Ubiquitinated by WWP1.
Belongs to the alpha/beta interferon family.
Belongs to the HAD-like hydrolase superfamily.
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).
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.
Expressed in astrocytes and glioma cells.
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. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis. Adapter for a subset of ESCRT-III proteins, such as CHMP4, to function at distinct membranes. Required for completion of cytokinesis. May play a role in the regulation of both apoptosis and cell proliferation. Regulates exosome biogenesis in concert with SDC1/4 and SDCBP (By similarity). 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 (By similarity). Interacts with SH3KBP1 (PubMed:10858458). Interacts with PDCD6 in a calcium-dependent manner (By similarity). Interacts with TSG101 in a calcium-dependent manner; PDCD6IP homooligomerization may be required for TSG101-binding (By similarity). Interacts with SGSM3 (By similarity). Directly interacts with CHMP4A, CHMP4B and CHMP4C (By similarity). Directly interacts with CEP55 in a 1:2 stoechiometry; this interaction is required for PDCD6IP targeting to the midbody (By similarity). May interact with PDGFRB (By similarity). Interacts with SH3GL1 and SH3GL2/endophilin-1 (By similarity). Forms a complex with SDCBP and SDC2 (By similarity). Found in a complex with F-actin, TJP1/ZO-1 and PARD3 (By similarity). Interacts with CD2AP (By similarity). Interacts with ARRDC1 (By similarity).
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.
Apoptosis regulator that functions through different apoptotic signaling pathways (PubMed:9356461, PubMed:9804769). 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 (By similarity). 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 (By similarity). In response to DNA damage, mediates intrinsic apoptotic process in a TP53-dependent manner. Plays a role in granulosa cell apoptosis by CASP3 activation (By similarity). 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. May also play a role as an inducer of autophagy by disrupting interaction between MCL1 and BECN1 (By similarity).
BH4 domain mediates interaction with ITPR1.
Isoform 1: Honomer; positively regulates apoptotic process. Homodimer (By similarity). Heterodimer (PubMed:9804769). Oligomer; promoted by apoptotic stimuli and BH3-only proteins; mediates constitutive activation. 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. 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. Interacts with BNIP3; promotes oligomerization (By similarity). Isoform 2: Does not heterodimerize with antiapoptotic Bcl-2 proteins (PubMed:9804769).
Positively regulates apoptotic process in an heterodimerization-independent manner with antiapoptotic Bcl-2 proteins.
Ubiquitinated by AMFR/gp78 E3 ubiquitin ligase complex; mediates degradation by ubiquitin-proteasome pathway in a VCP/p97-dependent manner; prevents from proapoptotic activity; promotes degradation of newly synthesized proteins that are not ITPR1 associated.
Belongs to the pancreatic ribonuclease family.
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 (By similarity).
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).
The synthesis of this protein in the absorptive cells of the rat duodenum is vitamin D3-dependent.
Was originally thought to originate from chick.
Ligand for members of the frizzled family of seven transmembrane receptors.
Interacts with the mTORC1 complex; this interaction mediates the recruitment of mTORC1 to the lysosome and its subsequent activation.
Symporter that selectively cotransports sodium ions and amino acids, such as L-glutamine and L-asparagine from the lysosome into the cytoplasm and may participates in mTORC1 activation. The transport activity requires an acidic lysosomal lumen.
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. 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).
A polymorphism exists that is responsible for the nonagouti phenotype, characterized by a plain black coat on the back and belly. This is due to a 19-bp deletion resulting in a frameshift at position 36 and a premature stop codon at position 48.
Both strain WKAH (agouti) and strain BN (nonagouti) contain a substitution at the splice donor site of intron 3, resulting in a shorter isoform lacking exon 3 which causes reduced expression levels in strain WKAH and almost undetectable levels in strain BN.
Involved in the regulation of melanogenesis. The binding of ASP to MC1R precludes alpha-MSH initiated signaling and thus blocks production of cAMP, leading to a down-regulation of eumelanogenesis (brown/black pigment) and thus increasing synthesis of pheomelanin (yellow/red pigment).
The presence of a 'disulfide through disulfide knot' structurally defines this protein as a knottin.
Detected in heart, brain, lung, liver, skeletal muscle, kidney, pituitary and testis.
Hydrolyzes the phosphodiester bond of glycerophosphodiesters such as glycerophosphoinositol (GroPIns) and glycerophosphoethanolamine (GroPEth), to yield a glycerol phosphate and an alcohol (PubMed:12576545). 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 (PubMed:12576545).
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 (PubMed:12576545).
Interacts with PRAF2 (By similarity). Interacts with RGS16 (PubMed:10760272).
Belongs to the snRNP Sm proteins family.
Binds specifically to the 3'-terminal U-tract of U6 snRNA.
LSm subunits form a heteromer with a doughnut shape.
Belongs to the ubiquitin family. SUMO subfamily.
Cleavage of precursor form by SENP1 or SENP2 is necessary for function.
Covalently attached to KCNB1; UBE2I increases cross-linking with KCNB1 and PIAS1 decreases cross-links with KCNB1 (By similarity). Interacts with SAE2, RANBP2, PIAS1 and PIAS2 (By similarity). Interacts with PRKN (PubMed:16955485). Covalently attached to a number of proteins such as IKFZ1, PML, RANGAP1, HIPK2, SP100, p53, p73-alpha, MDM2, JUN, DNMT3B and TDG (By similarity). Also interacts with HIF1A, HIPK2, HIPK3, CHD3, EXOSC9, RAD51 and RAD52 (By similarity). Interacts with USP25 (via ts SIM domain); the interaction weakly sumoylates USP25 (By similarity). Interacts with SIMC1, CASP8AP2, RNF111 and SOBP (via SIM domains) (By similarity). Interacts with BHLHE40/DEC1 (By similarity). Interacts with RWDD3 (By similarity). Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3 (By similarity). Interacts with MTA1 (By similarity). Interacts with SENP2 (By similarity). Interacts with HINT1 (By similarity).
Polymeric SUMO1 chains undergo polyubiquitination by RNF4.
Ubiquitin-like protein that can be covalently attached to proteins as a monomer or a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by E3 ligases such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Involved for instance in targeting RANGAP1 to the nuclear pore complex protein RANBP2. Covalently attached to the voltage-gated potassium channel KCNB1; this modulates the gating characteristics of KCNB1. Polymeric SUMO1 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. May also regulate a network of genes involved in palate development. Covalently attached to ZFHX3.
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 PCDH8; this complex may also include TAOK2 (PubMed:17988630). The interaction with PCDH8 may lead to internalization through TAOK2/p38 MAPK pathway (PubMed:17988630). 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).
In testis, expressed in Sertoli and germ cells.
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.
Besides being a 3-alpha-hydroxysteroid dehydrogenase, the enzyme can accomplish diverse functions: as quinone reductase, as an aromatic alcohol dehydrogenase, as dihydrodiol dehydrogenase, and as 9-, 11-, and 15-hydroxyprostaglandin dehydrogenase.
In brain, highest levels found in olfactory bulb. Moderate levels present in cerebellum, cerebral cortex, hypothalamus and pituitary. Low levels present in amygdala, brain stem, caudate putamen, cingulate cortex, hippocampus, midbrain, and thalamus.
Potently inhibited by the nonsteroidal anti-inflammatory drugs (NSAID).
Alpha-helical parts of the C-terminal intracellular region mediate heterodimeric interaction with GABA-B receptor 1.
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872315, PubMed:9872317, PubMed:9872744). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:9872317, PubMed:10658574). 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:9872315, PubMed:9872317, Ref.4, PubMed:10075644, PubMed:9872744, PubMed:10924501). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:9872315, PubMed:9872317, PubMed:10457184, PubMed:9872744, PubMed:10924501). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872317, PubMed:10457184, PubMed:9872744). 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:9872744, PubMed:10924501). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (By similarity).
Heterodimer of GABBR1 and GABBR2 (PubMed:9872315, PubMed:9872317, PubMed:9872744). Homodimers may form, but are inactive (PubMed:9872317). Interacts (via C-terminus) with ATF4 (via leucine zipper domain) (PubMed:10924501).
Highly expressed in areas of the brain including thalamic nuclei, the hippocampus, cerebellar Purkinje cells and the medial habenula, and moderately expressed in the cerebral cortex, certain anterioventral thalamic nuclei, dorsal medial hypothalamic nucleus and suprachiasmatic nuclei (PubMed:9872315, PubMed:9872317, PubMed:10727622, PubMed:9872744). Also weakly expressed in the testis (PubMed:9872744).
On the day of birth, expressed in the regions of the brain including hippocampus, thalamic nuclei and cortex (PubMed:9872744). Abundant in brain cortex and cerebellum throughout postnatal development whereas its expression in spinal cord gradually decreases (PubMed:9872317).
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.
Belongs to the chondroitin N-acetylgalactosaminyltransferase family.
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 (By similarity). 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 (By similarity).
Palmitoylated (PubMed:23687301). Probably palmitoylated by ZDHHC3 and ZDHHC7 (PubMed:23687301).
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. Thought to stabilize the calcium channel in an inactivated (closed) state.
Belongs to the calcium channel subunit alpha-2/delta family.
Detected in bone osteoblasts (at protein level).
Interacts with the cAMP-dependent protein kinase (PKA) holoenzyme and with the regulatory subunit PRKAR2A (PubMed:11696353). Interacts with RHOA (PubMed:11696353). Interacts also with RHOB and RHOC. Identified in a ternary complex with RHOA and PRKAR2A. Identified in a complex with NR3C1 and RHOA. Interacts with BRAF and KSR1. Identified in a complex with BRAF and KSR1 (By similarity). Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3 (PubMed:23716597). Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (By similarity). Interacts (phosphorylated form) with YWHAB and YWHAZ. Interaction with YWHAB inhibits activation of RHOA, interferes with PKN1 binding and activation of MAP kinases. Interacts with GNA12. Interacts with IKBKB (PubMed:23090968). Interacts with ESR1, THRA, PPARA and NME2 (By similarity). 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:17537920). May also activate other Rho family members. 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). 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 (By similarity). Part of a signaling cascade that stimulates MEF2C-dependent gene expression in response to lysophosphatidic acid (LPA) (PubMed:20139090). Part of a signaling pathway that activates MAPK11 and/or MAPK14 and leads to increased transcription activation of the estrogen receptors ESR1 and ESR2 (By similarity). 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 (By similarity). 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 (By similarity). 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). Required for normal adaptive cardiac hypertrophy in response to pressure overload (By similarity). 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. Forms that lack C-terminal regulatory domains have transforming activity and function as oncogenes.
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).
Up-regulated in cardiomyocytes in response to phenylephrine (in vitro).
Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.
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 ATPase alpha/beta chains family.
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:32165585). 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:32165585). 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).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:32165585). 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:32165585). 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:32165585).
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.
Belongs to the eukaryotic/archaeal RNase P protein component 2 family.
Growth factor that controls proliferation and cellular differentiation in the retina and bone formation. Plays a key role in regulating apoptosis during retinal development. Establishes dorsal-ventral positional information in the retina and controls the formation of the retinotectal map. Required for normal formation of bones and joints in the limbs, skull, digits and axial skeleton. Plays a key role in establishing boundaries between skeletal elements during development. Regulation of GDF6 expression seems to be a mechanism for evolving species-specific changes in skeletal structures. Seems to positively regulate differentiation of chondrogenic tissue through the growth factor receptors subunits BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the activation of SMAD1-SMAD5-SMAD8 complex. The regulation of chondrogenic differentiation is inhibited by NOG. Also involved in the induction of adipogenesis from mesenchymal stem cells. This mechanism acts through the growth factor receptors subunits BMPR1A, BMPR2 and ACVR2A and the activation of SMAD1-SMAD5-SMAD8 complex and MAPK14/p38.
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. 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. 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. Upon acute inflammation, inhibits oxidation of low-density lipoprotein particles by MPO and limits vascular damage. 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. Importantly, counteracts the oxidative damage at blood-placenta interface, preventing leakage of free fetal hemoglobin into the maternal circulation. 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. 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 (By similarity). 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.
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. Interacts with TNFAIP6 (via Link domain).
In the N-terminal section; belongs to the calycin superfamily. Lipocalin family.
Kunitz-type serine protease inhibitor and structural component of extracellular matrix with a role in extracellular space remodeling and cell adhesion. 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. 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 (By similarity). 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 (By similarity).
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. Also occurs as a complex with tryptase in mast cells.
Monomer. Homodimer. In plasma, it occurs as a monomer or dimer and in covalently-linked complexes with immunoglobulin A (IgA), ALB/albumin and F2/prothrombin. Chromophore-bound alpha-1-microglobulin interacts with the constant region of immunoglobulin A. 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. 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. Interacts with NDUFAB1, a subunit of mitochondrial complex I (By similarity). Interacts with FN1 (PubMed:7519849).
Proteolytically cleaved by PRSS3 at Kunitz domain 2.
The Kunitz domains 1 and 2 serve as protease inhibitor domains.
The precursor is proteolytically processed into separately functioning proteins.
Cytotoxin and helminthotoxin. MBP also induces non-cytolytic histamine release from basophils. It is involved in antiparasitic defense mechanisms and immune hypersensitivity reactions (By similarity).
Belongs to the acyl carrier protein (ACP) family.
Carrier of the growing fatty acid chain in fatty acid biosynthesis.
Interacts with M-Ras/MRAS, and RAF1. Forms a multiprotein complex with Ras (M-Ras/MRAS), Raf (RAF1) and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC). Interacts with ERBIN; disrupts the interaction with RAF1 and Ras, leading to prevent activation of the Ras signaling pathway. Specifically binds K-Ras/KRAS, M-Ras/MRAS and N-Ras/NRAS but not H-Ras/HRAS. Interacts with LZTR1.
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.
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. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. 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. Essential for the migration but not the maturation of dendritic cells (By similarity). Plays a role in keratinocyte differentiation (By similarity).
Gating is voltage-dependent and repressed by decavanadate. Calmodulin-binding confers the Ca(2+) sensitivity. ATP is able to restore Ca(2+) sensitivity after desensitization. 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. Activity is also enhanced by 3,5-bis(trifluoromethyl)pyrazole derivative (BTP2) (By similarity).
Isoform 1 is highly expressed in the testis with a moderate expression in the brain, spleen and thymus. Isoform 2 is only expressed in the brain and spleen.
Phosphorylation by PKC leads to increase the sensitivity to Ca(2+).
Belongs to the CorA metal ion transporter (MIT) (TC 1.A.35) family.
Magnesium transporter that mediates the influx of magnesium into the mitochondrial matrix. Required for normal expression of the mitochondrial respiratory complex I subunits.
Expressed in cerebral cortex, hippocampus, olfactory tubercle and striatum.
Homodimers. Interacts with NDE1 and NDEL1 (By similarity). Interacts with DISC1 (PubMed:17389905). Interacts with PARP1 (By similarity).
Involved in the positive regulation of oligodendrocyte differentiation during postnatal growth (PubMed:24481677). Involved in the morphogenesis of basket cells in the somatosensory cortex during embryogenesis. Involved in dendritic arborization, morphogenesis of spine density dendrite, and establishment of postsynaptic dendrite density in cortical pyramidal neurons (By similarity). Involved in the regulation of neurogenesis. Negatively regulates neurite outgrowth. 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. Contributes to genomic stability by preventing telomere dysfunction (By similarity).
Interacts with PDZ domains of SCRIB, with VASP 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. Also suggested to serve as a scaffold protein upon which distinct protein complexes are assembled in the cytoplasm and in the nucleus (By similarity).
Interacts with ERBB2 phosphorylated on 'Tyr-1250'.
May control cell migration by relaying extracellular chemotactic signals to the microtubule cytoskeleton. Mediator of ERBB2 signaling. 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 (By similarity).
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.
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.
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.
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.
Belongs to the multicopper oxidase family.
Belongs to the diacylglycerol acyltransferase family.
Activated by autocatalytic processing at pH 4.
Detected in kidney cortex (at protein level).
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. May be involved in the processing of proteins for MHC class II antigen presentation in the lysosomal/endosomal system (By similarity).
In the zymogen form, the uncleaved propeptide blocks access to the active site.
Monomer after autocatalytic processing. Homodimer before autocatalytic removal of the propeptide. May interact with integrins (By similarity).
Belongs to the zinc-containing alcohol dehydrogenase family. Quinone oxidoreductase subfamily.
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 and enhances their stability. NADPH binding interferes with mRNA binding (By similarity).
Belongs to the class-II 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:6315704). When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages (By similarity). Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity (PubMed:3988754, PubMed:2995387, PubMed:19524539).
Homodimer (By similarity). Part of the multisynthetase complex (MSC), a multisubunit complex that groups tRNA ligases for Arg (RARS), Asp (DARS), Gln (QARS), Ile (IARS), Leu (LARS), Lys (KARS), Met (MARS) the bifunctional ligase for Glu and Pro (EPRS) and the auxiliary subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:3988754, PubMed:2995387, PubMed:19524539). Interacts with AIMP2 (via N-terminus) and MITF (PubMed:23159739). Interacts with TARSL2 (By similarity).
It is likely that the same gene provides both this cytoplasmic isoform and an additional mitochondrial isoform.
Phosphorylated on a serine residue after mast cell stimulation with immunoglobulin E (IgE).
The N-terminal domain (1-65) is a functional tRNA-binding domain and is involved in the interaction with DARS, but has a repulsive role in the binding to EEF1A1. A central domain (208-259) is involved in homodimerization. The C-terminal domain (452-597) is not required for interaction with AIMP2 (By similarity).
Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.
Interacts with CBL and EPHB1. Interacts with FYN; this interaction takes place in a ligand-independent manner (By similarity).
Kinase-defective receptor for members of the ephrin-B family. Binds to ephrin-B1 and ephrin-B2. Modulates cell adhesion and migration by exerting both positive and negative effects upon stimulation with ephrin-B2. Inhibits JNK activation, T-cell receptor-induced IL-2 secretion and CD25 expression upon stimulation with ephrin-B2 (By similarity).
Ligand-binding increases phosphorylation on tyrosine residues. Phosphorylation on tyrosine residues is mediated by transphosphorylation by the catalytically active EPHB1 in a ligand-independent manner. Tyrosine phosphorylation of the receptor may act as a switch on the functional transition from cell adhesion/attraction to de-adhesion/repulsion (By similarity).
The protein kinase domain is predicted to be catalytically inactive. Its extracellular domain is capable of promoting cell adhesion and migration in response to low concentrations of ephrin-B2, but its cytoplasmic domain is essential for cell repulsion and inhibition of migration induced by high concentrations of ephrin-B2 (By similarity).
In the C-terminal section; belongs to the peptidase M41 family.
In the N-terminal section; belongs to the AAA ATPase family.
Belongs to the cyclic nucleotide phosphodiesterase family.
Composed of a C-terminal catalytic domain containing two divalent metal sites and an N-terminal regulatory domain which contains one cyclic nucleotide-binding region.
Detected in striatum and testis (at protein level). Detected in whole brain, hippocampus, olfactory bulb, striatum neurons and testis.
Inhibited by dipyridamole and moderately by IBMX, zaprinast and rolipram.
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.
The tandem GAF domains bind cAMP, and regulate enzyme activity. The binding of cAMP stimulates enzyme activity.
Up-regulated in brain after seizures. Up-regulated in the hippocampus one hour after induction of long-term potentiation.
Belongs to the SEC23/SEC24 family. SEC23 subfamily.
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.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE2 subfamily.
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 (By similarity). Specifically inhibited by Bay 60-7550. When repressed, protected from ionomycin- but not staurosporin-induced cell death.
The GAF 1 domain functions as a dimerization domain.
The GAF 2 domains binds cGMP, which acts as an allosteric activator.
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. Has a higher efficiency with cGMP compared to cAMP (By similarity). Plays a role in cell growth and migration (By similarity).
Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis.
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.
The HXXXXD motif is essential for acyltransferase activity and may constitute the binding site for the phosphate moiety of the glycerol-3-phosphate.
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).
Expressed in the digestive tract, where it was found predominantly in the stomach with highest expression in the antrum. It is secreted predominantly from antral mucous cells into the lumen of the gastrointestinal tract.
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.
Inhibits programmed -1 ribosomal frameshifting (-1PRF) of a variety of mRNAs from viruses and cellular genes. Interacts with the -1PRF signal of target mRNA and translating ribosomes and causes premature translation termination at the frameshifting site. May exhibit antiviral activity.
Interacts with PABPC1. Found in a complex with PABPC1 and LARP1. Interacts with ELAV1, MOV10 and UPF1; the interactions increase in presence of RNA. Binds to ribosomes. Interacts with GSPT1.
Heterodimer with RXRA (By similarity). Interacts with NCOA1 (By similarity). Interacts (via domain NR LBD) with CRY1 and CRY2 in a ligand-dependent manner (By similarity).
Nuclear receptor that binds and is activated by a variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, endogenous compounds and drugs. Response to specific ligands is species-specific, due to differences in the ligand-binding domain. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes (By similarity).
Belongs to the myo-inositol 1-phosphate synthase family.
Competitively inhibits the function of isoform 1, presumably by competing for NAD cofactor.
Expressed in intestine (at protein level).
Expressed in intestine, lung, liver, muscle, testis, spleen, brainstem, hippocampus, cerebellum, cortex and amygdala (PubMed:19188364). Absent or lowly expressed in heart and kidney (PubMed:19188364).
Expressed in testis, brain and epididymis (at protein level) (PubMed:6773943, PubMed:885873, PubMed:19188364, PubMed:23504145). Moderately expressed in brain, lung, liver, and kidney (PubMed:19188364). Low expression in heart and spleen (PubMed:19188364). Very low expression in skeletal muscle (PubMed:19188364).
Expressed in testis, spleen, heart, brainstem, hippocampus, cerebellum, cortex and amygdala (PubMed:19188364). Absent or very lowly expressed in intestine, lung and muscle (PubMed:19188364).
Inhibited by 2-deoxyglucitol 6-phosphate (dgtolP) and 2-deoxy-D-glucose 6-phosphate (PubMed:6773943). Inhibited by copper, mercury, cadmium, zinc and copper ions (PubMed:6773943). Activated by potassium and ammonium ions (PubMed:6773943).
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:885873, PubMed:6773943, PubMed:23504145). Rate-limiting enzyme in the synthesis of all inositol-containing compounds (By similarity).
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.
Phosphorylation at Ser-524 does not appear to affect enzyme activity, and is detected in brain and testis.
Belongs to the AVIT (prokineticin) family.
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 (By similarity).
Belongs to the glutathione peroxidase family.
E3 ubiquitin-protein ligase. Mediates TSG101 monoubiquitination at multiple sites. Plays a role in the regulation of endosome-to-lysosome trafficking. Impairs MC1R- and MC4R-signaling by competing with GNAS-binding to MCRs and inhibiting agonist-induced cAMP production. Does not inhibit ADRB2-signaling. Does not promote MC1R ubiquitination. Acts also as a negative regulator of hedgehog signaling (By similarity).
Interacts with MC1R and MC4R. Interacts with TSG101. Interacts with mislocalized cytosolically exposed PRNP; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement (By similarity).
The RING finger is required for ubiquitin ligase activity.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 1 subfamily.
Does not show tissue- or cell-type specificity although levels of transcription show variability. Macrophages showed higher levels of expression than lymphocytes.
Interacts with RMDN3. Interacts with TMED9. Interacts with STX17; dephosphorylates STX17. Interacts with ITGA1 (via cytoplasmic domain); activates the phosphatase activity towards EGFR. Interacts with TRAF2; probably involved in tumor necrosis factor-mediated signaling. Interacts with MET (By similarity).
Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Also plays an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. May also bind DNA (By similarity).
Specifically phosphorylated in a cell cycle-dependent manner by cyclin-dependent kinases CDK1 and CDK2. Probably activated through phosphorylation by PKR.
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).
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).
Expressed in heart, lung, kidney, skeletal muscle, liver, brain and spleen.
Interacts with HNRNPDL. Interacts with the 5FMC complex; the interaction requires association with CHTOP. Interacts with CAVIN1.
Involved in transcriptional regulation. Represses the transcription of a number of genes including gastrin, stromelysin and enolase. Binds to the G-rich box in the enhancer region of these genes.
Sumoylated with SUMO2. Desumoylated by SENP3, resulting in the stimulation of transcription of its target genes (By similarity).
Belongs to the amidinotransferase family.
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. Also capable of catalyzing the synthesis of a range of neuroactive guanidino compounds by utilizing alternative amidine donors and acceptors for the transamidination reaction.
Expressed throughout embryogenesis. Expression in the colon and small intestine is highest in newborns and declines with age. Expression in the kidney increases with age.
Expression is induced by growth hormone and repressed by dietary intake of creatine.
Highly expressed in the kidney and pancreas, especially in the proximal tubules of the kidney, and alpha cells of the pancreatic islets (at protein level). Moderately expressed in liver hepatocytes (at protein level). Expressed in the kidney, pancreas, liver, colon, ileum, jejunum, heart and skeletal muscle. In reproductive tissues, expressed in the testis, epididymis, ovary, oviduct and uterus. Expressed throughout the brain in neurons, astrocytes and oligodendrocytes. In 12.5 dpc embryos, it is expressed in the middle part of the somites, hepatic primordium and wall of the dorsal aorta. Expressed in 15.5 dpc embryos in isolated cells throughout the central nervous system, skeletal muscles, gonad primordia, caudal somites, liver and pancreas, but not in the choroid plexus, root ganglia or kidney. Expressed in skeletal muscle, kidney, pancreas, central nervous system, liver and intestine epithelial cells, but not in epidermis, dermis, olfactory epithelium, trachea, lung, stomach or heart in 18.5 dpc embryos.
Belongs to the eukaryotic AdoMetDC family.
Binds 1 pyruvoyl group covalently per subunit.
Essential for biosynthesis of the polyamines spermidine and spermine. Promotes maintenance and self-renewal of embryonic stem cells, by maintaining spermine levels.
Heterotetramer of two alpha and two beta chains.
Is synthesized initially as an inactive proenzyme. Formation of the active enzyme involves a self-maturation process in which the active site pyruvoyl group is generated from an internal serine residue via an autocatalytic post-translational modification. Two non-identical subunits are generated from the proenzyme in this reaction, and the pyruvate is formed at the N-terminus of the alpha chain, which is derived from the carboxyl end of the proenzyme. The post-translation cleavage follows an unusual pathway, termed non-hydrolytic serinolysis, in which the side chain hydroxyl group of the serine supplies its oxygen atom to form the C-terminus of the beta chain, while the remainder of the serine residue undergoes an oxidative deamination to produce ammonia and the pyruvoyl group blocking the N-terminus of the alpha chain.
Binds 1 Mg(2+) ion per subunit. Can also utilize other divalent metal cations, such as Ca(2+), Mn(2+) and Co(2+).
Binds 1 thiamine pyrophosphate per subunit.
Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate.
Belongs to the type II topoisomerase family.
Binds two Mg(2+) per subunit. The magnesium ions form salt bridges with both the protein and the DNA. Can also accept other divalent metal cations, such as Mn(2+) or Ca(2+).
Eukaryotic topoisomerase I and II can relax both negative and positive supercoils, whereas prokaryotic enzymes relax only negative supercoils.
Homodimer (By similarity). Interacts with COPS5 (By similarity). Interacts with RECQL5; this stimulates DNA decatenation (By similarity). Interacts with SETMAR; stimulates the topoisomerase activity (By similarity). Interacts with DHX9; this interaction occurs in a E2 enzyme UBE2I- and RNA-dependent manner, negatively regulates DHX9-mediated double-stranded DNA and RNA duplex helicase activity and stimulates TOP2A-mediated supercoiled DNA relaxation activity (By similarity). Interacts with HNRNPU (via C-terminus); this interaction protects the topoisomerase TOP2A from degradation and positively regulates the relaxation of supercoiled DNA in a RNA-dependent manner (PubMed:20554522). Interacts with MCM3AP (By similarity). Interacts with ERCC6 (By similarity). Interacts with PLSCR1 (By similarity). Interacts with GCNA; this interaction allows the resolution of topoisomerase II (TOP2A) DNA-protein cross-links (By similarity).
Key decatenating enzyme that alters DNA topology by binding to two double-stranded DNA molecules, generating a double-stranded break in one of the strands, passing the intact strand through the broken strand, and religating the broken strand (By similarity). May play a role in regulating the period length of BMAL1 transcriptional oscillation (By similarity).
Phosphorylation has no effect on catalytic activity.
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 (By similarity).
Glycosylation at Asn-51 reduces adhesive binding.
Belongs to the transglutaminase superfamily. Transglutaminase family.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.
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 (By similarity). May interact with STX1A.
Ubiquitously expressed. Expressed in brain, testis, heart, liver and kidney. Weakly expressed in lung, spleen and skeletal muscle (at protein level).
Was originally thought to be cytoplasmic and membrane-associated and to mediate ubiquitination and subsequent degradation of STX1A.
Expressed in striatum, cortex, midbrain, Purkinje cells of the cerebellum, pyramidal neurons of the hippocampus and neuropil. Expressed in heart, brain, lung, liver, kidney and testis.
Interacts with DLG4 and TUBB1. Interacts strongly with the PDZ3 domain of members of the DLG4 family. Associates with microtubules.
Involved in the cytoskeletal anchoring of DLG4 in excitatory synapses.
Belongs to the MMS22 family. MMS22L subfamily.
Motor protein that may participate in process critical to neuronal development and function such as cell migration, neurite outgrowth and vesicular transport.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-1 (MYH1).
Expressed in postmeiotic male germ cells (at protein level).
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 (PubMed:11319135). Interacts with KIF5C (PubMed:11319135). Interacts with ODF1 (PubMed:12594206). 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.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. IRG family.
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 (By similarity).
Promotes the exchange of Ras-bound GDP by GTP.
The DH (DBL-homology) domain mediates interaction with RASGRF2.
Ubiquitinated and degraded following phosphorylation by PLK2.
Belongs to the chloride channel CLIC family.
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 (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).
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 (By similarity).
Belongs to the plakin or cytolinker family.
Belongs to the bacterial ribosomal protein bL9 family.
Component of the mitochondrial ribosome large subunit (39S) which comprises a 16S rRNA and about 50 distinct proteins.
Interacts with UBR2; does not lead to Tex19.1 degradation and stabilizes it. Interacts with piRNA-associated proteins DDX4, EDC4, MAEL, PIWIL1, PIWIL2, RANBP9 and TDRD6. Interacts with L1RE1.
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. Interacts with LINE-1 retrotransposon encoded LIRE1, stimulates LIRE1 polyubiquitination, mediated by UBR2, and degradation, inhibiting LINE-1 retrotransposon mobilization.
Belongs to the eukaryotic ribosomal protein eL22 family.
Expressed at the highest levels in ovary and uterus. In ovary expression is strictly confined to granulosa cells of preantral and small antral follicles. Detected also in testis and prostate.
Protease. May regulate the surface expression of some potassium channels by retaining them in the endoplasmic reticulum.
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.
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 (By similarity).
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 (By similarity).
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).
Interacts with RNA polymerase I 194 kDa subunit (RPA194) and with casein kinase-II (By similarity). Interacts with DKC1/NAP57, NOP58 and fibrillarin (PubMed:10679015).
Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification. Required for neural crest specification: following monoubiquitination by the BCR(KBTBD8) complex, associates with TCOF1 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. Involved in nucleologenesis, possibly by playing a role in the maintenance of the fundamental structure of the fibrillar center and dense fibrillar component in the nucleolus. It has intrinsic GTPase and ATPase activities.
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.
Undergoes rapid and massive phosphorylation/dephosphorylation cycles on CK2 and PKC sites. NOLC1 is one of the mostly phosphorylated proteins in the cell.
Expressed during the process of ciliated cell differentiation. In seminiferous tubules of the testis, its expression is stage-specific and is highest in spermatocytes and round spermatids.
Interacts (via C-terminus) with IFT20. Interacts with DYNC1I2.
Predominantly expressed in ciliated tissues such as lung, trachea, testis, brain, and at lower levels in kidney and spleen.
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. Also plays a role in bone growth where it seems to be required for normal osteoblast differentiation.
Detected at embryonic day 18 dpc and at later stages. The expression does not significantly change during the developmental stages tested.
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.
Predominantly expressed in brain, including hippocampus, cortex, cerebellum, amygdala and olfactory bulb.
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.
Catalyzes the peptide bond hydrolysis in dipeptides having basic amino acids lysine, ornithine or arginine at C-terminus.
Belongs to the apolipoprotein C2 family.
Component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) in plasma. Plays an important role in lipoprotein metabolism as an activator of lipoprotein lipase.
Proapolipoprotein C-II is synthesized as a sialic acid containing glycoprotein which is subsequently desialylated prior to its proteolytic processing.
Proapolipoprotein C-II, the major form found in plasma undergoes proteolytic cleavage of its N-terminal hexapeptide to generate the mature form apolipoprotein C-II, which occurs as the minor form in plasma.
Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (PubMed:9405631). Interacts with EXOC3L1 (By similarity).
PHM-27 is a potent agonist of the calcitonin receptor CALCR, with similar efficacy as calcitonin (By similarity). PHI also causes vasodilation.
VIP causes vasodilation, lowers arterial blood pressure, stimulates myocardial contractility, increases glycogenolysis and relaxes the smooth muscle of trachea, stomach and gall bladder.
Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.
Highly expressed in stomach, small intestine and colon. Concentrated in the brush border membranes of epithelial cells, throughout the maturation axis of the adult small intestine.
Interacts (via the SH3-domain) with PTEN. Interacts with RB1 (By similarity).
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 (By similarity).
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.
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).
Interacts with RAC1, AJUBA, PLD1, PLD2 and ARF1.
There is confusion in the literature with phosphatidylinositol 4-phosphate 5-kinase type I nomenclature due to the fact that frequently mouse PIP5K1B is named Phosphatidylinositol 4-phosphate 5-kinase type I alpha.
A pair of annexin repeats may form one binding site for calcium and phospholipid.
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 (By similarity).
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.
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 (By similarity).
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 (By similarity). Interacts with NCKAP1L (By similarity).
PP1 comprises a catalytic subunit, and one or several targeting or regulatory subunits.
Phosphorylated on upon DNA damage, probably by ATM or ATR (By similarity). Phosphorylated by CIT (Rho-associated kinase). Phosphorylated cooperatively by ROCK1 and CDC42BP on Thr-697. In vitro, phosphorylation of Ser-696 by PKA and PKG appears to prevent phosphorylation of the inhibitory site Thr-697, probably mediated by PRKG1 (By similarity). Phosphorylated on upon DNA damage, probably by ATM or ATR (By similarity). Phosphorylated by CIT (Rho-associated kinase). Phosphorylated cooperatively by ROCK1 and CDC42BP on Thr-697. May be phosphorylated at Thr-697 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 (By similarity).
Smooth muscle. Detected in aorta, portal vein, stomach, intestine, bladder and lung.
The KVKF motif mediates interaction with PPP1CB.
ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. Plays a role in membrane trafficking between the plasma membrane and endosomes. 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. Regulates the equilibrium between cell surface-associated and cell surface-dissociated caveolae by constraining caveolae at the cell membrane.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. EHD subfamily.
Homodimer and homooligomer. Interacts with EHD1. May also interact with EHD3 and EHD4. Interacts with MYOF. Interacts with EHBP1. Interacts with FER1L5 (via second C2 domain). Interacts with CAV1 in a cholesterol-dependent manner. Interacts (via EH domain) with PACSIN2 (via NPF motifs); this interaction probably stabilizes the caveolae (By similarity).
The EH domain interacts with Asn-Pro-Phe (NPF) motifs of target proteins.
The very low intrinsic ATPase activity is increased upon interaction with liposomes.
Belongs to the TRAPP small subunits family. BET5 subfamily.
May play a role in vesicular transport from endoplasmic reticulum to Golgi.
Part of the multisubunit transport protein particle (TRAPP) complex. The heterodimer TRAPPC6B-TRAPPC3 interacts with TRAPPC1 likely providing a core for TRAPP complex formation.
Expressed in the brain (at protein level). Also expressed in the retina, mainly in the ganglion cell layer and in the amacrine cell subregion of the inner nuclear layer. Expressed at high levels in the epithelial cells of the posterior iris and the ciliary body and, at lower levels, in the trabecular meshwork. Isoform 2 preferentially expressed in retina and brain, while isoform 1 preferentially expressed in the tissues of the eye angle.
Peripherally associated with AMPAR complex. AMPAR complex consists of an inner core made of 4 pore-forming GluA/GRIA proteins (GRIA1, GRIA2, GRIA3 and GRIA4) and 4 major auxiliary subunits arranged in a twofold symmetry. One of the two pairs of distinct binding sites is occupied either by CNIH2, CNIH3 or CACNG2, CACNG3. The other harbors CACNG2, CACNG3, CACNG4, CACNG8 or GSG1L. This inner core of AMPAR complex is complemented by outer core constituents binding directly to the GluA/GRIA proteins at sites distinct from the interaction sites of the inner core constituents. Outer core constituents include at least PRRT1, PRRT2, CKAMP44/SHISA9, FRRS1L and NRN1. The proteins of the inner and outer core serve as a platform for other, more peripherally associated AMPAR constituents, including OLFM3. Alone or in combination, these auxiliary subunits control the gating and pharmacology of the AMPAR complex and profoundly impact their biogenesis and protein processing (PubMed:22632720). Homodimer. Interacts with MYOC (PubMed:12019210). Interacts with OLFM2 (By similarity).
Binds 1 Mg(2+) ion per subunit. May bind a second metal ion at a regulatory site, or after substrate binding.
Endonuclease that specifically degrades the RNA of RNA-DNA hybrids. Plays a role in RNA polymerase II (RNAp II) transcription termination by degrading R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site and behind the elongating RNAp II.
In the presence of magnesium, manganese is inhibitory.
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. Its function in translational initiation regulation can either be enhanced by PAIP1 or repressed by PAIP2. 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. 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. 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. By binding to long poly(A) tails, may protect them from uridylation by ZCCHC6/ZCCHC11 and hence contribute to mRNA stability.
May form homodimers. Component of a multisubunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1. Directly interacts with IGF2BP1. Part of a complex associated with the FOS mCRD domain and consisting of HNRPD, SYNCRIP, PAIP1 and CSDE1/UNR. Interacts with PAIP1 and PAIP2 (via the PABPC1-interacting motifs PAM1 and PAM2). 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 (By similarity). Found in a mRNP complex with YBX2. Interacts with TENT2/GLD2 (By similarity). Identified in the spliceosome C complex. 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. This interaction increases in stressed cells and decreases during cell recovery. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with NXF1/TAP (By similarity). Interacts with PIWIL1 (By similarity). Interacts with AGO1, AGO2, GSPT1 and GSPT2. Interacts with LARP4B. Interacts (via the second and third RRM domains and the C-terminus) with PAIP2B (via central acidic portion and C-terminus). Forms a complex with LARP1 and SHFL. Interacts with LARP4. Interacts with ZFC3H1 in a RNase-sensitive manner. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner. Interacts with TENT5C; the interaction has no effect on TENT5C poly(A) polymerase function. Interacts with G3BP1 and G3BP2 (By similarity). Interacts with ENDOV; the interaction is RNA-dependent and stimulates ENDOV activity (By similarity). Interacts with UPF1; the interaction is RNA-dependent (By similarity). Interacts with IGF2BP2 and IGF2BP3. May interact with SETX.
Methylated by CARM1. Arg-493 is dimethylated, probably to asymmetric dimethylarginine (By similarity).
The RNA-binding domains RRM1 and RRM2 and the C-terminus (last 138 amino acids) regions interact respectively 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.
Belongs to the glycosyltransferase 22 family.
Belongs to the Integrator subunit 3 family.
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.
High expression in the ventral medulla surface (VMS), heart and skeletal muscle. Lower expression in the cerebral cortex, cerebellum, liver, stomach and intestine.
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. Interacts with CREBBP; the interaction leads to acetylation of the basic region of MAFG and stimulation of NFE2 transcriptional activity through increased DNA binding.
Increased levels in the VMS after hypercapnic stimulation.
Since they lack a putative transactivation domain, the small Mafs behave as transcriptional repressors when they dimerize among themselves (By similarity). 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 (By similarity). Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NFE2L2 transcription factor (By similarity). Transcription factor, component of erythroid-specific transcription factor NFE2L2 (By similarity). Activates globin gene expression when associated with NFE2L2 (By similarity). May be involved in signal transduction of extracellular H(+) (PubMed:11583919).
Sumoylation at Lys-41 is required for active transcriptional repression.
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 (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.
May have a role in hematopoietic cell differentiation.
Belongs to the TFS-II family. TFA subfamily.
Highly expressed in kidney. Moderately expressed in heart and lung. Low expression in brain and liver. Expression is up-regulated in nephrectomized kidney.
May be involved in transcriptional regulation.
Belongs to the immunoglobulin superfamily. L1/neurofascin/NgCAM family.
Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions. Isoform 2/isoform 3 may be responsible for mediating and signaling axon-glial interaction during the early stages of myelination.
Homophilic adhesion is primarily mediated by the interaction of the second Ig-like domains.
Horseshoe-shaped homodimer (By similarity). Probable constituent of a NFASC/NRCAM/ankyrin G complex. Associates with the sodium channel beta-1 (SCN1B) and beta-3 (SCN3B) subunits. Associates to subunit beta-1 in developing axons as early as postanatal day 5, during the period that nodes of Ranvier are forming. Isoform 2/isoform 3 is likely to interact with axonal proteins in close association with CNTNAP1. Interacts with GLDN/gliomedin. Interacts with MYOC (By similarity).
Isoform 1 is expressed at Nodes of Ranvier while isoform 2/isoform 3 is expressed in unmyelinated axons.
Isoform 2/isoform 3 is phosphorylated at P12. Dephosphorylation is required for ankyrin binding.
Strongly but transiently up-regulated in oligodendrocytes at the onset of myelinogenesis. Once these last have engaged their target exons, expression declines precipitously.
Belongs to the Tim17/Tim22/Tim23 family.
Component of the TIM23 complex at least composed of TIMM23, TIMM17 (TIMM17A or TIMM17B) and TIMM50.
Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.
Belongs to the PNP/UDP phosphorylase family.
Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.
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). The recruitment of the retriever complex to the endosomal membrane involves CCC and WASH complexes. 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. 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.
Component of the heterotrimeric retriever complex formed by VPS26C, VPS29 and VPS35L. Interacts with VPS29. 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. Interacts with WASHC1, WASHC2A and WASHC2C. Interacts with SNX17 and SNX31.
Homohexamer (By similarity). Interacts with MAVS (By similarity). Interacts with TUFM (By similarity).
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. Instead, promotes autophagy by interacting with TUFM and subsequently recruiting the autophagy-related proteins ATG5 and ATG12. Regulates also MAVS-dependent NLRP3 inflammasome activation to attenuate apoptosis. 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 (By similarity). Regulates viral mediated-inflammation and energy metabolism in a sex-dependent manner. 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.
S-nitrosylation is induced by interferon-gamma and oxidatively-modified low-densitity lipoprotein (LDL(ox)) possibly 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.
This protein is an anticoagulant protein that acts as an indirect inhibitor of the thromboplastin-specific complex, which is involved in the blood coagulation cascade.
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). 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. Interacts with HMGCR (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with AMFR/gp78 (via its membrane domain); the interaction recruits HMCR at the ER membrane for its ubiquitination and degradation by the sterol-mediated ERAD pathway. Interacts with SOAT2/ACAT2; leading to promote recruitment of AMFR/gp78 and subsequent ubiquitination of SOAT2/ACAT2. Interacts with RNF139. Interacts with RNF145.
Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR. 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. Binds oxysterol, including 25-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum. 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. Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG1 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2. 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 ligases AMFR/gp78 and/or RNF139. Also regulates degradation of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78.
Phosphorylation at Ser-189 by PCK1 reduces binding to oxysterol, disrupting the interaction between INSIG1 and SCAP, thereby promoting nuclear translocation of SREBP proteins (SREBF1/SREBP1 or SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-related genes.
The KxHxx motif mediates association with the coatomer complex.
Ubiquitinated by AMFR/gp78 in response to sterol deprivation, leading to its degradation: when the SCAP-SREBP complex becomes dissociated from INSIG1, INSIG1 is then ubiquitinated and degraded in proteasomes. Although ubiquitination is required for rapid INSIG1 degradation, it is not required for release of the SCAP-SREBP complex. Ubiquitinated by RNF139.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Trm1 family.
Belongs to the cyclophilin-type PPIase family. PPIase D subfamily.
Identified in ESR1 or NR3C1/GCR steroid receptor-chaperone complexes. Found in HSP90 chaperone complexes with kinase clients LCK or EIF2AK1. Two monomers associate with one HSP90 homodimer. Interacts with HSP90AA1. Interacts with HSP90AB1; PPID and FKBP4 compete for binding to HSP90AB1 and the interaction is mutually exclusive with the PPID:HSPA8 interaction. Interacts with HSPA8; PPID and STIP1 but not FKBP4 compete for binding to HSPA8 and the interaction is mutually exclusive with the PPID:HSP90AB1 interaction. Interacts with S100A1 and S100A2; the interactions dissociate the PPID:HSP90AA1 interaction. Interacts with S100A6. Interacts with MYB, ILF2, XRCC6, RACK1 and RPS3. Interacts with cytoplasmic dynein 1 intermediate chain (DYNC1I1 or DYNC1I2) (By similarity).
Less sensitive to inhibition by cyclosporin A than is CYP-18.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. Proposed to act as a co-chaperone in HSP90 complexes such as in unligated steroid receptors heterocomplexes. Different co-chaperones seem to compete for association with HSP90 thus establishing distinct HSP90-co-chaperone-receptor complexes with the potential to exert tissue-specific receptor activity control. May have a preference for estrogen receptor complexes and is not found in glucocorticoid receptor complexes. May be involved in cytoplasmic dynein-dependent movement of the receptor from the cytoplasm to the nucleus. May regulate MYB by inhibiting its DNA-binding activity. Involved in regulation of AHR signaling by promoting the formation of the AHR:ARNT dimer; the function is independent of HSP90 but requires the chaperone activity region. Involved in regulation of UV radiation-induced apoptosis.
This protein should not be confused with mitochondrial peptidyl-prolyl cis-trans isomerase F (PPIF) which is often referred to as cyclophilin D or CypD.
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 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 brain, almost exclusively in neurons, and spinal chord. Detected in pancreas islet beta cells.
Expression is low in embryonic brains (12 dpc to 16 dpc) but increases dramatically after birth (postnatal days P0-P3) and reaches a plateau during the period when most synapses are formed (P5-P8).
Interacts with NRXN1, NRXN2 and NRXN3. Interacts with NLGN3. Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3). Interacts with GOPC (By similarity). Interacts with AIP1 and PDZRN3.
Catalyzes the irreversible transamination of the L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA). As a member of the malate-aspartate shuttle, it has a key role in the intracellular NAD(H) redox balance. Is important for metabolite exchange between mitochondria and cytosol, and for amino acid metabolism. Facilitates cellular uptake of long-chain free fatty acids (By similarity).
Expressed in all tissues tested: liver, pancreas, kidney, heart, spleen, arterioles, and lymphocytes.
In eukaryotes there are cytoplasmic, mitochondrial and chloroplastic isozymes.
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).
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 hedgehog signaling transduction (By similarity).
Belongs to the SLC26A/SulP transporter (TC 2.A.53) family.
Chloride/bicarbonate exchanger. Mediates the efficient absorption of chloride ions in the colon, participating in fluid homeostasis. Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (By similarity).
Interacts with PDZK1, CFTR, SLC26A6 and SLC9A3R1.
N-glycosylation is required for efficient cell surface expression, and protection from proteolytic degradation.
Belongs to the peptidase M67A family. MYSM1 subfamily.
Stabilizes the aggregates of proteoglycan monomers with hyaluronic acid in the extracellular cartilage matrix.
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. The physiological significance of its role in apoptosis is unclear (By similarity). 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.
Down-regulated upon hypertonic conditions.
Homodimer (By similarity). Interacts with CEBPB (By similarity). Interacts with CIDEA (By similarity). Interacts with PLIN1 (By similarity). Interacts with NFAT5; this interaction is direct and retains NFAT5 in the cytoplasm.
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 (about 15 minutes in 3T3-L1 cells). Protein stability depends on triaclyglycerol synthesis, fatty acid availability and lipid droplet formation (By similarity).
Belongs to the acid sphingomyelinase family.
Has in vitro nucleotide phosphodiesterase activity with nucleoside triphosphates, such as ATP. Has in vitro activity with p-nitrophenyl-TMP. Has lower activity with nucleoside diphosphates, and no activity with nucleoside monophosphates. Has in vitro activity with CDP-choline, giving rise to CMP and phosphocholine. Has in vitro activity with CDP-ethanolamine. Does not have sphingomyelin phosphodiesterase activity.
Belongs to the glycosyl hydrolase 56 family.
Belongs to the bacterial ribosomal protein bS16 family.
Belongs to the Toll-like receptor family.
Belongs to the small heat shock protein (HSP20) family.
Interacts with DMPK; may enhance its kinase activity.
Acetylated; acetylation impairs nuclear localization and ability to transactivate expression of target genes. Deacetylated by SIRT1.
Homodimer; homodimerization is required for activity. Interacts (via C-terminus) with ZNF219; forming a complex that binds to the COL2A1 promoter and activates COL2A1 expression (By similarity). Interacts with DDRGK1. Interacts with EP300/p300 (By similarity). Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1 (By similarity).
Phosphorylation at Ser-64 and Ser-211 by PKA increases transcriptional activity and may help delay chondrocyte maturation downstream of PTHLH/PTHrP signaling. Phosphorylation at either Ser-64 or Ser-211 is required for sumoylation, but phosphorylation is not dependent on sumoylation. Phosphorylated on tyrosine residues; tyrosine dephosphorylation by PTPN11/SHP2 blocks SOX9 phosphorylation by PKA and subsequent SUMOylation.
Sumoylated; phosphorylation at either Ser-64 or Ser-211 is required for sumoylation. Sumoylation is induced by BMP signaling pathway.
The PQA region (for proline, glutamine and alanine-rich) helps stabilize SOX9 and facilitates transactivation. It lacks intrinsic transactivation capability.
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 plays a key role in chondrocytes differentiation and skeletal development (By similarity). Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes COL2A1, COL4A2, COL9A1, COL11A2 and ACAN, SOX5 and SOX6 (PubMed:26150426). Also binds to some promoter regions (By similarity). Plays a central role in successive steps of chondrocyte differentiation (By similarity). Absolutely required for precartilaginous condensation, the first step in chondrogenesis during which skeletal progenitors differentiate into prechondrocytes (By similarity). Together with SOX5 and SOX6, required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes, the second step in chondrogenesis (By similarity). Later, required to direct hypertrophic maturation and block osteoblast differentiation of growth plate chondrocytes: maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation of chondrocytes by lowering beta-catenin (CTNNB1) signaling and RUNX2 expression (By similarity). Also required for chondrocyte hypertrophy, both indirectly, by keeping the lineage fate of chondrocytes, and directly, by remaining present in upper hypertrophic cells and transactivating COL10A1 along with MEF2C (By similarity). Low lipid levels are the main nutritional determinant for chondrogenic commitment of skeletal progenitor cells: when lipids levels are low, FOXO (FOXO1 and FOXO3) transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Mechanistically, helps, but is not required, to remove epigenetic signatures of transcriptional repression and deposit active promoter and enhancer marks at chondrocyte-specific genes (By similarity). Acts in cooperation with the Hedgehog pathway-dependent GLI (GLI1 and GLI3) transcription factors (By similarity). In addition to cartilage development, also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells: involved in the lung epithelium during branching morphogenesis, by balancing proliferation and differentiation and regulating the extracellular matrix (By similarity). Controls epithelial branching during kidney development (By similarity).
Ubiquitinated; ubiquitination leads to proteasomal degradation and is negatively regulated by DDRGK1.
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.
Belongs to the Nudix hydrolase family. NudC subfamily.
Activated in retinal ganglion cells (RGCs) following optic nerve transection. Also induced under starvation conditions, through the action of the foxo1 and foxo3 transcription factors.
Forms a conjugate with ATG5. The ATG12-ATG5 conjugate forms a complex with several units of ATG16L1. Forms an 800-kDa complex composed of ATG12-ATG5 and ATG16L2 (By similarity). Interacts with ATG3, ATG7 and ATG10. ATG12-ATG5 also interacts with MAVS, MGA, RARRES3 and TECPR1 (By similarity). Interacts with SH3BGRL (By similarity).
Shares weak sequence similarity with ubiquitin family, but contains an 'ubiquitin superfold' and the C-terminal Gly is required for isopeptide linkage.
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. The ATG12-ATG5 conjugate also regulates negatively the innate antiviral immune response by blocking the type I IFN production pathway through direct association with RARRES3 and MAVS. Also plays a role in translation or delivery of incoming viral RNA to the translation apparatus (By similarity).
Belongs to the 5'(3')-deoxyribonucleotidase family.
Belongs to the SNF2/RAD54 helicase family.
Plays a role in the assembly/stability of the mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V).
Appears in the mid embryonic period and becomes abundant at 16 dpc to 19 dpc. 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.
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 (By similarity). 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 (By similarity).
Heterodimer of two subunits, one of which binds GTP (By similarity). Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex (By similarity). Interacts with JMJD4 (By similarity). The ETF1-GSPT1 complex interacts with JMJD4 (By similarity).
Hydroxylation at Lys-63 by JMJD4 promotes its translational termination efficiency.
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 (By similarity).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 (By similarity). Component of neuron-specific chromatin remodeling complex (nBAF complex) composed of at least, ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A or SMARCD2/BAF60B or SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, DPF1/BAF45B, DPF3/BAF45C, ACTL6B/BAF53B and actin (ACTB). Note that the nBAF complex is polymorphic in regard to the ATPase, SMARCA2 and SMARCA4 occupying mutually exclusive positions (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 (By similarity).
Expressed in hippocampus, exclusively in neurons, but not in glial cells.
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 neuron-specific chromatin remodeling complex (nBAF complex), as such plays a role in remodeling mononucleosomes in an ATP-dependent fashion, and is required for postmitotic neural development and dendritic outgrowth. 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. ACTL6B/BAF53B is not essential for assembly of the nBAF complex but is required for targeting the complex and CREST to the promoter of genes essential for dendritic growth. Essential for neuronal maturation and dendrite development (By similarity).
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. 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.
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.
Belongs to the Mediator complex subunit 25 family.
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 (By similarity). 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. 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 (By similarity). Futhemore, coexpression of NALCN, UNC79, UNC80, and NALF1 results in voltage-dependent NALCN currents (By similarity).
Predominantly expressed in the brain, moderately in the heart and weakly in the pancreas.
Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability. NALCN channel functions as a multi-protein complex, which consists at least of NALCN, NALF1, UNC79 and UNC80. NALCN is the voltage-sensing, pore-forming subunit of the NALCN channel complex. NALCN channel complex is constitutively active and conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations (By similarity). 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. NALCN channel is also activated by neuropeptides such as neurotensin and substance P (SP) through a SRC family kinases-dependent pathway. In addition, NALCN activity is enhanced/modulated by several GPCRs, such as CHRM3 (By similarity).
Acetylated by CREBBP/CBP, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me), without affecting rRNA methylation. Deacetylation by SIRT7 restores methylation of 'Gln-105' of histone H2A (H2AQ104me).
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. It is associated with the U3, U8, U13, X and Y small nuclear RNAs. Component of several ribosomal and nucleolar protein complexes. Interacts with PRMT5 and UTP20. Interacts with DDX5 and C1QBP. Interacts with NOL11. Interacts with PIH1D1. Interacts with RRP1B (By similarity). Interacts with NOLC1 (PubMed:10679015). Interacts with SDE2 (By similarity).
S-adenosyl-L-methionine-dependent methyltransferase that has the ability to methylate both RNAs and proteins. Involved in pre-rRNA processing by catalyzing the site-specific 2'-hydroxyl methylation of ribose moieties in pre-ribosomal RNA (By similarity). 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. U6 snRNA 2'-O-methylation is required for mRNA splicing fidelity. 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 (By similarity).
Ubiquitinated. Ubiquitination leads to proteasomal degradation. Deubiquitinated by USP36.
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. Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices. Catalyzes with a lower efficiency the sulfation of Gal residues of keratan sulfate, another glycosaminoglycan (By similarity). 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).
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.
Homodimer; disulfide-linked. Seems to also exist as monomers (By similarity).
Galactose-specific lectin which binds IgE. May mediate with the alpha-3, beta-1 integrin the stimulation by CSPG4 of endothelial cells migration. 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 (By similarity). Together with DMBT1, required for terminal differentiation of columnar epithelial cells during early embryogenesis.
Probably forms homo- or heterodimers. Interacts with DMBT1 (By similarity). Interacts with CD6 and ALCAM. 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 (By similarity).
PA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides.
A secreted form is released from the membrane after cleavage by gamma-secretase.
Belongs to the glycosyltransferase 18 family.
Catalyzes the addition of N-acetylglucosamine (GlcNAc) in beta 1-6 linkage to the alpha-linked mannose of biantennary N-linked oligosaccharides (PubMed:8340368, PubMed:7615638). Catalyzes an important step in the biosynthesis of branched, complex-type N-glycans, such as those found on EGFR, TGFR (TGF-beta receptor) and CDH2 (By similarity). Via its role in the biosynthesis of complex N-glycans, plays an important role in the activation of cellular signaling pathways, reorganization of the actin cytoskeleton, cell-cell adhesion and cell migration (PubMed:7615638). MGAT5-dependent EGFR N-glycosylation enhances the interaction between EGFR and LGALS3 and thereby prevents rapid EGFR endocytosis and prolongs EGFR signaling. Required for efficient interaction between TGFB1 and its receptor. Enhances activation of intracellular signaling pathways by several types of growth factors, including FGF2, PDGF, IGF, TGFB1 and EGF. MGAT5-dependent CDH2 N-glycosylation inhibits CDH2-mediated homotypic cell-cell adhesion and contributes to the regulation of downstream signaling pathways. Promotes cell migration. Contributes to the regulation of the inflammatory response. MGAT5-dependent TCR N-glycosylation enhances the interaction between TCR and LGALS3, limits agonist-induced TCR clustering, and thereby dampens TCR-mediated responses to antigens. Required for normal leukocyte evasation and accumulation at sites of inflammation (By similarity). Inhibits attachment of monocytes to the vascular endothelium and subsequent monocyte diapedesis (By similarity).
Detected in kidney (at protein level). Detected in kidney.
Promotes proliferation of umbilical vein endothelial cells and angiogenesis, at least in part by promoting the release of the growth factor FGF2 from the extracellular matrix.
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 (By similarity).
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. 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). Plays a role, together with DISC1, in the regulation of neurite outgrowth.
Self-associates. Interacts with dynactin, tubulin gamma, KATNA1, KATNB1, microtubules, PCM1, PCNT, and YWHAE. Interacts directly with NEFL and indirectly with NEFH. Interacts (via C-terminus) with CENPF. Interacts with DISC1, dynein and PAFAH1B1. Interacts with ZNF365. Interacts with PLEKHM1 (via N- and C-terminus).
Up-regulated during neurite outgrowth upon differentiation with NGF.
Was originally thought to function as an oligopeptidase (NUDEL-oligopeptidase or endooligopeptidase A) which could regulate peptide levels relevant to brain function.
Although similar to members of the ADAMTS family, it lacks the metalloprotease and disintegrin-like domains which are typical of that family.
Glycosylated (By similarity). Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion (By similarity).
Interacts with CTSB. Interacts with FBN1 (By similarity).
Positive regulation of apoptosis. May facilitate FBN1 microfibril biogenesis (By similarity).
Interacts with KIF1A; the interaction decreases in presence of calcium.
Scaffolding protein in the dendritic spines which acts as immobile postsynaptic posts able to recruit KIF1A-driven dense core vesicles to dendritic spines.
The C-terminal part of the hedgehog protein precursor displays an autoproteolysis activity that results in the cleavage of the full-length protein into two parts (N-product and C-product). In addition, the C-terminal part displays a cholesterol transferase activity that results by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product.
The dually lipidated hedgehog protein N-product is a morphogen which is essential for a variety of patterning events during development.
Detected in intestine, kidney, seminal vesicles and testis.
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:8617223, PubMed:20133611). Regulates the zinc concentration of milk, through the transport of zinc ions into secretory vesicles of mammary cells (By similarity). By concentrating zinc ions into lysosomes participates to lysosomal-mediated cell death during early mammary gland involution (By similarity).
Homodimer. Interacts (via lysosomal targeting motif) with AP3D1; in AP-3-mediated transport to lysosomes.
Phosphorylated at Ser-283. Phosphorylation at Ser-283 prevents localization to lysosomes. Dephosphorylation of Ser-283 which triggers localization to lysosomes, accumulation of zinc into lysosomes and lysosomal-mediated cell death is induced by TNF-alpha.
Up-regulated by dexamethasone (at protein level).
Belongs to the nucleosome assembly protein (NAP) family.
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. 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. 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. 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. May be involved in meiotic recombination process.
Histone deacetylase that catalyzes 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.
Belongs to the TPT transporter family. SLC35E subfamily.
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.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho.
This subunit carries the benzodiazepine binding site.
Belongs to the G-protein coupled receptor 1 family. FSH/LSH/TSH subfamily.
Interacts with heterodimer GPHA2:GPHB5; this interaction stimulates cAMP production. Interacts (via the PDZ-binding motif) with SCRIB; regulates TSHR trafficking and function.
Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin (PubMed:1696008). Also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin (PubMed:12045258). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (By similarity). Plays a central role in controlling thyroid cell metabolism (PubMed:12045258).
Sulfated. Sulfation on Tyr-385 plays a role in thyrotropin receptor binding and activation.
Involved in angiogenesis; promotes angiogenic sprouting. May have potent implications in lung endothelial cell-leukocyte interactions (By similarity).
O-glycosylated; contains chondroitin sulfate and dermatan sulfate.
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 (By similarity). 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 (By similarity).
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. Truncated SELENOS proteins produced by failed UGA/Sec decoding are also ubiquitinated by the CRL5(KLHDC1) complex.
Transfers N-acetylgalactosamine (GalNAc) from UDP-GalNAc to N-acetylglucosamine-beta-benzyl with a beta-1,4-linkage to form N,N'-diacetyllactosediamine, GalNAc-beta-1,4-GlcNAc structures in N-linked glycans and probably O-linked glycans.
Belongs to the class I-like SAM-binding methyltransferase superfamily. EEF2KMT family.
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.
Expressed predominantly in oligodendrocytes, in CNS myelin of the cerebrum and spinal cord. No expression seen in sciatic nerve.
Expression in different brain regions during development is correlated with the progression of myelin formation. Isoform 5 seems to be the most abundant spliced form expressed during development. Expressed at P7 in optic nerve, at this time point, the first compact myelin is formed. At P9 abundantly expressed in the optic nerve.
May play a role in compacting or stabilizing the myelin sheath, possibly by binding the negatively charged acidic phospholipids of the cytoplasmic membrane.
Functions in endoplasmic reticulum to Golgi vesicle-mediated transport and regulates the proper organization of the endoplasmic reticulum and the Golgi (By similarity). Plays a key role in targeting to neuronal dendrites receptors such as HTR1A (PubMed:18685031). Plays also a role in primary cilium and sperm flagellum assembly probably through protein transport to these compartments (By similarity).
Highly expressed in brain. Expressed in heart, kidney, and lung and lower levels in spleen, muscle, and intestine (at protein level) (PubMed:18685031). Expressed in serotoninergic neurons (at protein level) (PubMed:18685031).
Interacts with HTR1A (via C-terminus) (PubMed:18685031). Interacts with ABCB9 (via TMD0); this interaction allows (but is not essential) the ER-to-Golgi trafficking and strongly depends on a salt bridge within TMD0 (By similarity).
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family.
Has a role in pre-mRNA splicing. Phosphorylates SF2/ASF (By similarity).
Identified in the spliceosome C complex. Interacts with Clk1 C-terminus.
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 (By similarity).
Inhibits BMP signaling. Acts as a transcriptional corepressor of LBX1 (By similarity).
Interacts with LBX1. Interacts with SMAD1, SMAD2 and SMAD3 (By similarity).
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.
Ca(2+) sensor involved in Ca(2+)-dependent exocytosis of secretory and synaptic vesicles through Ca(2+) and phospholipid binding to the C2 domain (PubMed:11395007, PubMed:10725327, PubMed:11511344). Ca(2+) induces binding of the C2-domains to phospholipid membranes and to assembled SNARE-complexes; both actions contribute to triggering exocytosis (PubMed:11395007). 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:10725327, PubMed:11511344). Ca(2+)-regulated delivery of lysosomal membranes to the cell surface is also involved in the phagocytic uptake of particles by macrophages. Ca(2+)-triggered lysosomal exocytosis also plays a role in bone remodeling by regulating secretory pathways in osteoclasts and osteoblasts. 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. 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. Probably mediates synaptic facilitation by directly increasing the probability of release. 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. Also acts as a regulator of Ca(2+)-dependent insulin and glucagon secretion in beta-cells. 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 (PubMed:15456748).
Expressed in the brain (at protein level).
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 (PubMed:11823420). Binding to membranes involves Ca(2+)-dependent phospholipid binding (PubMed:11823420). 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. The two C2 domains bind independently to planar membranes, without interdomain cooperativity. Moreover, SYT7 C2 domains insert more deeply into membranes compared to other synaptotagmins (By similarity).
A helix bundle is formed by helices from the N-terminal and the C-terminal part of the protein. The GTPase domain cannot be expressed by itself, without the helix bundle. Rearrangement of the helix bundle and/or of the coiled coil domains may bring membranes from adjacent mitochondria into close contact, and thereby play a role in mitochondrial fusion.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family. Mitofusin subfamily.
Homodimer, also in the absence of bound GTP. Forms higher oligomers in the presence of a transition state GTP analog (By similarity). Forms homomultimers and heteromultimers with MFN2 (PubMed:14561718). Oligomerization is essential for mitochondrion fusion. Component of a high molecular weight multiprotein complex (By similarity). Interacts with VAT1 (PubMed:17105775). 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:14561718, PubMed:12589796). Membrane clustering requires GTPase activity. It may involve a major rearrangement of the coiled coil domains (By similarity). Mitochondria are highly dynamic organelles, and their morphology is determined by the equilibrium between mitochondrial fusion and fission events (PubMed:14561718). Overexpression induces the formation of mitochondrial networks (in vitro) (PubMed:14561718). Has low GTPase activity (By similarity).
Ubiquitinated by non-degradative ubiquitin by PRKN (By similarity). Deubiquitination by USP30 inhibits mitochondrial fusion (By similarity). Ubiquitinated by MARCHF5. 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 (By similarity).
Ubiquitous. In brain, it is expressed at weaker level than MFN2, while it is expressed at a higher level than MFN2 in heart and testis. Expressed at high level in elongating spermatids of seminiferous tubules.
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). 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 activity in liver and kidney. Low activity in spleen, stomach, intestinal tract, esophagus, heart and lung.
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.
Potential NADPH-dependent oxidoreductase. May be involved in the regulation of neuronal survival, differentiation and axonal outgrowth (By similarity).
Frequently detected in granular vesicles, in the cytoplasm of some epithelial, stromal and sperm cells and in varicosities lining nervous fibers, while it appears to be absent in endothelial and smooth muscle cells (at protein level). Widely expressed. Expressed at high level in testis.
Required for S phase entry of the cell cycle.
The Val-109 variant is degraded by the proteasome suggesting that it is polyubiquitinated.
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. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments.
As a subunit of eukaryotic initiation factor 2 (eIF-2), involved in the early steps of protein synthesis. In the presence of GTP, eIF-2 forms a ternary complex with initiator tRNA Met-tRNAi and then recruits the 40S ribosomal complex and initiation factors eIF-1, eIF-1A and eIF-3 to form the 43S pre-initiation complex (43S PIC), a step that determines the rate of protein translation. The 43S PIC binds to mRNA and scans downstream to the initiation codon, where it forms a 48S initiation complex by codon-anticodon base pairing. This leads to the displacement of eIF-1 to allow GTPase-activating protein (GAP) eIF-5-mediated hydrolysis of eIF2-bound GTP. Hydrolysis of GTP and release of Pi, which makes GTP hydrolysis irreversible, causes the release of the eIF-2-GDP binary complex from the 40S subunit, an event that is essential for the subsequent joining of the 60S ribosomal subunit to form an elongation-competent 80S ribosome. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must be exchanged with GTP by way of a reaction catalyzed by GDP-GTP exchange factor (GEF) eIF-2B (By similarity). Along with its paralog on chromosome Y, may contribute to spermatogenesis up to the round spermatid stage (By similarity).
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EIF2G subfamily.
Has a homolog on chromosome X (Eif2s3x).
The eukaryotic translation initiation factor 2 complex/eIF2 is a heterotrimer composed of an alpha subunit, also called subunit 1 (encoded by EIF2S1), a beta subunit, also called subunit 2 (encoded by EIF2S2) and a gamma subunit, also called subunit 3 (encoded by 2 homologous genes Eif2s3x and Eif2s3y).
Homodimer, and heterodimer with SH3GLB1.
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 (By similarity).
There are six different gamma crystallins identified in rat lens.
Allosterically activated by benzodiazepines and the anesthetic etomidate (By similarity). Inhibited by the antagonist bicuculline (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. 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:18281286). Interacts with UBQLN1 (PubMed:11528422). 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 (PubMed:20400944). May interact with KIF21B (PubMed:25172774). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (PubMed:28279354).
Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:2548852). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (By similarity). 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 (By similarity). Functions also as histamine receptor and mediates cellular responses to histamine (PubMed:18281286).
The extracellular domain contributes to synaptic contact formation.
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. 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). May activate NTMT1 by priming its substrates for trimethylation.
Belongs to the methyltransferase superfamily. NTM1 family.
Plays a role in store-operated Ca(2+) entry (SOCE).
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 (By similarity). Binding is pH dependent, and is optimal at pH 5-5.4 (By similarity).
Belongs to the peptidase S9B family. DPPIV subfamily.
Detected in brain cortex, hippocampus, thalamus and cerebellum Purkinje cells (at protein level) (PubMed:16123112).
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 (By similarity). Interacts with KCND2 (PubMed:15671030, PubMed:16123112). Identified in a complex with KCND2 and KCNIP3 (PubMed:16123112).
N-glycosylation is important for cell surface expression, specially at Asn-257, which is crucial.
Promotes cell surface expression of the potassium channel KCND2. Modulates the activity and gating characteristics of the potassium channel KCND2 (PubMed:16123112, PubMed:19901547). Has no dipeptidyl aminopeptidase activity (Probable).
Belongs to the AB hydrolase superfamily. ABHD17 family.
Expressed in brain (at protein level). Expressed in hippocampal neurons.
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins (PubMed:27307232). Has depalmitoylating activity towards NRAS (By similarity). Has depalmitoylating activity towards DLG4/PSD95 (PubMed:27307232). May have depalmitoylating activity towards MAP6 (PubMed:28521134).
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.
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.
Down-regulated by hemin in the liver and by 6-amino-levulinate (or its methyl ester) in the liver, kidney, heart, testis and brain.
Expressed in the liver, kidney, brain and testis.
Homodimer (By similarity). Interacts (hydroxylated form) with VHL (By similarity).
In normoxia, is hydroxylated at Pro-578, 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.
Belongs to the acireductone dioxygenase (ARD) family.
Binds either 1 Fe or Ni cation per monomer. Iron-binding promotes an acireductone dioxygenase reaction producing 2-keto-4-methylthiobutyrate, while nickel-binding promotes an acireductone dioxygenase reaction producing 3-(methylsulfanyl)propanoate.
Catalyzes 2 different reactions between oxygen and the acireductone 1,2-dihydroxy-3-keto-5-methylthiopentene (DHK-MTPene) depending upon the metal bound in the active site. Fe-containing acireductone dioxygenase (Fe-ARD) produces formate and 2-keto-4-methylthiobutyrate (KMTB), the alpha-ketoacid precursor of methionine in the methionine recycle pathway. Ni-containing acireductone dioxygenase (Ni-ARD) produces methylthiopropionate, carbon monoxide and formate, and does not lie on the methionine recycle pathway. Also down-regulates cell migration mediated by MMP14.
Detected in prostate, liver, heart, brain, muscle, kidney and seminal vesicles.
Up-regulated by androgens in the prostate, but not in the other tissues tested.
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.
Interacts with TBC1D32; may play a role in cilium assembly.
Involved in the localization of proteins to the cilium and cilium assembly. Indirectly regulates the signaling functions of the cilium, being required for normal SHH/smoothened signaling and proper development.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A19 subfamily.
By high salt intake in SHR rats. Reduced level upon high salt intake in Wistar Kyoto rats.
Interacts in a tissue-specific manner with ACE2 in small intestine and with CLTRN in the kidney. Interacts with CLTRN; this interaction is required for trafficking of SLC6A19 to the plasma membrane and for its catalytic activation in kidneys. Interacts with ACE2; this interaction is required for trafficking of SLC6A19 to the plasma membrane and for its catalytic activation in intestine. Interacts with ANPEP; the interaction positively regulates its amino acid transporter activity (By similarity).
Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells. This uptake is sodium-dependent and chloride-independent. Requires CLTRN in kidney or ACE2 in intestine for cell surface expression and amino acid transporter activity.
Belongs to the Odd C2H2-type zinc-finger protein family.
Transcription factor that plays a role in the regulation of embryonic heart and urogenital development.
Autophosphorylated on serine and threonine residues (PubMed:8570168). Phosphorylation at Thr-157 increases kinase activity (By similarity).
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.
Expressed in embryonic heart from day 11. Highly expressed in the uterus and at lower levels in brain, heart, lung, kidney, skeletal muscle, ovary and liver in adult tissues.
Required for ciliogenesis, particularly in neuronal and retinal progenitor cells (By similarity). Phosphorylates KIF3A (By similarity). Involved in the control of ciliary length (By similarity). Regulates the ciliary localization of SHH pathway components as well as the localization of IFT components at ciliary tips (By similarity). May play a role in cardiac development (PubMed:8570168). 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).
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 (By similarity).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family.
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.
Belongs to the nuclear hormone receptor family. NR0 subfamily.
Homodimer. Interacts with NR5A1, NR5A2, NR0B2 and with COPS2 (By similarity). Interacts with ESRRB; represses ESRRB activity at the GATA6 promoter (By similarity).
Homodimerization involved an interaction between amino and carboxy termini involving LXXLL motifs and steroid binding domain (AF-2 motif). Heterodimerizes with NR5A1 and NROB2 through its N-terminal LXXLL motifs (By similarity).
Orphan nuclear receptor. Component of a cascade required for the development of the hypothalamic-pituitary-adrenal-gonadal axis. Acts as a coregulatory protein that inhibits the transcriptional activity of other nuclear receptors through heterodimeric interactions. May also have a role in the development of the embryo and in the maintenance of embryonic stem cell pluripotency (By similarity).
Belongs to the argonaute family. Ago subfamily.
Interacts with EIF4B, IMP8, PRMT5 and TNRC6B. Interacts with APOBEC3F, APOBEC3G and APOBEC3H.
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.
Belongs to the NF-kappa-B inhibitor family.
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 (By similarity).
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 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 (By similarity). Interacts with HIF1AN (By similarity). Interacts with MEFV (By similarity). Interacts with DDRGK1; positively regulates NFKBIA phosphorylation and degradation (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with HNRNPLL. Interacts with APEX1; the interaction is DNA-dependent. Component of a complex with SETD2 (By similarity). Interacts with ELAVL1 (PubMed:18161049). Part of a transcription inhibitory ribonucleoprotein complex composed at least of the circular RNA circZNF827, ZNF827 and HNRNPK (By similarity).
Phosphorylation at Ser-578 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.
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. Component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and associated with most nascent transcripts. Associates, together with APEX1, to the negative calcium responsive element (nCaRE) B2 of the APEX2 promoter. 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 (By similarity).
Belongs to the glycosyl hydrolase 99 family.
Cloning artifact. The sequence differs from that shown at the N-terminus (1-54).
Highly expressed in the liver and kidney.
Undergoes proteolytic cleavage in the C-terminal region.
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 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:16218937). In vitro, also synthesizes sialyl-dimeric-Lex structures, from VIM-2 structures and both di-fucosylated and trifucosylated structures from mono-fucosylated precursors. 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. 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. 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. May enhance embryo implantation through sialyl Lewis X (sLeX)-mediated adhesion of embryo cells to endometrium. 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 (By similarity).
Inhibited by NaCl. Inhibited by GDP in a concentration dependent manner, with an IC(50) value of 93 uM. Also inhibited by GMP and GTP. Inhibited by N-ethylmaleimide. Activated by poly(ethylene glycol) by enhancing the thermal stability of FUT7. Activated by Mn2+, Ca2+, and Mg2+. Both panosialin A and B inhibit activity with IC(50) values of 4.8 and 5.3 ug/ml, respectively. 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.
Strongly induced in kidney allograft during rejection.
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. May play a role in hypoxia-induced oncogenesis.
Plays a role in the recruitment of the exosome to pre-rRNA to mediate the 3'-5' end processing of the 5.8S rRNA.
Component of the signal peptidase complex paralog A (SPC-A) composed of a catalytic subunit SEC11A and three accessory subunits SPCS1, SPCS2 and SPCS3. Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3. Within the complex, interacts with SEC11A or SEC11C and SPCS1. 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. This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids.
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 (By similarity). Essential for the SPC catalytic activity, possibly by stabilizing and positioning the active center of the complex close to the lumenal surface (By similarity).
Involved in several stages of intracellular trafficking.
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. Probably also part of an LSm subunits-containing complex involved in the general process of mRNA degradation.
Belongs to the peptidase C19 family. USP16 subfamily.
Contaminating sequence. Potential poly-A sequence.
Phosphorylated at the onset of mitosis and dephosphorylated during the metaphase/anaphase transition. Phosphorylation by AURKB enhances the deubiquitinase activity.
Specifically deubiquitinates 'Lys-120' of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Deubiquitination of histone H2A is a prerequisite for subsequent phosphorylation at 'Ser-11' of histone H3 (H3S10ph), and is required for chromosome segregation when cells enter into mitosis. In resting B- and T-lymphocytes, phosphorylation by AURKB leads to enhance its activity, thereby maintaining transcription in resting lymphocytes. Regulates Hox gene expression via histone H2A deubiquitination. Prefers nucleosomal substrates. Does not deubiquitinate histone H2B.
The UBP-type zinc finger binds 3 zinc ions that form a pair of cross-braced ring fingers encapsulated within a third zinc finger in the primary structure. It recognizes the C-terminal tail of free ubiquitin.
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 (PubMed:11809740).
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.
Heterotetramer of two type I and two type II keratins. Keratin-3 associates with keratin-12 (By similarity).
Involved in corneal epithelium organization, integrity and corneal keratin expression.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type IV family.
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). Specific for lipid substrates, inactive towards water soluble inositol phosphates (By similarity) (PubMed:10405344). Plays an essential role in the primary cilium by controlling ciliary growth and phosphoinositide 3-kinase (PI3K) signaling and stability (By similarity).
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. 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.
Interacts with ATP6V0B (By similarity). Interacts with CD81 (By similarity). Interacts with SPP1; the interaction reduces OPN expression (By similarity). Interacts with BRI3 (By similarity).
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.
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins.
By acting through a filamin-A/F-actin axis, it controls the start of neocortical cell migration from the ventricular zone. May be able to induce the degradation of Filamin A.
Expressed in muscle tissue, including heart. Found in cortical ventricular zone.
Interacts with FLNA. Interacts with RHOD (in GTP-bound form).
Belongs to the cytochrome c oxidase subunit 6A family.
Belongs to the snail C2H2-type zinc-finger protein family.
GSK3B-mediated phosphorylation results in cytoplasmic localization and degradation.
Interacts (via SNAG domain) with LIMD1 (via LIM domains), WTIP (via LIM domains) and AJUBA (via LIM domains) (By similarity). Interacts (via zinc fingers) with KPNA2, KPNB1 and TNPO1. May interact (via zinc fingers) with IPO7 (By similarity).
Repression activity depends on the C-terminal DNA-binding zinc fingers and on the N-terminal repression domain.
Transcriptional repressor that modulates both activator-dependent and basal transcription. Involved in the generation and migration of neural crest cells. Plays a role in mediating RAF1-induced transcriptional repression of the TJ protein, occludin (OCLN) and subsequent oncogenic transformation of epithelial cells. Represses BRCA2 expression by binding to its E2-box-containing silencer and recruiting CTBP1 and HDAC1 in breast cells. In epidermal keratinocytes, binds to the E-box in ITGA3 promoter and represses its transcription. Involved in the regulation of ITGB1 and ITGB4 expression and cell adhesion and proliferation in epidermal keratinocytes. Binds to E-box2 domain of BSG and activates its expression during TGFB1-induced epithelial-mesenchymal transition (EMT) in hepatocytes. Represses E-Cadherin/CDH1 transcription via E-box elements. Involved in osteoblast maturation. Binds to RUNX2 and SOC9 promoters and may act as a positive and negative transcription regulator, respectively, in osteoblasts. Binds to CXCL12 promoter via E-box regions in mesenchymal stem cells and osteoblasts. Plays an essential role in TWIST1-induced EMT and its ability to promote invasion and metastasis (By similarity).
Negative regulator of sphingolipid synthesis.
By estrogen in vagina, cervix, uterus and kidney.
Monomer. Interacts with NEDD4. Interacts (via PSAP motif) with TSG101, a component of the ESCRT-I complex (endosomal sorting complex required for transport I). Interacts with WWOX. Interacts with STAM, a component of the ESCRT-0 complex; the interaction is direct. Identified in a complex with STAM and HGS; within this complex, interacts directly with STAM, but not with HGS. Interacts with STAT6.
Phosphorylated on tyrosine residues in response to EGF.
Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation. Plays a role in targeting endocytosed EGFR and ERGG3 for lysosomal degradation, and thereby helps down-regulate downstream signaling cascades. Helps recruit the ESCRT complex components TSG101, HGS and STAM to cytoplasmic membranes. Probably plays a role in regulating protein degradation via its interaction with NEDD4. May also contribute to the regulation of gene expression in the nucleus. Binds DNA (in vitro) and may play a synergistic role with STAT6 in the nucleus in regulating the expression of various cytokines. May regulate the expression of numerous cytokines, such as TNF, CCL2, CCL5, CXCL1, IL1A and IL10.
The LITAF domain is stabilized by a bound zinc ion. The LITAF domain contains an amphipathic helix that mediates interaction with lipid membranes. It interacts specifically with phosphatidylethanolamine lipid headgroups, but not with phosphoglycerol, phosphocholine, phosphoserine or inositolhexakisphosphate.
The PPxY motif mediates interaction with WWOX and NEDD4.
Interacts with GNB2 (By similarity). Homooligomer. Interacts with OGT in the brain. Interacts with IQCB1 (By similarity).
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.
Ubiquitous distribution. Markedly increased expression in testis, adrenals, and brain.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. DMPK subfamily.
Found in a complex with YY1, SIN3A and HDAC1.
Has transcriptional repressor activity, probably as part of a complex with YY1, SIN3A and HDAC1. Required for B cell lymphopoiesis.
Belongs to the CRF-binding protein family.
Binds CRF and inactivates it. May prevent inappropriate pituitary-adrenal stimulation in pregnancy.
Acetylation stimulates the transcriptional activity.
Belongs to the nuclear hormone receptor family. NR5 subfamily.
Binds DNA as a monomer (By similarity). Part of a complex consisting of SFPQ, NONO and NR5A1. Interacts with NR0B2, NCOA2 and PPARGC1A. Interacts with DGKQ and CDK7. Binds to and activated by HIPK3 (By similarity).
Phosphorylated on Ser-203 by CDK7. This phosphorylation promotes transcriptional activity (By similarity).
Sumoylation reduces CDK7-mediated phosphorylation on Ser-203.
Transcriptional activator. Seems to be essential for sexual differentiation and formation of the primary steroidogenic tissues. 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. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. Binds phosphatidylcholine and 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 (By similarity).
May play a role in motor coordination and exploratory behavior.
Acetylation at Lys-125 markedly inhibits catalysis of cis to trans isomerization (By similarity). PPIA acetylation also antagonizes the immunosuppressive effects of cyclosporine by inhibiting the sequential steps of cyclosporine binding and calcineurin inhibition (By similarity). Acetylation at Lys-125 favors the interaction with TARDBP (By similarity).
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 (By similarity). 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 (By similarity). Activates endothelial cells (ECs) in a proinflammatory 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 (By similarity). Induces apoptosis in ECs by promoting the FOXO1-dependent expression of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (By similarity). 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 (By similarity). Negatively regulates MAP3K5/ASK1 kinase activity, autophosphorylation and oxidative stress-induced apoptosis mediated by MAP3K5/ASK1 (By similarity). 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 (By similarity). 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 (By similarity).
Interacts with protein phosphatase PPP3CA/calcineurin A (By similarity). Interacts with isoform 2 of BSG/CD147 (By similarity). Interacts with FOXO1; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (By similarity). 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 (By similarity). 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 (By similarity). Interacts with HNRNPA1, HNRNPA2B1, HNRNPC, RBMX, HNRNPK and HNRNPM (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.
Belongs to the proteasome subunit S3 family.
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 cerebral cortex and cerebellum. Expressed in retina (at protein level).
Expression starts at 16 dpc in the cerebral cortex and increases to reach a maximum 20 days after birth. Then it decreases till adulthood to be expressed half of the peak level. In the retina, expression reaches a maximum at postnatal day 14 (P14). It starts weakly at 16 dpc in the retinal pigment epithelium (RPE). At P0 it is detected in nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL) and RPE. At P7, it becomes intense in the NFL and IPL. At P14, expression becomes intense in the area of outer segments (OS) of the photoreceptor cells as well as in RPE, whereas in the inner layers it becomes gradually fainter. From P21 to P42, it decreases in inner retinal layers. OS and RPE still express, whereas expression in the NFL and IPL decreases (at protein level).
Interacts with ERBB3 and GOPC. Binds TNR and probably TNC (By similarity). Interacts with MDK; this interaction is independent of the presence of chondroitin sulfate chains and promotes elongation of oligodendroglial precursor-like cells (PubMed:16901907).
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.
Up-regulated in nucleus accumbens shell by cocaine administration.
By oxidative stress, and thioredoxin. Under oxidative stress conditions, the catalytic cysteine site is converted to a sulfenate which inhibits the MPST enzyme activity. Reduced thioredoxin cleaves an intersubunit disulfide bond to turn on the redox switch and reactivate the enzyme. Inhibited by different oxidants, hydrogen peroxide and tetrathionate.
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).
Expressed in liver, heart, kidney and brain. Localizes to tubular epithelium in the kidney, pericentral hepatocytes in the liver, cardiac cells in the heart and neuroglial cells in the brain. Also expressed in vascular endothelium of the thoracic aorta. Weak expression in lung and thymus.
Monomer (active form). Homodimer; disulfide-linked (inactive form).
Thioredoxin (Trx) or dihydrolipoic acid (DHLA) are required to release hydrogen sulfide from the persulfide intermediate.
Transfer of a sulfur ion to cyanide or to other thiol compounds. Also has weak rhodanese activity. Detoxifies cyanide and is required for thiosulfate biosynthesis. Acts as an antioxidant. In combination with cysteine aminotransferase (CAT), contributes to the catabolism of cysteine and is an important producer of hydrogen sulfide in the brain, retina and vascular endothelial cells. Hydrogen sulfide H(2)S is an important synaptic modulator, signaling molecule, smooth muscle contractor and neuroprotectant. Its production by the 3MST/CAT pathway is regulated by calcium ions.
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) (By similarity). 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.
Heterodimer with TFF1; disulfide linked. Interacts with TFF2 (By similarity).
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.
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.
Belongs to the carbon-nitrogen hydrolase superfamily. NIT1/NIT2 family.
Catalyzes the hydrolysis of the amide bond in N-(4-oxoglutarate)-L-cysteinylglycine (deaminated glutathione), a metabolite repair reaction to dispose of the harmful deaminated glutathione. Plays a role in cell growth and apoptosis: loss of expression promotes cell growth, resistance to DNA damage stress and increased incidence to NMBA-induced tumors. Has tumor suppressor properties that enhances the apoptotic responsiveness in cancer cells; this effect is additive to the tumor suppressor activity of FHIT. It is also a negative regulator of primary T-cells.
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. 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. 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. 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 (By similarity).
Highly expressed in 12-day embryo. In the adult, strongly expressed in liver, small intestine, jejunum, and to a lesser extent in kidney, lung, spleen and thymus. Expression in the liver is up-regulated following partial hepatectomy.
Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA (By similarity).
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.
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 (By similarity).
Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.
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 cerebellum (PubMed:18179769, PubMed:29055082). Detected on pericapillary astrocyte endfeet in cerebellum, and in skeletal muscle (PubMed:29055082). Detected in glial lamellae in the hypothalamus (at protein level) (PubMed:16325200). Abundant in mature brain cortex, cerebellum and spinal cord. Highly expressed in the ependymal cell lining the aqueductal system and over the space of the brain in contact with the subarachnoid space. Detected in paraventricular and supraoptic nuclei, the granule cell layer of the dentate gyrus and the Purkinje cell layer in the cerebellum. Only weakly detectable in eye, kidney, intestine, and lung (PubMed:7528931).
Detected in mature brain, but not in fetal brain.
Forms a water-specific channel (PubMed:7528931, PubMed:7509789, PubMed:19800950). 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:16325200, PubMed:19406128). The tetramers can form oligomeric arrays in membranes (PubMed:18179769, PubMed:29055082). The size of the oligomers differs between tissues and is smaller in skeletal muscle than in brain (PubMed:29055082). Interaction between AQP4 oligomeric arrays in close-by cells can contribute to cell-cell adhesion (PubMed:16325200). Part of a complex containing MLC1, TRPV4, HEPACAM and ATP1B1 (By similarity).
Isoform Long: Palmitoylated on its N-terminal region. Isoform 3: Not palmitoylated.
Phosphorylation by PKC at Ser-180 promotes internalization from the cell membrane, reducing the conductance by 50% (PubMed:19800950). Phosphorylation by PKG at Ser-111 in response to glutamate increases conductance by 40% (By similarity).
Belongs to the MAP1A/MAP1B/MAP1S family.
Expressed in cortex cerebellum, dorsal root ganglia, frontal cortex, hippocampus, hypothalamus, mesencephalon, medulla oblongata, occipital cortex, pons, spinal cord, striatum of the brain, neurons, heart, testis and skeletal muscle (at protein level).
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 with LRPPRC, RASSF1, microtubules and VCY2. Interacts (via C-terminus) with GAN (via Kelch domains). Interacts with WDR47 (via N-terminus of light chain) (By similarity). Interacts with ESR1.
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. Its C-terminal part of the heavy chain interacts with ESR1 (By similarity).
In isoform 1, the N-terminal region preceding the ANK repeats interacts with the 6 ANK repeats in an intramolecular manner, thereby restricting access to ligands, such as SHARPIN and SPTAN1.
Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. 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 through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation.
May homomultimerize via its SAM domain. Interacts with BAIAP2, DBNL and SLC17A7/VGLUT1. Interacts with DLGAP1/GKAP, GRM1/MGLUR1, GRM5/MGLUR5 and LZTS3 C-termini via its PDZ domain. Interacts with ABI1, HOMER1, HOMER2, HOMER3 and CTTN/cortactin SH3 domain. Is part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts (via PDZ domain) with the GRIA1 subunit of the AMPA receptor (via PDZ-binding motif). Interacts with WASF1 and CYFIP2; the interactions mediate the association of SHANK3 with the WAVE1 complex. Interacts with ARPC2; the interaction probably mediates the association of SHANK3 with the Arp2/3 complex. Interacts (via ANK repeats) with SHARPIN and SPTAN1. Interacts (via PDZ domain) with ARHGAP44 (probably via PDZ-binding motif); the interaction takes place in dendritic spines and promotes GRIA1 exocytosis. Interacts with CAMK2A (By similarity). Interacts with DIP2A (By similarity).
Widely expressed in brain (at protein level).
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.
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.
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.
The UBAX-like region mediates the interaction with VCP.
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.
Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo.
Belongs to the peptidase S1 family. Plasminogen subfamily.
Converted into plasmin by plasminogen activators, both plasminogen and its activator being bound to fibrin. Cannot be activated with streptokinase.
In the presence of the inhibitor, the activation involves only cleavage after Arg-581, resulting in 2 chains held together by 2 disulfide bonds. Without the inhibitor, the activation involves also removal of the activation peptide (By similarity).
In the presence of the inhibitor, the activation involves only cleavage after Arg-581, 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 (By similarity).
Interacts (both mature PLG and the angiostatin peptide) with AMOT and CSPG4. Interacts (via the Kringle domains) with HRG; the interaction tethers PLG to the cell surface and enhances its activation. Interacts (via Kringle 4 domain) with ADA; the interaction stimulates PLG activation when in complex with DPP4. Angiostatin: Interacts with ATP5F1A; the interaction inhibits most of the angiogenic effects of angiostatin.
Kringle domains mediate interaction with CSPG4.
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 (By similarity).
Plasmin is inactivated by alpha-2-antiplasmin immediately after dissociation from the clot.
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 (By similarity).
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 (By similarity).
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.
Belongs to the interleukin-1 receptor family.
Although related to peptidase S1 family, lacks the essential His, Asp, and Ser residues of the catalytic triad at positions 73, 119 and 210 and is therefore predicted to have lost protease activity.
Belongs to the peptidase S1 family. Plasma kallikrein subfamily.
Activated by divalent cations (PubMed:17655883). Activated by bile acids (By similarity). Activated by membrane phospholipids such as phosphatidylethanolamines. Inhibited by cardiolipins (PubMed:17655883).
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:17655883). 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).
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 (By similarity).
Highly expressed in heart, in particular in right and left atrium, and detected at lower levels in the right and left ventricle.
Potassium channel subunit. Modulates channel activity by shifting the threshold and the half-maximal activation to more negative values (By similarity).
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). 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. Interacts with RNF139. Interacts with RNF145.
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. 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. 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. 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. 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. 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.
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. In differentiated myotubes, Cys-215 oxidation prevents ubiquitination at the same site, resulting in protein stabilization.
Mitochondrial acyltransferase which transfers an acyl group to the N-terminus of glycine and glutamine, although much less efficiently. Can conjugate a multitude of substrates to form a variety of N-acylglycines, thereby detoxify xenobiotics, such as benzoic acid or salicylic acid, and endogenous organic acids, such as isovaleric acid.
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).
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.
Expressed in skeletal and cardiac muscle. Expressed in replicating myoblasts. In differentiated muscle fibers localizes between fibers and the surrounding matrix. Isoform Alpha-7X1A and isoform Alpha-7X1B are expressed at myotendinous and neuromuscular junctions; isoform Alpha-7X1C is expressed at neuromuscular junctions and at extrasynaptic sites.
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. Involved in the maintenance of the myofibers cytoarchitecture as well as for their anchorage, viability and functional integrity. Required to promote contractile phenotype acquisition in differentiated airway smooth muscle (ASM) cells (By similarity). 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.
Interacts (via C-terminus intracellular tail region) with CIB1; the interaction is stabilized/increased in a calcium- and magnesium-dependent manner (By similarity). Heterodimer of an alpha and a beta subunit. The alpha subunit is composed of a heavy and a light chain linked by a disulfide bond. Alpha-7 associates with beta-1. Interacts with COMP.
Isoforms are developmentally regulated during the formation of skeletal muscle. Isoform Alpha-7X1A and isoform Alpha-7X1C are induced upon terminal myogenic differentiation; isoform Alpha-7X1B is present earlier in replicating cells and diminishes upon differentiation.
Monomethylation at Lys-85 (K85me1) 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.
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.
Present in the brain, in particular in the postsynaptic density and the dendritic lipid raft fractions (at protein level).
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.
Belongs to the glycosyltransferase 41 family. O-GlcNAc transferase subfamily.
Catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in cytoplasmic and nuclear proteins resulting in their modification with a beta-linked N-acetylglucosamine (O-GlcNAc) (PubMed:24995978, PubMed:10542233). Has 3 distinct KM values for UDP-GlcNAc; GlcNAc concentration modulates its affinity for different substrates (PubMed:10542233). Glycosylates a large and diverse number of proteins including histone H2B, AKT1, ATG4B, EZH2, PFKL, KMT2E/MLL5, MAPT/TAU and HCFC1. Can regulate their cellular processes via cross-talk between glycosylation and phosphorylation or by affecting proteolytic processing. Probably by glycosylating KMT2E/MLL5, stabilizes KMT2E/MLL5 by preventing its ubiquitination (By similarity). Involved in insulin resistance in muscle and adipocyte cells via glycosylating insulin signaling components and inhibiting the 'Thr-308' phosphorylation of AKT1, enhancing IRS1 phosphorylation and attenuating insulin signaling (PubMed:18288188). Involved in glycolysis regulation by mediating glycosylation of 6-phosphofructokinase PFKL, inhibiting its activity. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. Plays a key role in chromatin structure by mediating O-GlcNAcylation of 'Ser-112' of histone H2B: recruited to CpG-rich transcription start sites of active genes via its interaction with TET proteins (TET1, TET2 or TET3). As part of the NSL complex indirectly involved in acetylation of nucleosomal histone H4 on several lysine residues. O-GlcNAcylation of 'Ser-75' of EZH2 increases its stability, and facilitating the formation of H3K27me3 by the PRC2/EED-EZH2 complex. Regulates circadian oscillation of the clock genes and glucose homeostasis in the liver. Stabilizes clock proteins BMAL1 and CLOCK through O-glycosylation, which prevents their ubiquitination and subsequent degradation. Promotes the CLOCK-BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2 and CRY1/2. O-glycosylates HCFC1 and regulates its proteolytic processing and transcriptional activity (By similarity). Regulates mitochondrial motility in neurons by mediating glycosylation of TRAK1 (PubMed:24995978). Glycosylates HOXA1 (By similarity). O-glycosylates FNIP1 (By similarity). Promotes autophagy by mediating O-glycosylation of ATG4B (By similarity).
Expressed in brain, heart, liver, thymus, muscle, lung, spleen, uterus and ovary; in the kidney only an immunologically-related 78 kDa band is present, which is also present in liver and muscle (PubMed:9083067). In the pancreas, expressed in both exocrine acinar cells and in endocrine cells of the islets of Langerhans.
Homotrimer, oligomerizes via TPR repeats 6 and 7. Trimerization is not necessary for activity in vitro, however it increases affinity for UDP-GlcNAc (PubMed:10542233). A heterotrimer consisting of two 110 kDa subunits and one highly related 78 kDa subunit is isolated from liver (PubMed:1533623). Component of a THAP1/THAP3-HCFC1-OGT complex. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1. Interacts directly with HCFC1; the interaction O-glycosylates HCFC1, regulates its proteolytic processing and transcriptional activity and, in turn, stabilizes OGT in the nucleus. Interacts (via TPRs 1-6) with SIN3A; the interaction mediates transcriptional repression in parallel with histone deacetylase. Interacts (via TPR 5-6) with TET1, TET2 and TET3 (By similarity). Interacts (via TPR repeats 6 and 7) with ATXN10 (PubMed:16714295). Interacts with histone H2B (By similarity). Interacts with BMAL1. Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SINHCAF (By similarity). Component of a complex composed of KMT2E/MLL5, OGT and USP7; the complex stabilizes KMT2E/MLL5, preventing KMT2E/MLL5 ubiquitination and proteosomal-mediated degradation. Interacts (via TRP repeats) with KMT2E (via N-terminus). Interacts with USP7 (By similarity). Interacts with TRAK1; this interaction is not required for glycosylation of TRAK1 by this protein. Found in a complex with KIF5B, RHOT1, RHOT2 and TRAK1 (PubMed:24995978). Interacts (via TPR repeats domain) with HOXA1; the interaction takes place mainly in the nucleus (By similarity). Interacts with NSD2 (By similarity).
Inhibited by UDP, UTP and UDP-GlcNAc; 50 mM NaCl or KCl inhibit activity about 70%.
O-glycosylated; contains O-GlcNAc. Both p110 and p78 forms are O-glycosylated.
Phosphorylation on Ser-3 or Ser-4 by GSK3-beta positively regulates its activity.
Several different immunologically-related forms of this protein are found in different tissues (with apparent molecular weights of 110, 80 and 78 kDa); they are probably the result of alternative splicing and/or proteolysis.
The TPR repeat domain is required for substrate binding and oligomerization.
Ubiquitinated, leading to its proteasomal degradation.
Belongs to the eukaryotic ribosomal protein eL42 family.
Belongs to the glycosyltransferase 61 family.
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 (By similarity).
At neuronal promoters, displaces LDB1 from LHX3 LIM domain to form a ternary complex in which ISL1 contacts both LHX3 and LDB1; allosteric structural changes in the DNA binding domain of LHX3, induced by the ISL1:LHX3 interaction, may explain differences in sequence specificity of the different complexes. Interacts with LHX3. Interacts (via C-terminus) with POU4F2 (via C-terminus) isoform 1. Interacts with POU3F2. Interacts with POU4F3. Interacts (via N-terminal domain) with MLIP; the interaction represses ISL1 transactivator activity.
DNA-binding transcriptional activator. Recognizes and binds to the consensus octamer binding site 5'-ATAATTAA-3' in promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Cooperates with the transcription factor POU4F2 to achieve maximal levels of expression of RGC target genes and RGC fate specification in the developing retina. Involved in the specification of motor neurons in cooperation with LHX3 and LDB1 (By similarity). Binds to insulin gene enhancer sequences (PubMed:1691825). Essential for heart development. Marker of one progenitor cell population that give rise to the outflow tract, right ventricle, a subset of left ventricular cells, and a large number of atrial cells as well, its function is required for these progenitors to contribute to the heart. Controls the expression of FGF and BMP growth factors in this cell population and is required for proliferation and survival of cells within pharyngeal foregut endoderm and adjacent splanchnic mesoderm as well as for migration of cardiac progenitors into the heart (By similarity).
Expressed in islet cells of the pancreas (PubMed:7907017, PubMed:1691825).
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 activation (By similarity). 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, KHDC3, OOEP, and TLE6 (By similarity). Within the complex, interacts with NLRP5, KHDC3 and TLE6 (By similarity). The SCMC may facilitate translocation of its components between the nuclear and cytoplasmic compartments (By similarity). 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 (By similarity). Interacts (via C-terminus) with NUMA1 (By similarity).
Belongs to the dynein light chain Tctex-type family.
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 (By similarity).
Homodimer (By similarity). Interacts with APOA1 and APOA2 (By similarity).
Undergoes physiological phosphorylation during sperm capacitation, downstream to PKA activation.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. SerC subfamily.
Catalyzes the reversible conversion of 3-phosphohydroxypyruvate to phosphoserine and of 3-hydroxy-2-oxo-4-phosphonooxybutanoate to phosphohydroxythreonine.
Belongs to the chloride channel MCLC family.
Expressed in testis (spermatocytes), liver and lung (at protein level). Expressed in spleen, liver, testis, kidney, heart, brain and lung.
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 (By similarity). Interacts with CALR (By similarity).
Seems to act as a chloride ion channel (PubMed:11279057). Plays a role in retina development (By similarity).
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 (By similarity). Binds ASAP2 (By similarity). Interacts with NCS1/FREQ at the Golgi complex. Interacts with RAB11FIP3 and RAB11FIP4 (By similarity).
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the N-acetyl glucosamine (GlcNAc) of a distal lactosamine unit of a glycoprotein or a glycolipid-linked polylactosamine chains through an alpha-1,3 glycosidic linkage and participates in particular to the Lewis x (Lex)/CD15 epitope biosynthesis in neurons which allows cell differentiation, cell adhesion, and initiation of neurite outgrowth (PubMed:11020213, PubMed:11675393). Also fucosylates di-, tri- and tetraantennary N-glycans linked to glycoproteins and the inner lactosamine unit of the alpha2,3-sialylated polylactosamine resulting in sLex (CD15s) epitope synthesis. Furthermore, it is capable of synthesizing Lewis a (Lea), although to a lesser extent than Lex and Lewis y (Ley) and to confer SELE-dependent, but not SELL- and SELP-selectin-dependent, cell rolling and adhesion by enhancing Lex and sLex synthesis (By similarity). May also fucosylate the internal LacNAc unit of the polylactosamine chain to form VIM-2 antigen that serves as recognition epitope for SELE.
N-glycosylated with complex-type N-glycans.
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.
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 protease inhibitor I47 (latexin) family.
Belongs to the proteasome subunit p55 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). 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. 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. The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression. 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). Probably by regulating HR, plays a key role during gametogenesis. Stabilizes MCM9 protein.
Component of the MCM8-MCM9 complex, which forms a hexamer composed of MCM8 and MCM9. Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1. Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites. Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1. Interacts with CDC6 and ORC2. Interacts with HROB; the interaction recruits the MCM8-MCM9 complex to DNA damage sites (By similarity).
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.
Generally pentameric. There are five types of GABA(A) receptor chains: alpha, beta, gamma, delta, and rho. Interacts with SQSTM1.
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.
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 (By similarity).
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 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 (By similarity).
Receptor for lutropin-choriogonadotropic hormone. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.
Belongs to the organo anion transporter (TC 2.A.60) family.
May mediate the Na(+)-independent transport of organic anions.
Homodimer. 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 (By similarity). Interacts with GABRB1, GABRB2 and GABRB3.
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.
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. Binds to anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) that modulate enzymatic activity and subcellular location (By similarity). Regulates the cell cycle by acting as a growth suppressor in confluent cells. Acts as a regulator of postnatal development and participates in bone and dentin mineralization. May be involved in IL-1-beta-induced JNK activation in hepatocytes. May act as a mediator in transcriptional regulation of NOS2/iNOS via the NF-kappa-B activation under inflammatory conditions.
In brain sections, it is restricted to neurons and especially prominent in large cells, including Purkinje cells, pyramidal cells, neurons of the dentate gyrus granular layer, and neurons in the pontine nuclei. Also present in the hypothalamic nuclei, neurons in the piriform cortex, and nuclei of the brainstem (at protein level). Mainly expressed in brain and jejunum. Weakly or not expressed in heart, spleen, lung, liver, kidney and testis.
Inhibited by nSMase inhibitor GW4869. Binding of anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) increases enzymatic activity.
Palmitoylated, palmitoylation-deficient proteins are targeted for lysosomal degradation.
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Negative regulator of signaling cascades that mediate activation of MAP kinases via AKAP13.
Homodimer (By similarity). Interacts with SAMSN1 and PRKCE (By similarity). Interacts with AKAP13. Interacts with SSH1 and TORC2/CRTC2. Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhibition of cABL-mediated apoptosis. Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues. Interacts with GAB2. Interacts with YAP1 (phosphorylated form). Interacts with the phosphorylated (by AKT1) form of SRPK2 (By similarity). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with MYO1C. Interacts with SIRT2 (By similarity). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B. Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (By similarity). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (By similarity). Interacts with SLITRK1. Interacts with SYNPO2 (phosphorylated form); YWHAB competes with ACTN2 for interaction with SYNPO2 (By similarity). Interacts with RIPOR2 (via phosphorylated form); this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (By similarity). Interacts with MARK2 and MARK3 (By similarity). Interacts with TESK1; the interaction is dependent on the phosphorylation of TESK1 'Ser-439' and inhibits TESK1 kinase activity (PubMed:11555644). Interacts with MEFV (By similarity). Interacts with HDAC4 (By similarity). Interacts with ADAM22 (via C-terminus) (By similarity).
Isoform Short contains a N-acetylmethionine at position 1.
The alpha, brain-specific form differs from the beta form in being phosphorylated. Phosphorylated on Ser-60 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.
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.
Contains glycosaminoglycans of chondroitin-sulfate and heparan types.
Belongs to the eukaryotic ribosomal protein eS27 family.
Binds to SUMO2 and SUMO3 (By similarity). Interacts with the C-terminal domain of NUP153 via its N-terminus (By similarity). Interacts with MTA1 (By similarity). Binds to AXIN1 (PubMed:10944533).
Polyubiquitinated; which leads to proteasomal degradation.
Protease that catalyzes two essential functions in the SUMO pathway (By similarity). 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 (By similarity). 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 (By similarity). May down-regulate CTNNB1 levels and thereby modulate the Wnt pathway (PubMed:10944533, PubMed:11997515). Deconjugates SUMO2 from MTA1 (By similarity). Plays a dynamic role in adipogenesis by desumoylating and promoting the stabilization of CEBPB (By similarity). 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).
Ubiquitous. Highly expressed in brain, lung and testis.
Found in a complex with COX20, COA6, MT-CO2/COX2, COX18, SCO1 and SCO2. Interacts with COX20. Interacts with COX1, MT-CO2/COX2, SCO1 and SCO2 in a COX20-dependent manner.
Plays a role in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation and is required for the stabilization of COX20 and the newly synthesized MT-CO2/COX2 protein.
Detected in spleen, lung, liver, skeletal muscle, kidney, testis and in cerebellar Purkinje cells (at protein level). Ubiquitous. Highly expressed in brain, spleen, liver and kidney.
Interacts with TMEM39A (By similarity). Interacts with SEC23A and SEC24A; this interaction is reduced in the absence of TMEM39A (By similarity). Interacts with PLEKHA3 and VAPA and/or VAPB to form a ternary complex (By similarity).
Phosphoinositide phosphatase which catalyzes the hydrolysis of phosphatidylinositol 4-phosphate (PtdIns(4)P), phosphatidylinositol 3-phosphate (PtdIns(3)P) and has low activity towards phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:10887188, PubMed:27044890). 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 (By similarity). PtdIns(4)P phosphatase activity (when it binds PtdIns(4)P in 'trans' configuration) is enhanced in the presence of PLEKHA3 (By similarity).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type V subfamily.
Catalytically inactive regulatory factor of DNA methyltransferases that can either promote or inhibit DNA methylation depending on the context. Essential for the function of DNMT3A and DNMT3B: activates DNMT3A and DNMT3B by binding to their catalytic domain. 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 (By similarity). Recognizes unmethylated histone H3 lysine 4 (H3K4me0) and induces de novo DNA methylation by recruitment or activation of DNMT3 (By similarity). Plays a key role in embryonic stem cells and germ cells. In germ cells, required for the methylation of imprinted loci together with DNMT3A. In male germ cells, specifically required to methylate retrotransposons, preventing their mobilization. Plays a key role in embryonic stem cells (ESCs) by acting both as an positive and negative regulator of DNA methylation. 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. 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. Promotes differentiation of ESCs into primordial germ cells by inhibiting DNA methylation at the promoter of RHOX5, thereby activating its expression (By similarity).
Homodimer (By similarity). Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (By similarity). Interacts with histone H3 (via N-terminus); interaction is strongly inhibited by methylation at lysine 4 (H3K4me) (By similarity). Interacts with EZH2; the interaction is direct (By similarity). Interacts with SPOCD1 (By similarity).
Belongs to the polyribonucleotide nucleotidyltransferase family.
Regulates drug efflux through modulation of ABCB1 localization and activity.
Belongs to the glycosyl hydrolase 13 family. GlgB subfamily.
Belongs to the major facilitator superfamily.
Mediates high-affinity intracellular uptake of the rare oligo-element molybdenum.
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.
Acyltransferase which catalyzes the transfert of an acyl group from an acyl-CoA to a lysophospholipid leading to the production of a phospholipid and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle. May catalyze preferentially the acylation of lysophosphatidylethanolamine (1-acyl-sn-glycero-3-phosphoethanolamine or LPE) and lysophosphatidic acid (LPA) and to a lesser extend lysophosphatidylcholine (LPC) and lysophosphatidylserine (LPS). Prefers oleoyl-CoA as the acyl donor (By similarity). May be involved in chondrocyte differentiation (By similarity).
Belongs to the membrane-bound acyltransferase family.
CNTF is a survival factor for various neuronal cell types. Seems to prevent the degeneration of motor axons after axotomy.
Belongs to the 'GDXG' lipolytic enzyme family.
Can also utilize the flavins FMN and riboflavin.
Homotrimer. 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:23733181). Can also reduce Cu(2+) to Cu(1+) (PubMed:23733181). Plays a role in systemic metabolic homeostasis, integrating inflammatory and metabolic responses (By similarity). Associated with obesity and insulin-resistance (By similarity). Involved in inflammatory arthritis, through the regulation of inflammatory cytokines (By similarity). Inhibits anchorage-independent cell proliferation (By similarity).
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 (By similarity).
Belongs to the splicing factor SR family.
Extensively phosphorylated on serine residues in the RS domain. Phosphorylated by SRPK2 and this controls cell fate decision in response to cisplatin treatment. SRSF2 and SRPK2 cooperate to induce apoptosis through regulation of the splicing switch of caspase-8 pre-mRNA and in the absence of SRPK2, cisplatin-treated cells accumulate in G2/M phase. KAT5/TIP60 inhibits its phosphorylation by preventing SRPK2 nuclear translocation (By similarity).
In vitro, self-associates and binds SRSF1/SFRS1 (ASF/SF2), SNRNP70 and U2AF1 but not U2AF2. Binds SREK1/SFRS12. Interacts with CCNL2. Interacts with SCAF11. Interacts with ZRSR2/U2AF1-RS2. Interacts with CCDC55 (via C-terminus). Interacts with BRDT (By similarity). Interacts with CCNL1.
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. The phosphorylated form (by SRPK2) is required for cellular apoptosis in response to cisplatin treatment (By similarity).
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. 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 (By similarity). Interacts with DHX36 (By similarity). 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) (By similarity). Interacts with PHF5A (via C-terminus) (By similarity). Interacts with MBNL1 (By similarity). Interacts with CSTF2 (By similarity). Interacts with HNRNPK (By similarity). Interacts with ATM (By similarity). Interacts with RELA (via C-terminus) (By similarity). Component of the tRNA-splicing ligase complex (By similarity). Interacts with PQBP1 (By similarity). Interacts with ERCC6 (By similarity).
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.
Belongs to the methyltransferase superfamily. METL family.
S-adenosyl-L-methionine-dependent methyltransferase.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC5/Polo subfamily.
By the intense activity associated with seizures.
Constitutively expressed in post-mitotic neurons.
Interacts with GOLGB1 (By similarity). Interacts (via the POLO-box domain) with CIB1; leading to inhibit PLK3 kinase activity.
Phosphorylated in an ATM-dependent manner following DNA damage. Phosphorylated as cells enter mitosis and dephosphorylated as cells exit mitosis (By similarity).
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 (By similarity).
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. The POLO box domains mediates localization to the centrosome (By similarity).
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. Plays a role in apoptosis negative control involved in brain development (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.
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 (By similarity).
TFIIA is a heterodimer of a unprocessed large subunit 1 and a small subunit gamma. It was originally believed to be a heterotrimer of an alpha, a beta and a gamma subunit. TFIIA forms a complex with TBP (By similarity).
The alpha and beta subunits are postranslationally produced from the precursor formby TASP1. The cleavage promotes proteasomal degradation (By similarity).
Interaction with the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit (By similarity). Interacts with RANBP3L (By similarity).
Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase (By similarity). Phosphorylated by activin type I receptor-like kinase-2 (ALK-2).
Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD9 is a receptor-regulated SMAD (R-SMAD) (By similarity). Has been shown to be activated by activin type I receptor-like kinase-2 (ALK-2) which stimulates heteromerization between SMAD9 and SMAD4. ALK-2 binds TGF-beta, activin and BMP.
Belongs to the metallophosphoesterase superfamily. CPPED1 family.
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 (By similarity).
Detected in liver, lung and testis, but not in kidney (at protein level).
FAEE-synthesizing and PNPB-hydrolyzing activities are both inhibited by DFP.
Major lipase in white adipose tissue (By similarity). Involved in the metabolism of xenobiotics and of natural substrates. Hydrolyzes triacylglycerols and monoacylglycerols, with a preference for monoacylglycerols. The susceptibility of the substrate increases with decreasing acyl chain length of the fatty acid moiety. Catalyzes the synthesis of fatty acid ethyl esters (PubMed:1429692). Hydrolyzes retinyl esters (PubMed:12230550).
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.
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.
Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin.
Belongs to the glycoprotein hormones subunit alpha family.
Functions as a heterodimeric glycoprotein hormone with GPHB5 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production. Plays a central role in controlling thyroid cell metabolism.
Heterodimer with GPHB5; this heterodimer interacts with thyroid-stimulating hormone receptor (TSHR), and hence stimulates cAMP production.
Belongs to the heat shock protein 70 family.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (By similarity). Interacts with PACRG (By similarity). Interacts with HSPH1/HSP105 (By similarity). Interacts with IRAK1BP1 and BAG1 (By similarity). Interacts with DNAJC7 (PubMed:10567422). Interacts with DNAJB12 (via J domain) (By similarity). Interacts with DNAJB14 (via J domain) (By similarity). Interacts (via C-terminus) with the E3 ligase STUB1 forming a 210 kDa complex of one STUB1 and two HSPA8 molecules (By similarity). Interacts with CITED1 (via N-terminus); the interaction suppresses the association of CITED1 to p300/CBP and Smad-mediated transcription transactivation (By similarity). 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 (By similarity). Interacts with TRIM5 (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). Interacts with METTL21A (By similarity). Following LPS binding, may form a complex with CXCR4, GDF5 and HSP90AA1 (By similarity). Interacts with PRKN (By similarity). Interacts with FOXP3 (By similarity). Interacts with DNAJC9 (via J domain) (By similarity). Interacts with MLLT11 (By similarity). Interacts with RNF207 (By similarity). Interacts with DNAJC21 (By similarity). Interacts with DNAJB2 (By similarity). Interacts with TTC1 (via TPR repeats) (By similarity). Interacts with SGTA (via TPR repeats) (PubMed:15708368). Interacts with HSF1 (via transactivation domain) (By similarity). Interacts with HOPX, STUB1, HSP40, HSP90, BAG2 and BAG3 (By similarity). Interacts with DNAJC12 (By similarity). Interacts with HSPC138 (By similarity). Interacts with ZMYND10 (By similarity). Interacts with VGF-derived peptide TLQP-21 (By similarity). Interacts with BCL2L1, GIMAP5 and MCL1; the interaction with BCL2L1 or MCL1 is impaired in the absence of GIMAP5 (By similarity). Interacts with NLPR12 (By similarity). Interacts with TTC4 (By similarity). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import (By similarity). May interact with DNJC9; the interaction seems to be histone-dependent (By similarity). Interacts with BAG5 and JPH2; the interaction with JPH2 is increased in the presence of BAG5 (By similarity).
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 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. 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. Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70. 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. Participates in the ER-associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1. Interacts with VGF-derived peptide TLQP-21.
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.
Trimethylation at Lys-561 reduces fibrillar SNCA binding.
Belongs to the RRM HNRPC family. RALY subfamily.
Contains an N-terminal anti-parallel coiled coil formed by two BRMS1 chains; this region can form homohexamers.
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 (By similarity).
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 (By similarity).
Ubiquitinated by a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing SPOP, leading to proteasomal degradation.
A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.
Cleaved by the protease thrombin to yield monomers which, together with fibrinogen alpha (FGA) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the antibacterial immune response via both innate and T-cell mediated pathways.
Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot.
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 (By similarity).
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. Induces, through 'trans-signaling' and synergistically with IL1B and TNF, the production of VEGF. Involved in metabolic controls, is discharged into the bloodstream after muscle contraction increasing lipolysis and improving insulin resistance. 'Trans-signaling' in central nervous system regulates energy and glucose homeostasis. 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 (By similarity). Plays a protective role during liver injury, being required for maintenance of tissue regeneration. Also has a pivotal role in iron metabolism by regulating HAMP/hepcidin expression upon inflammation or bacterial infection. 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. Interacts with IL6R (via the N-terminal ectodomain); this interaction may be affected by IL6R-binding with SORL1, hence decreasing IL6 cis signaling. Interacts with SORL1 (via the N-terminal ectodomain); this interaction leads to IL6 internalization and lysosomal degradation. 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.
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. 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.
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. In the adaptive immune response, is required for the differentiation of B-cells into immunoglolin-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. Together with IL21, controls the early generation of Tfh cells and are critical for an effective antibody response to acute viral infection. Required to drive naive CD4(+) T cells to the Th17 lineage, through 'cluster signaling' by dendritic cells. Also required for proliferation of myeloma cells and the survival of plasmablast cells.
In pancreatic islets, secretion is stimulated by IL1B. In islets from Zucker diabetic fatty (ZDF) rats, but not lean animals, secretion is also increased by endocannabinoid anandamide/AEA.
Belongs to the protein kinase superfamily. Tyr protein kinase family.
Polypeptide N-acetylgalactosaminyltransferase that catalyzes the initiation of protein O-linked glycosylation and is involved in left/right asymmetry by mediating O-glycosylation of NOTCH1. O-glycosylation of NOTCH1 promotes activation of NOTCH1, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO). Polypeptide N-acetylgalactosaminyltransferases catalyze the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Displays the same enzyme activity toward MUC1, MUC4, and EA2 than GALNT1. Not involved in glycosylation of erythropoietin (EPO) (By similarity).
Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in the mitochondria. The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln).
Belongs to the GatB/GatE family. GatB subfamily.
Subunit of the heterotrimeric GatCAB amidotransferase (AdT) complex, composed of A (QRSL1), B (GATB) and C (GATC) subunits.
Transcriptional activator. May be involved in transcriptional activation of erythroid genes (By similarity).
Expressed predominantly in brain and testis.
Interacts with APP (via intracellular domain) (PubMed:9461550). Interacts with APLP1 and APLP2 (via intracellular domain) (By similarity).
May modulate the internalization of amyloid-beta precursor protein.
Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
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. During bacterial clearance, recognizes 'Lys-33'-linked polyubiquitinated TRAF3 and subsequently mediates assembly of the exocyst complex.
Interacts with RIT1 and RIT2 (By similarity). Interacts with TRAF3. Interacts with HRAS (By similarity).
Phosphorylation of Tyr-795 by MET blocks HRAS binding.
The Ras-associating domain interacts with Ras.
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 (By similarity). Interacts with ARMCX3 (By similarity). Found in a complex with KIF5B, OGT, RHOT1 and TRAK1 (PubMed:24995978).
Mitochondrial GTPase involved in mitochondrial trafficking. Probably involved in control of anterograde transport of mitochondria and their subcellular distribution (By similarity).
Ubiquitinated by PRKN in a PINK1-dependent manner, leading to its degradation.
Expressed in tongue and gastrointestinal tract.
Belongs to the Mediator complex subunit 22 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 (By similarity).
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.
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 (By similarity). Interacts with TRAP1 (By similarity). Interacts with LACC1 (By similarity).
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). Can act as a tumor suppressor.
Phosphorylation at Tyr-207 is important for efficient electron transfer in complex II and the prevention of ROS generation.
Belongs to the immunoglobulin superfamily. DCC family.
Detected in embryonic spinal cord, predominantly in axons of commissural neurons (at protein level). Detected in embryonic spinal cord.
Interacts with the cytoplasmic part of UNC5A, UNC5B and UNC5C (PubMed:10399920). Interacts with DSCAM (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with MYO10 (By similarity). Interacts with MAPK1 (PubMed:21070949). Interacts with NTN1 (PubMed:8861902). Interacts with CBLN4; this interaction can be competed by NTN1 (By similarity). Interacts with SIAH1 and SIAH2 (By similarity).
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 (By similarity).
Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation.
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.
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.
Belongs to the proteasome inhibitor PI31 family.
Monomer and homodimer. Interacts with FBXO7 (By similarity).
Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28 (By similarity).
Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.
Component of the 7-subunit TFIIH core complex.
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.
Dephosphorylated at Tyr-530 by PTPRJ. Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src (By similarity). 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 SRX 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 (By similarity). Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (By similarity).
Displays enhanced levels of autophosphorylation at Tyr-419 compared to isoform 1 (PubMed:26026271). Shows reduced phosphorylation at Tyr-527 compared to isoforms 1 and 2 (PubMed:26026271).
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 very low levels in the forebrain.
Expressed in the brain with highest expression in the pyramidal layers of the hippocampus and the granular layer of the dentate gyrus and moderate expression in cortical regions, with higher levels in the superficial layers than in the deep layers. May be neuron-specific.
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) (By similarity). 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. Plays a role in EGF-mediated calcium-activated chloride channel activation (By similarity). 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. 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. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (By similarity). 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-738'. Enhances RIGI-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-226'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Phosphorylates synaptic vesicle protein synaptophysin (SYP) (PubMed:26026271). Involved in anchorage-independent cell growth (By similarity). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (By similarity).
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 (PubMed:26026271). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (PubMed:26026271). 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 (PubMed:26026271). Plays a role in L1CAM-mediated neurite elongation, possibly by acting downstream of L1CAM to drive cytoskeletal rearrangements involved in neurite outgrowth (PubMed:28220894).
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 (PubMed:26026271). The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (PubMed:26026271). 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 (PubMed:26026271). Plays a role in neurite elongation (PubMed:28220894).
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 (By similarity). 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 CDCP1, TGFB1I1 and TOM1L2 (By similarity). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (By similarity). Interacts with RALGPS1; via the SH3 domain (By similarity). Interacts with CAV2 (tyrosine phosphorylated form) (By similarity). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (PubMed:10995467). Interacts with ARRB1 and ARRB2 (PubMed:10995467) (By similarity). Interacts with SRCIN1 (By similarity). Interacts with NDFIP2 and more weakly with NDFIP1 (By similarity). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1 and ESR1 (dimethylated on arginine) (PubMed:8849729). Interacts with FASLG (By similarity). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:8849729). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (By similarity). Interacts (via SH2 and SH3 domain) with TNK2 (By similarity). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (By similarity). Interacts with TRAF3 (via RING-type zinc finger domain) (By similarity). Interacts with RIGI, MAVS and TBK1 (By similarity). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (By similarity). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (By similarity). Interacts with FCAMR (By similarity). Interacts with PDGFRA (tyrosine phosphorylated) (By similarity). Interacts with CSF1R (By similarity). Interacts with DDR1 (By similarity). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (By similarity). Interacts with AMOTL2; this interaction promotes the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (By similarity). Interacts with DDR2 and DAB2 (PubMed:11884411, PubMed:12473651, PubMed:16186108). Interacts with TRAP1 (By similarity). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at Tyr-419 (By similarity). Interacts with ARHGEF5 (By similarity). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:19948503). Interacts with MPP2 (By similarity). Interacts with PRR7 (By similarity). 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 (By similarity). Interacts with P85 (PIK3R1 or PIK3R2) (By similarity). Interacts with HNRNPA2B1 (By similarity). Interacts with IL6ST/gp130 (By similarity). Interacts (via SH3 domain) with PELP1 in the presence of 17-beta-estradiol (By similarity). 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 (By similarity). Phosphorylation at Tyr-419 increases kinase activity.
S-nitrosylation is important for activation of its kinase activity.
Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-419 and may lead to lysosomal degradation (By similarity).
Up-regulated by MK-801, an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, mostly in the superficial layers of the parietal, temporal, occipital and frontal cortices.
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 and cerebellum (PubMed:1279699, PubMed:8387171). Both isoform GLAST-1 and GLAST-1A are expressed in bone and brain (PubMed:11086157). In brain isoform GLAST-1 is highly enriched in the Purkinje cell layer in cerebellum (PubMed:11086157).
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:1279699, PubMed:8387171). 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 (By similarity). 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).
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family.
Belongs to the intercrine beta (chemokine CC) family.
Belongs to the bZIP family. ATF subfamily.
Binds DNA as a dimer. Forms a heterodimer with CREM isoform Delta (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). PS1 cleavage may be suppressed by a determinant in the C-terminal region (By similarity).
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. Increases the binding of CREM isoform Delta with CRE. The CREM isoform Delta-CREB3L4 heterodimer functions through CRE but not through UPRE and may recruit HIRA to CRE to regulate histone exchange (By similarity).
Plays an important role in membrane trafficking through the secretory apparatus.
CD200 and CD200R1 interact via their respective N-terminal Ig-like domains.
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 (By similarity).
Restricted to cells of the myeloid lineage.
Bifunctional phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase catalyzing two reactions of the de novo purine biosynthetic pathway.
In the C-terminal section; belongs to the AIR carboxylase family. Class II subfamily.
In the N-terminal section; belongs to the SAICAR synthetase family.
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).
Belongs to the glycosyltransferase 13 family.
Interacts with DAG1 (via O-linked mannose moiety). Interacts (via transmembrane domain) with FKTN; the interaction is direct and is required for normal location in Golgi membranes.
Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins. Catalyzes the synthesis of the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety on alpha-dystroglycan and other O-mannosylated proteins, providing the necessary basis for the addition of further carbohydrate moieties. Is specific for alpha linked terminal mannose.
The manganese ion interacts primarily with the substrate UDP-N-acetylglucosamine.
The stem domain mediates specific interaction with beta-linked N-acetylglucosamine moieties of O-glycosylated proteins. It also interacts with its product, N-acetyl-beta-D-glucosaminyl-(1->2)-O-alpha-D-mannosylprotein.
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 (By similarity).
Self-associates. Interacts with BBS9; the interaction mediates the association of LZTL1 with the BBsome complex and regulates BBSome ciliary trafficking (By similarity).
Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.
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 (By similarity).
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 (By similarity).
Up-regulated by interferon gamma. Up-regulated by theophylline (THP) and down-regulated by 1,3-dinitrobenzene (DNB), two reprotoxic agents thought to induce infertility.
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins (By similarity). Interacts with TP53INP2 (By similarity). Interacts with TP53INP1 and SQSTM1 (PubMed:22421968). Directly interacts with SQSTM1; this interaction leads to MAP1LC3A recruitment to inclusion bodies containing polyubiquitinated protein aggregates and to inclusion body degradation by autophagy (By similarity). Interacts with ATG13 and ULK1 (By similarity). Interacts with TBC1D5 (By similarity). Found in a complex with UBQLN1 and UBQLN2 (By similarity). Interacts with UBQLN4 (via STI1 1 and 2 domains) (By similarity). Interacts with UBQLN1 in the presence of UBQLN4 (By similarity). Interacts with TRIM5 (By similarity). Interacts with MEFV. Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (By similarity). Interacts with PICALM (By similarity). Interacts with the reticulophagy receptor TEX264 (By similarity). Interacts with MOAP1 (via LIR motif) (By similarity).
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:16874114). 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. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms. In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy. ATG4B constitutes the major protein for proteolytic activation (By similarity). ATG4D is the main enzyme for delipidation activity (By similarity).
Ubiquitin-like modifier involved in formation of autophagosomal vacuoles (autophagosomes). While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation. 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.
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.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IV subfamily.
Belongs to the WD repeat Groucho/TLE family.
Highly expressed in adrenal gland, small intestine, kidney, lung, ovary and thyroid. Detected at lower levels in pituitary, hippocampus, cortex, cerebellum and testis.
Homotetramer and heterooligomer with other family members. Binds LEF1, TCF7, TCF7L1, TCF7L2 and 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 (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.
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).
In brain, by repeated injections of fluoxetine or cocaine.
Interacts with FNBP3 (By similarity). Interacts with CDKL5 (By similarity). Interacts with ATRX; MECP2 recruits ATRX to pericentric heterochromatin in neuronal cells (PubMed:17296936). Interacts with NCOR2 (By similarity). Interacts with TBL1XR1; bridges interaction between MECP2 and NCOR1. Interacts with TBL1X; recruits TBL1X to the heterochromatin foci (By similarity).
Phosphorylated on Ser-421 by CaMK2 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.
Expressed in the brain, kidney and spleen. Expressed in postnatal central nervous system (CNS) germinal zones and, in early postnatal life, within numerous cells throughout the CNS. Found in both subventricular and ventricular germinal zones.
Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination (By similarity). 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 (By similarity). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (By similarity). Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus (By similarity). Important for follicular differentiation and possibly cell fate selection within the follicle (By similarity). During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia (PubMed:11182080). Represses neuronal and myogenic differentiation (By similarity). May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation (By similarity). May be involved in mesoderm development, somite formation and neurogenesis (By similarity). May enhance HIF1A function by sequestering HIF1AN away from HIF1A (By similarity). Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury (By similarity). Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (By similarity).
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. Notch 1 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. 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. 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 (By similarity). Interacts with THBS4 (By similarity). Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (By similarity). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (PubMed:25700513). Interacts with ZMIZ1 (By similarity). 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 (By similarity). Interacts with ZFP64 (By similarity).
Hydroxylated at Asn-1945 and Asn-2012 by HIF1AN. Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).
In the embryo, highest levels occur between days 12 and 14 and decrease rapidly to much lower levels in the adult.
Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.
O-glycosylated on the EGF-like domains. O-glucosylated at Ser-435 by KDELC1 and KDELC2 (By similarity). 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 (PubMed:25700513). 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). 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. 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). 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.
Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1. Monoubiquitination at Lys-1749 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.
After water restriction, up-regulated in inner medulla ascending thin limbs (ATLs) and lower descending thin limbs.
Expressed in brain, liver, lung, and kidney. In kidney expressed in cortex and inner medulla, in ascending thin limbs (ATLs) and lower descending thin limbs (DTLs). Primarily expressed in the proximal tubules of the kidney.
May function as a sodium-dependent glucose transporter (PubMed:12590146). Potential channels for urea in the inner medulla of kidney (PubMed:26423860).
Belongs to the apolipoprotein O/MICOS complex subunit Mic27 family.
Component of the mitochondrial contact site and cristae organizing system (MICOS) complex.
It is uncertain whether Met-1 or Met-16 is the initiator.
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).
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 (By similarity).
Proteolytically cleaved in the Golgi by a furin-like convertase to generate bioactive peptides.
Expressed in both somata and dendrites of hippocampal neurons.
Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. Interacts with the exportin XPO5. This requires RNA and RAN bound to GTP (By similarity). Interacts with microtubules. Isoform 2 and isoform 3 may also interact with ribosomes, and this association is independent of translation. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (By similarity).
RNA-binding protein required for the microtubule-dependent transport of neuronal RNA from the cell body to the dendrite. As protein synthesis occurs within the dendrite, the localization of specific mRNAs to dendrites may be a prerequisite for neurite outgrowth and plasticity at sites distant from the cell body.
The DRBM 3 domain appears to be the major RNA-binding determinant (By similarity). This domain also mediates interaction with XPO5 and is required for XPO1/CRM1-independent nuclear export.
XPO1/CRM1-dependent nuclear export is mediated by residues 4-14 and is abrogated by mutagenesis of Ile-4 or Leu-12.
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. In complex with B2M preferentially presents riboflavin-derived metabolites to semi-invariant TCRs on MAIT cells, guiding immune surveillance of the microbial metabolome at mucosal epithelial barriers (By similarity). 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 (By similarity). May present microbial antigens to various MAIT cell subsets, providing for unique recognition of diverse microbes, including pathogens that do not synthesize riboflavin. Upon antigen recognition, elicits rapid innate-type MAIT cell activation to eliminate pathogenic microbes by directly killing infected cells (By similarity). 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. May present a tumor-specific or -associated metabolite essential for cancer cell survival to a pan-cancer TCR on a non-MAIT CD8-positive T cell clone, triggering T cell-mediated killing of a wide range of cancer cell types (By similarity).
Expressed in kidney, liver, testis, spleen, thymus, brain, and heart.
Heterotrimer that consists of MR1, B2M and a metabolite antigen. 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. On antigen-presenting cells, the ternary complex interacts with TCR on CD8-positive T cells. 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. The ribityl moiety of pyrimidine-based antigens is recognized by Tyr-95 residue in the CDR3 alpha loop of the invariant TRAV1-2 TCR.
MR1 is detected in an open versus folded conformation. Only the folded MR1 conformer activates MAIT cells (By similarity).
The alpha-1 domain is a structural part of antigen-binding cleft.
The alpha-2 domain is a structural part of antigen-binding cleft.
Found at relatively high levels in testes, at moderate levels in brain, heart and skeletal muscle, at lower levels in lung, skin, kidney and small intestine, and is undetectable in liver or spleen.
May have a regulatory bifunctional role.
Isoform 1 is widely expressed with highest levels in the hippocampus, spinal cord, atrium, colon, testis and ovaries. Detected in the liver of females but not males. Isoform 2 is not detected in brain or lung.
There are 3 carboxypeptidase-like domains. Only the first two domains seem to have kept a catalytic activity.
Up-regulated by exposure to prolactin or interleukin-2.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class CDC14 subfamily.
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 (Probable). The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio (Probable). Interacts with CACNA2D4. Interacts with FASLG (By similarity). Interacts with CBARP; prevents the interaction of CACNB3 with the alpha subunit CACNA1C thereby negatively regulating the activity of the corresponding calcium channel (PubMed:24751537).
Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (PubMed:7679112, PubMed:10666413, PubMed:24751537, PubMed:29742403, PubMed:15170217). 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 (PubMed:7679112, PubMed:10666413, PubMed:24751537, PubMed:29742403, PubMed:15170217).
Interacts with SYTL2, SYTL4, MYRIP and MLPH. Interacts with RPH3A and RPH3A (By similarity). Interacts (GDP-bound form preferentially) with DENND10 (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 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 (By similarity). Plays a role in NTRK2/TRKB axonal anterograde transport by facilitating the association of NTRK2/TRKB with KLC1 (PubMed:21775604). May be involved in targeting uroplakins to urothelial apical membranes.
Belongs to the glyceraldehyde-3-phosphate dehydrogenase family.
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 (By similarity).
A cytochrome P450 monooxygenase that catalyzes omega and omega-1 hydroxylation of saturated fatty acids. Exhibits preferential omega versus omega-1 regioselectivity and (R) versus (S) stereoselectivity for hydroxylation of lauric and myristic acids (PubMed:10869363, PubMed:10620324). Has low activity toward palmitic acid (PubMed:10620324). 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:10869363, PubMed:10620324).
Broad specificity aminopeptidase which plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Also involved in the processing of various peptides including peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. May also be involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis and promote cholesterol crystallization. May have a role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 and regulating its activity (By similarity).
Homodimer. Interacts with SLC6A19 (By similarity).
May undergo proteolysis and give rise to a soluble form.
Widely distributed throughout the CNS. Particularly abundant in kidney and intestinal microvilli, also detected in lung and liver. Weakly expressed in heart and aorta.
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 (By similarity). Interacts with EML3 (phosphorylated form) and TUBG1 (By similarity).
Contributes to mitotic spindle assembly, maintenance of centrosome integrity and completion of cytokinesis as part of the HAUS augmin-like complex.
Interacts with FMR1 (By similarity). Interacts with ZNHIT3 (By similarity).
Belongs to the TALE/IRO homeobox family.
Belongs to the universal ribosomal protein uS15 family.
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamine release from adrenal medulla, as well as mediating neurotransmission in the central nervous system.
Phosphorylation at sites in the second and third cytoplasmic loops independently contribute to agonist-induced receptor down-regulation.
Belongs to the eukaryotic RPB8 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 small RNAs, such as 5S rRNA and tRNAs, respectively.
3'-to-5'exoribonuclease that preferentially degrades DNA and RNA oligonucleotides composed of only two nucleotides (By similarity). Binds and degrades longer oligonucleotides with a lower affinity (By similarity). 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 (By similarity). Essential for correct initiation of mitochondrial transcription, degrading mitochondrial RNA dinucleotides to prevent RNA-primed transcription at non-canonical sites in the mitochondrial genome (By similarity). Essential for embryonic development (By similarity).
Belongs to the oligoribonuclease family.
Homodimer (By similarity). Homotetramer (By similarity).
Belongs to the ankyrin SOCS box (ASB) family.
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-cells differentiation (By similarity).
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. 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-lymphocytes migration. Associates with ZAP70 and RHOH; these interactions allow LCK-mediated RHOH and CD3 subunit phosphorylations in presence of a functional ZAP70. Interacts with CEACAM1 (via cytoplasmic domain); mediates CEACAM1 phosphorylation resulting in PTPN6 recruitment that dephosphorylates TCR stimulation-induced CD247 and ZAP70. Interacts with FYB2. Interacts with CD160. Interacts with CD48.
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 (By similarity). Interacts with UNC119; this interaction plays a crucial role in activation of LCK (By similarity).
Palmitoylation regulates association with the plasma membrane and could be mediated by ZDHHC2.
Proviral insertion upstream of the Lck gene causes overexpression, leading to the development of thymic lymphoma.
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 (By similarity).
Activated by nitric oxide in the presence of magnesium or manganese ions.
Binds 1 or 2 heme groups per heterodimer. Heme is required for responding to nitric oxide, but not for catalytic activity.
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. Homotetramer; dimer of dimers (in vitro) (PubMed:20105301). Heterodimer with GUCY1A1. Can also form inactive homodimers in vitro (By similarity).
There are two types of guanylate cyclases: soluble forms and membrane-associated receptor forms.
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.
Acetylation of Lys-531 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation. Deacetylated by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (By similarity).
Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID) (By similarity).
Expressed in the kidney, higher expression is seen in the renal medulla than in the cortex. Expressed also in the perivenous zone of the liver.
Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (By similarity). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300. Activity is enhanced by interaction with NCOA1 and/or NCOA2. Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (By similarity).
In normoxia, is hydroxylated on Pro-402 and Pro-563 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1. EGLN3/PHD3 has also been shown to hydroxylate Pro-563. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (By similarity). In normoxia, is hydroxylated on Asn-802 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation.
Induced by reactive oxygen species (ROS).
Interacts with the ARNT; forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability (By similarity). Interacts with EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domains). Interacts with NCOA1, NCOA2, APEX1 and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation. During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A (By similarity). Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription (By similarity). Interacts (via the ODD domain) with NAA10; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF1A sumoylation (By similarity). Interacts with TSGA10. Interacts with HIF3A (By similarity). Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia-mimicking conditions. Interacts with USP20. Interacts with RACK1; promotes HIF1A ubiquitination and proteasome-mediated degradation. Interacts (via N-terminus) with USP19. Interacts with SIRT2. Interacts (deacetylated form) with EGLN1. Interacts with CBFA2T3. Interacts with HSP90AA1 and HSP90AB1. Interacts with DCUN1D1; this interaction increases the interaction between VHL and DCUN1D1. Interacts with HIF1AN (By similarity).
Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding. Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome (By similarity).
S-nitrosylation of Cys-799 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.
Sumoylated; with SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia. Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation. Desumoylation by SENP1 increases its stability amd transcriptional activity. There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity (By similarity).
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.
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 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.
Acetylation at Lys-118 dramatically enhances enzymatic activity and promotes adipogenic differentiation.
Belongs to the LDH/MDH superfamily. MDH type 2 family.
Catalyzes the reduction of aromatic alpha-keto acids in the presence of NADH. Plays essential roles in the malate-aspartate shuttle and the tricarboxylic acid cycle, important in mitochondrial NADH supply for oxidative phosphorylation.
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:11390972, PubMed:12598615). May be involved in the efflux from the lysosomal compartment of neutral amino acids resulting from proteolysis (PubMed:12598615). May play a role in specifying sites for exocytosis in neurons (PubMed:12598615).
Widely expressed and predominantly expressed in brain. Within the brain, expression restricted to neurons and not detected in glial cells. Abundant in regions rich in neurons using glutamate and GABA such as Purkinje cells in the cerebellum and pyramidal cells in the hippocampus.
Belongs to the SLC29A/ENT transporter (TC 2.A.57) family.
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is insensitive (EI) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. Specific for nucleosides, but may also transport hypoxanthine. May also play a role in the efflux of inosine and hypoxanthine from muscle cells during the net degradation of purine nucleotides that occurs during strenuous exercise and/or in the reuptake of these purines during the recovery process (By similarity).
Resistant to dipyridamole and dilazep inhibition (anticancer chemotherapeutics drugs).
Belongs to the Integrator subunit 10 family.
Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.
Dynein-attachment factor required for cilia motility.
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 (By similarity). Interacts with RPA1; this interaction associates HROB with the RPA complex (By similarity).
A connexon is composed of a hexamer of connexins. Interacts with CNST (By similarity).
A connexon is composed of a hexamer of connexins. Interacts with CNST.
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.
Belongs to the DNA polymerase epsilon subunit B family.
Participates in DNA repair and in chromosomal DNA replication.
Identified in a complex containing STX6, STX12, VAMP4 and VTI1A (By similarity). Binds EEA1 (PubMed:10506127). Interacts with VPS45A and GOPC (By similarity). Interacts with MARCHF2; the interaction promotes MARCHF2-mediated ubiquitination and degradation of CFTR (PubMed:15689499). Interacts with MARCHF3 (PubMed:16428329). Interacts with BLTP3B (via C-terminal coiled-coil domain) (PubMed:20163565). Interacts with BAIAP3; this interaction is increased in the presence of calcium (By similarity). Interacts (via N-terminus) with VPS51 (PubMed:30962439). Interacts with VPS13B (PubMed:30962439).
SNARE promoting movement of transport vesicles to target membranes (PubMed:30962439). Targets endosomes to the trans-Golgi network, and may therefore function in retrograde trafficking (PubMed:30962439). Together with SNARE STX12, promotes movement of vesicles from endosomes to the cell membrane, and may therefore function in the endocytic recycling pathway (PubMed:30962439).
Widely expressed, with relatively higher expression in brain, lung and kidney.
Binds DNA as a dimer. Interacts with CDC34. Interacts with FHL5. Isoform delta forms a heterodimer with CREB3L4. May interact with TSSK4.
Isoform Tau is expressed in testis germ cells. CREM-theta1- and CREM-theta2-containing isoforms are expressed in testis.
Produced by alternative promoter usage. Activator.
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. Isoform Delta is an activator. Plays a role in spermatogenesis and is involved in spermatid maturation. Binding of isoform Tau (activator) to CRE is increased by CREB3L4. The CREM isoform Tau-CREB3L4 heterodimer functions through CRE and may recruit HIRA to CRE to regulate histone exchange (By similarity).
Ubiquitinated by CDC34 and RAD6B in order to be degraded by the proteasome.
Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.
Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.
Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.
A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.
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, LCK, IL-3 and GM-CSF promoters. The alpha subunit binds DNA and appears to have a role in the development of normal hematopoiesis. Isoform AML-1L interferes with the transactivation activity of RUNX1. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation. 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 (By similarity). Positively regulates the expression of RORC in T-helper 17 cells (By similarity).
Expression increases following denervation.
Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX.
Heterodimer with CBFB. RUNX1 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Interacts with TLE1 and ALYREF/THOC4. Interacts with ELF1, ELF2 and SPI1. Interacts via its Runt domain with the ELF4 N-terminal region. Interaction with ELF2 isoform 2 (NERF-1a) may act to repress RUNX1-mediated transactivation. Interacts with KAT6A and KAT6B. Interacts with SUV39H1, leading to abrogation of transactivating and DNA-binding properties of RUNX1. Interacts with YAP1 and HIPK2. Interaction with CDK6 prevents myeloid differentiation, reducing its transcription transactivation activity. Found in a complex with PRMT5, RUNX1 and CBFB. Interacts with FOXP3. Interacts with TBX21. Interacts with DPF2 (By similarity).
Phosphorylated in Ser-249 Thr-272 and Ser-275 by HIPK2 when associated with CBFB and DNA. This phosphorylation promotes subsequent EP300 phosphorylation (By similarity).
Phosphorylated in its C-terminus upon IL-6 treatment. Phosphorylation enhances interaction with KAT6A (By similarity).
All cysteine residues are assumed to be cross-linked to one another. Individual modules containing an even number of conserved cysteine residues are supposed to have disulfide linkages only within the same module (By similarity).
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 (By similarity).
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.
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. Interacts with ADAM15, ARHGEF2, DAPK1 (via death domain), HSF4, IER3, IPO7, MKNK2, MORG1, NISCH, PEA15, SGK1, and isoform 1 of NEK2 (By similarity). 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 (By similarity). Interacts with MAP2K1 (By similarity). Interacts with DUSP6 (PubMed:16567630). Interacts with ARRB2 (PubMed:11226259). Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation (PubMed:19778377, PubMed:19427337). MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation (By similarity). Interacts with DCC (PubMed:21070949). The phosphorylated form interacts with PML (By similarity). Interacts with STYX (By similarity). Interacts with CDK2AP2 (PubMed:12944431). Interacts with CAVIN4 (PubMed:24567387). Interacts with DUSP7; the interaction enhances DUSP7 phosphatase activity (PubMed:27783954). Interacts with GIT1; this interaction is necessary for MAPK1 localization to focal adhesions (PubMed:15923189). Interacts with ZNF263 (By similarity).
Dually phosphorylated on Thr-183 and Tyr-185, which activates the enzyme. Phosphorylated upon FLT3 and KIT signaling. Ligand-activated ALK induces tyrosine phosphorylation (By similarity). Dephosphorylated by PTPRJ at Tyr-185 (By similarity). Autophosphorylated on threonine and tyrosine residues in vitro, which correlates with a slow and low level of activation. Phosphorylation on Ser-27 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2 (By similarity). Dephosphorylated by DUSP1 and DUSP2 at Thr-183 and Tyr-185 (By similarity).
Highest levels within the nervous system, expressed in different tissues, mostly in muscle, thymus and heart.
Increased expression during development.
Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-183 and Tyr-185 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-27 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.
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 (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431).
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
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. 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.
Interacts with HSPA5, HSP90B1, TUBULIN, UGGT1 and UGGT2 (By similarity). Interacts with TET3. Interacts with STPG4 (By similarity).
Belongs to the calycin superfamily. Lipocalin family. Highly divergent.
Expressed by the liver; secreted in plasma.
Interacts with LRP2; LRP2 mediates APOM renal uptake and subsequent lysosomal degradation.
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 (By similarity).
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 (By similarity). Interacts with GORASP1 and GORASP2.
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 (By similarity).
Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily.
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.
Monomer (By similarity). Interacts with NEK9 (By similarity). Interacts with ANKS3; this interaction alters the subcellular distribution of NEK7 by preventing its nuclear translocation (By similarity). 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. Required for microtubule nucleation activity of the centrosome, robust mitotic spindle formation and cytokinesis (By similarity). Phosphorylates RPS6KB1 (PubMed:11516946). Phosphorylates EML4 at 'Ser-146', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression (By similarity). 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 (By similarity).
The NTE (N-terminal extension) motif is a structural component of the catalytic domain and thus contributes to activity.
Belongs to the metallo-beta-lactamase superfamily. Glyoxalase II family.
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-50 of isoform 1. Alternative initiation has been proven in human.
Strongly expressed in testis, skeletal muscle and heart. Weakly expressed in placenta, pancreas, spleen and peripheral blood leukocytes.
Thiolesterase that catalyzes the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid.
Belongs to the PUR DNA-binding protein family.
This is a receptor for glucagon-like peptide 2. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family.
Monomer and homodimer; homodimerization is induced by binding of the substrate.
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 (By similarity).
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 (By similarity).
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 1011 and is predicted to be inactive.
Interacts with BRI3BP. Interacts with MGAT1 and IFITM3 (By similarity).
Participates in tumor necrosis factor-alpha (TNF)-induced cell death. May be a target of Wnt/beta-catenin signaling in the liver.
Expressed in kidney and small intestine.
Involved in the sodium-dependent cotransport of myo-inositol (MI) with a Na(+):MI stoichiometry of 2:1. Exclusively responsible for apical MI transport and absorption in intestine (PubMed:17932225). Can also transport D-chiro-inositol (DCI) but not L-fucose. Exhibits stereospecific cotransport of both D-glucose and D-xylose. May induce apoptosis through the TNF-alpha, PDCD1 pathway. 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(+)) (PubMed:17932225). Insulin increases D-chiro-inositol uptake (By similarity).
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.
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). It can then undergo a detyrosination cycle by the tubulin tyrosine carboxypeptidase (KIAA0895L/MATCAP).
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).
Methylation of alpha chains at Lys-40 is found in mitotic microtubules and is required for normal mitosis and cytokinesis contributing to genomic stability.
Some glutamate residues at the C-terminus are polyglutamylated, resulting in polyglutamate chains on the gamma-carboxyl group (By similarity). 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 (By similarity). Glutamylation is also involved in cilia motility (By similarity).
Some glutamate residues at the C-terminus are polyglycylated, resulting in polyglycine chains on the gamma-carboxyl group. Glycylation is mainly limited to tubulin incorporated into axonemes (cilia and flagella) whereas glutamylation is prevalent in neuronal cells, centrioles, axonemes, and the mitotic spindle. Both modifications can coexist on the same protein on adjacent residues, and lowering polyglycylation levels increases polyglutamylation, and reciprocally. Cilia and flagella glycylation is required for their stability and maintenance. Flagella glycylation controls sperm motility.
The MREC motif may be critical for tubulin autoregulation.
This tubulin does not have a C-terminal tyrosine.
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.
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.
Expressed in heart, liver, kidney, brain, liver and testis. Highest levels in heart, lowest in liver.
Increased activation in hypoxia. Hydroxylation of the C-terminal ODD domain (CODD) proline of HIF1A is activated by cyclosporin A (CsA).
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 and HIF1A.
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-238 or Cys-241.
The beta(2)beta(3) 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity.
Up-regulated by hypoxia especially in liver and testis. Levels up-regulated also in myocardial infarction predominantly in cardiomyocytes.
Belongs to the oxygen-dependent FAD-linked oxidoreductase family.
Oxidizes L-gulono-1,4-lactone to hydrogen peroxide and L-xylo-hexulonolactone which spontaneously isomerizes to L-ascorbate.
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.
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 (By similarity).
Isoforms HMG-I and HMG-Y can be phosphorylated by HIPK2. Phosphorylation may modulate DNA-binding affinity (By similarity).
Methylation at Arg-58 is mutually exclusive with methylation at Arg-60.
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).
Spleen and thymus, B-cells, monocytes, macrophages, neutrophils, single (CD4 or CD8) positive thymocytes, peripheral T-cells.
Autophosphorylated (By similarity). Phosphorylated on serine and threonine residues.
Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors (By similarity). Could play an important function in spermatogenesis. Phosphorylates FZR1 in a cell cycle-dependent manner (By similarity). Plays a role in the transcriptional coactivation of AR (By similarity).
Expressed mainly in testicular cells at and after meiosis.
Expression in testis is detected 16 days after birth and increases gradually to reach a plateau about 4 weeks after birth (at protein level).
Interacts with RP1. Interacts with AR and CDK20. Found in a complex containing MAK, AR and NCOA3. Interacts with FZR1 (via WD repeats) (By similarity).
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 (By similarity).
Belongs to the glycosyltransferase 6 family.
Predominantly expressed in the sublingual salivary gland, in the mucous cells of the acini, but not in the serous cells, nor in the duct system (at protein level). Not detected in the submandilar, nor the parotid glands. Expressed in the mucous glands, but not detected in the serous glands (at protein level). Besides the salivary glands, expressed in the Brunner's glands in the duodenum, but no other mucous or serous glands (at protein level).
Detected in all tissues tested. Highest expression is found in kidney followed by lung, spleen, heart and brain. Lower expression, in skeletal muscle, liver and testis.
Interacts with VPS11, VPS16 and VPS18. Interacts with VPS33A (By similarity). Forms a SNARE complex with VTI1B, STX8 and VAMP8 which functions in the homotypic fusion of late endosomes. Component of the SNARE complex composed of STX7, STX8, VAMP7 and VTI1B that is required for heterotypic fusion of late endosomes with lysosomes. Interacts with TPC1 (By similarity).
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 (By similarity).
Belongs to the actin family. ARP6 subfamily.
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 in the kynurenine pathway of tryptophan catabolism. Involved in immune regulation.
Ido1 and Ido2 are 2 distinct enzymes which catalyze the same reaction. Ido2 affinity for tryptophan is much lower than that of Ido1. Ido2 may play a role as a negative regulator of Ido1 by competing for heme-binding with Ido1. Low efficiency Ido2 enzymes have been conserved throughout vertebrate evolution, whereas higher efficiency Ido1 enzymes are dispensable in many lower vertebrate lineages. Ido1 may have arisen by gene duplication of a more ancient proto-IDO gene before the divergence of marsupial and eutherian (placental) mammals.
Belongs to the U2 small nuclear ribonucleoprotein A family.
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.
Activates insulin and somatostatin gene transcription. Key regulator of islet peptide hormone expression but also responsible for the development of the pancreas, most probably by determining maturation and differentiation of common pancreatic precursor cells in the developing gut. 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 the DNA sequence 5'-CC[CT]TAATGGG-3'.
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 and the methyltransferase SETD7. Part of a PDX1:PBX1b:MEIS2b complex (By similarity).
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).
Acts as a transcriptional repressor. 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.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.
Component of a Sin3A corepressor complex consisting of SIN3A, SAP130, SUDS3/SAP45, SAP180, HDAC1 and HDAC2. Interacts with ARID4A (By similarity). Interacts with AR (By similarity).
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.
Homodimer or heterodimer; dimerization is mediated via the coiled coil region (By similarity). Efficient DNA binding requires dimerization with another bHLH protein (By similarity). Binds DNA in the form of homodimer or heterodimer with either TFE3, TFEB or TFEC (By similarity). Identified in a complex with HINT1 and CTNNB1 (By similarity). Interacts with KARS1 (By similarity). Interacts with VSX2 (By similarity).
Osteopetrotic rat of unknown genetic defect microphthalmia-blanc (mib) has been described whose skeletal sclerosis improves dramatically with age and that is associated with pigmentation defects. Mib at the homozygous state shows absence of skin and fur pigmentation, small eyes, and defects of incisor tooth eruption.
Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter (By similarity). 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 (By similarity). Phosphorylated in response to blue light (415nm) (By similarity).
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.
Catalyzes the dephosphorylation of the nucleoside 5'-monophosphates deoxyadenosine monophosphate (dAMP), deoxycytidine monophosphate (dCMP), deoxyguanosine monophosphate (dGMP) and deoxythymidine monophosphate (dTMP).
Belongs to the TFIIE alpha 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.
Highly expressed in brain, and to a lower extent in heart and testis.
The [NKR]KIAxRE motif seems to be a cyclin-binding region.
Interacts with PRAF2. 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. Interacts with GRK2. Interacts with ARRB1 and ARRB2. Interacts with CNIH4. Interacts with S100A4; this interaction stimulates T-lymphocyte chemotaxis.
O-glycosylated, but not N-glycosylated. Ser-6 appears to be the major site. Also sialylated glycans present which contribute to chemokine binding. Ser-17 may also be glycosylated and, if so, with small moieties such as a T-antigen (By similarity).
Palmitoylation in the C-terminal is important for cell surface expression.
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.
Sulfated on at least 2 of the N-terminal tyrosines. Sulfation is required for efficient binding of the chemokines, CCL3 and CCL4 (By similarity).
Belongs to the YY transcription factor family.
Belongs to the GST superfamily. Zeta family.
Glutathione is required for the MAAI activity.
Probable 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 (By similarity). Is able to catalyze the glutathione dependent oxygenation of dichloroacetic acid to glyoxylic acid.
Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (By similarity). 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). 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. 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 (By similarity).
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. In response to endoplasmic reticulum stress, de-AMPylation by the same protein, FICD, restores the chaperone activity.
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 (PubMed:12475965). Interacts with TMEM132A and TRIM21 (PubMed:12514190). May form a complex with ERLEC1, OS9, SEL1L and SYVN1 (By similarity). Interacts with DNAJC10 (By similarity). 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 (By similarity). Interacts with CEMIP; the interaction induces calcium leakage from the endoplasmic reticulum and cell migration (By similarity). Interacts with PCSK4 form; the interaction takes place in the endoplasmic reticulum (By similarity). Interacts with CIPC (By similarity). Interacts with CCDC88B (via C-terminus); the interaction opposes ERN1-mediated JNK activation, protecting against apoptosis (By similarity). Interacts with INPP5K; necessary for INPP5K localization at the endoplasmic reticulum (By similarity). Interacts with MANF; the interaction is direct (By similarity). Interacts with LOXL2; leading to activate the ERN1/IRE1-XBP1 pathway of the unfolded protein response (By similarity). 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 (By similarity). Interacts with CCDC47 (By similarity). Interacts with CLN3 (By similarity). Interacts with KIAA1324; may regulate the function of HSPA5 in apoptosis and cell proliferation. Interacts with CASP7 (By similarity). 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 (By similarity). In the ADP-bound and nucleotide-free (apo) states, the two domains have little interaction (By similarity). 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 (By similarity). J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP. 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.
Acetylated, leading to enhanced enzyme activity. Acetylation is enhanced by up to 80% after treatment either with trichostin A (TCA) or with nicotinamide (NAM) with highest increase on Lys-345. Acetylation and enzyme activity increased by about 1.5% on addition of fatty acids (By similarity).
Enzyme activity enhanced by acetylation.
In the C-terminal section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.
Peroxisomal trifunctional enzyme possessing 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and delta 3, delta 2-enoyl-CoA isomerase activities (PubMed:2303409, PubMed:12106015, PubMed:23351063). Catalyzes two of the four reactions of the long chain fatty acids peroxisomal beta-oxidation pathway (PubMed:2303409, PubMed:12106015). 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 (Probable). Optimal isomerase for 2,5 double bonds into 3,5 form isomerization in a range of enoyl-CoA species. Also able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species (PubMed:11781327). 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 (By similarity).
Forms a multiprotein complex with MMACHC, MMADHC and MTR.
It is debated whether the reduction of free aquacob(II)alamin occurs spontaneously or is enzyme catalyzed.
Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin. Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine (By similarity). Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance (By similarity). Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme. Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme (By similarity).
Belongs to the Dus family. Dus1 subfamily.
Belongs to the MINDY deubiquitinase family. FAM63 subfamily.
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.
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. Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE. 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. The IB complex does not contain PRPF19. 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).
Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis. Also plays a role in the regulation of the endocytic trafficking of EGFR.
Activated by phosphorylation on Thr-212 by STK11 in complex with STE20-related adapter-alpha (STRAD alpha) pseudo kinase and CAB39.
Expressed in liver, skin, testis, uterus, ovary, adrenal gland and brain (at protein level). Expressed in kidney, heart, skin, spleen, lung, uterus, liver and the exocrine and endocrine compartments of the human pancreas. A kinase-inactive isoform also appears to be expressed in the skin, spleen, lung, uterus, liver and testis.
Phosphorylated at Thr-212 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Autophosphorylation is also possible at Thr-212.
Stress-activated kinase involved in tolerance to glucose starvation. Induces cell-cell detachment by increasing F-actin conversion to G-actin. Expression is induced by CD95 or TNF-alpha, via NF-kappa-B. Protects cells from CD95-mediated apoptosis and is required for the increased motility and invasiveness of CD95-activated tumor cells. Phosphorylates LATS1 and LATS2. Plays a key role in neural tube closure during embryonic development through LATS2 phosphorylation and regulation of the nuclear localization of YAP1 a critical downstream regulatory target in the Hippo signaling pathway.
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 (By similarity).
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 (By similarity).
Component of RNA polymerase I core factor complex that acts as a GTF2B/TFIIB-like factor and plays a key role in multiple steps during transcription initiation such as pre-initiation complex (PIC) assembly and postpolymerase recruitment events in polymerase I (Pol I) transcription. Binds rDNA promoters and plays a role in Pol I recruitment as a component of the SL1/TIF-IB complex and, possibly, directly through its interaction with RRN3.
Interacts with FLNA (via N-terminus) (By similarity). Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1C. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with TBP and RRN3 (By similarity).
Interacts with RCHY1, RAB6A/RAB6 and SCYL1.
Belongs to the glycosyltransferase 11 family.
Detected in trigeminal nerve Schwann cells (PubMed:11430802). Detected in brain cortex and hippocampus. Detected in brain membrane fractions and highly enriched in the postsynaptic density (at protein level).
Interacts with PRX; this enhances phosphorylation (PubMed:11430802). Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity).
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.
Pancreas and brain. Also expressed in the gastrointestinal system and vagus nerve.
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.
Belongs to the nuclear hormone receptor family. NR2 subfamily.
Binds DNA as dimer; homodimer and heterodimer with NR2F2 and probably NR2F1. Interacts with THRB (By similarity).
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) (By similarity).
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).
Autophosphorylated in response to ligand binding on Tyr-1235 and Tyr-1236 in the kinase domain leading to further phosphorylation of Tyr-1350 and Tyr-1357 in the C-terminal multifunctional docking site. Dephosphorylated by PTPRJ at Tyr-1350 and Tyr-1366. Dephosphorylated by PTPN1 and PTPN2 (By similarity).
By interleukin-6 and acute acid-induced gastric injury. Inhibited by prolactin.
Expressed at highest levels in lung, liver and kidney, also expressed in stomach, intestine, spleen, testis and brain. Not expressed in heart or muscle.
Expression is down-regulated during pregnancy and is virtually undetectable during lactation. Expression progressively increases post-lactation.
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. Interacts with INPP5D/SHIP1. When phosphorylated at Tyr-1357, 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 HSP90AA1 and HSP90AB1; the interaction suppresses MET kinase activity.
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 (By similarity).
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 (By similarity).
The beta-propeller Sema domain mediates binding to HGF.
The kinase domain is involved in SPSB1 binding.
Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation (By similarity).
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.
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.
Belongs to the RNR ribonuclease family. DIS3L2 subfamily.
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.
Belongs to the G-protein coupled receptor 3 family.
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity.
Prominent expression in olfactory bulb, pontine gray, lateral reticular nucleus of the thalamus, and piriform cortex. Less abundant expression incerebral cortex, hippocampus, cerebellum, and mammillary body.
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 (By similarity). Interacts with GIT1 (By similarity). Interacts with NUDT16L1/SDOS (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with PTK2B/PYK2 (By similarity). Interacts with ASAP2 (By similarity). Interacts with unphosphorylated ITGA4 (By similarity). Interacts with RNF5 (By similarity). Interacts with PDCD10 (By similarity). Interacts with NEK3, the interaction is prolactin-dependent (By similarity). Interacts with PTK6 (By similarity). Interacts with TGFB1I1 (PubMed:16546139). Interacts with SORBS1 (By similarity). Interacts with PARVB (By similarity). Interacts (via LD motif 4) with PARVA/PARVIN (PubMed:11134073). Interacts (via LD motif 4) with ILK (By similarity). Interacts (via cytoplasmic domain) with CEACAM1; the interaction is phosphotyrosyl-dependent (By similarity). Interacts with LIMA1; this complex stabilizes actin dynamics (By similarity). Interacts with CD36 (via C-terminus) (By similarity).
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-273 by CDK5 reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation (By similarity). Phosphorylation at Tyr-31 and Tyr-118 by PTK6 promote the activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion (By similarity). Phosphorylation at Ser-279 by SLK is required for PXN redistribution and cell motility (By similarity).
Expressed exclusively in brain with significant levels in cortex, cerebellum and olfactory bulb. Detected at lower level in hippocampus.
Belongs to the eukaryotic ribosomal protein eL30 family.
Interacts with PRKCI. Interacts with TRIP11 (By similarity). 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.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins. 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. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis. 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. Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer. Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA. May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin. Metabolizes caffeine via N3-demethylation.
Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization.
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 signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER).
Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PubMed:29253589). Exhibits specificity for the nature of the acyl chains at the sn-1 and sn-2 positions in the substrate, PA and the preferred acyl chain composition is 1-stearoyl-2-arachidonoyl-sn-phosphatidic acid (By similarity). Plays an important role in regulating the growth and maturation of lipid droplets which are storage organelles at the center of lipid and energy homeostasis (By similarity).
Expressed in brain cortex, hippocampus, striatum, hypothalamus, cerebellum and brainstem (at protein level).
Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors.
Belongs to the mitochondrion-specific ribosomal protein mS23 family.
Follow 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. Expressed during S-phase in mitogen-stimulated hepatocytes.
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. Interacts with NR1D1 (By similarity). Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).
Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-161 activates it.
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 (By similarity).
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:10542199, PubMed:19821535). Required in higher cells for entry into S-phase and mitosis (By similarity). 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:10542199, PubMed:19821535). CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs (By similarity). Essential for early stages of embryonic development (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression (By similarity). 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 (By similarity). The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis (By similarity). 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 (By similarity). In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis (By similarity). The phosphorylation of Bcl-xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis (By similarity). In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis (By similarity). This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes (By similarity). EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing (By similarity). CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration (PubMed:17200138). CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis (By similarity). 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 (By similarity). Phosphorylates EML3 at 'Thr-881' which is essential for its interaction with HAUS augmin-like complex and TUBG1 (By similarity). Phosphorylates CGAS during mitosis, leading to its inhibition, thereby preventing CGAS activation by self DNA during mitosis (By similarity).
Polyubiquitinated upon genotoxic stress.
Detected at 20 dpc, and between P0 and P5 in olfactory mitral cells. Detected between 18 dpc and 20 dpc, between P0 and P10, and in adult in anterior olfactor, hypothalamus ventromedial nuclei. Detected at 15 dpc in cortex marginal zone. Detected between 15 dpc and 20 dpc, between P0 and P10, and in adult in cortex entorhinal and periform region, hippocampal regions, basal telencephalon bed stria terminalis nuclei. Detected at 20 dpc, between P0 and P10, and in adult in cortex induseum griseum and tenia tecta, and basal telencephalon olfactory tubercle. Detected between P0 and P10, and in adult in ventral thalamus zona incerta. Detected between P5 and P10, and in adult in ventral thalamus reticular nuclei. Detected between P0 and P10, and in adult in dorsal thalamus regions.
May act as molecular guidance cue in cellular migration, and function may be mediated by interaction with roundabout homolog receptors.
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). Interacts (via N-terminus) with DAPK1. Interacts with TMEM185A. Interacts with MAP1LC3B. Interacts with KIRREL3 (By similarity). 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).
A C-terminal fragment of this protein (residues 1599 to 2461) was originally described as neuraxin in PubMed:2555150.
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.
In cerebral cortex, spinal cord and sciatic nerve levels are high early in development but decrease during postnatal development and are low in adults. In dorsal root ganglia levels remain high throughout development.
LC1 is coexpressed with MAP1B. It is a polypeptide generated from MAP1B by proteolytic processing. It is free to associate with both MAP1A and MAP1B. It interacts with the N-terminal region of MAP1B (By similarity).
Nervous system (spinal cord, brain stem, cerebellum and cerebrum). Not expressed in liver, spleen, kidney, heart or muscle.
Required for proper microtubule dynamics. Plays a role in the cytoskeletal changes that accompany neuronal differentiation and neurite extension (By similarity). 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 (By similarity). Facilitates tyrosination of alpha-tubulin in neuronal microtubules. Required for synaptic maturation (By similarity).
S-nitrosylation at Cys-2457 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.
Intrinsic membrane protein of small synaptic vesicles. Probable vesicular channel protein.
May be involved in the endocytic machinery.
Catalyzes the formation of L-carnitine from gamma-butyrobetaine.
Expressed in the liver and in some extend in the testis and the epididymis.
Undetectable during the perinatal period. During development, expression appears after the weaning of the young rat and reaches a maximal expression at the adult stage.
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 (By similarity).
Possible cell-cycle regulation with highest expression during the S-phase (at protein level). Probably rapidly degraded by the proteasome.
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. 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 (By similarity).
UTP--glucose-1-phosphate uridylyltransferase catalyzing the conversion of glucose-1-phosphate into UDP-glucose, a crucial precursor for the production of glycogen.
Cytoplasmic retinol-binding protein (PubMed:7683727, PubMed:12850148). Accepts retinol from the transport protein STRA6, and thereby contributes to retinol uptake, storage and retinoid homeostasis (By similarity).
Interacts (only as retinol-free apoprotein) with STRA6.
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:12473691, PubMed:15037600). Necessary for VCP-mediated reassembly of Golgi stacks after mitosis (PubMed:12473691, PubMed:15037600). Plays a role in VCP-mediated formation of transitional endoplasmic reticulum (tER) (PubMed:12473691, PubMed:15037600). Mediates dissociation of the ternary complex containing STX5A, NSFL1C and VCP (PubMed:12473691, PubMed:15037600). 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) (By similarity). Hydrolyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitin chains (By similarity).
Phosphorylated at Ser-1206 by ATM or ATR following induction of covalent DNA-protein cross-links (DPCs).
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.
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 (By similarity).
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 (By similarity).
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.
Expressed in all tissues tested including brain, heart, ovary, uterus, skeletal muscle and testis.
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. Within the SF3B complex interacts directly with SF3B1 and SF3B3. The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2. SF3B associates with the splicing factor SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (By similarity). 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. 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 (By similarity). Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha (PubMed:12810571).
Belongs to the CNF-like-inhibitor family.
Expressed abundantly in bone, including the lengthening growth plate where cartilage is remodeled into bone.
May play a novel role in the growth or remodeling of bone.
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 higher oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L.
Monomer. Homotetramer. Interacts with OAS1D.
Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection. The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated. ssRNA or dsDNA do not act as activators.
Essential for the proper assembly of the glomerular and tubular basement membranes in kidney.
Interacts with integrins ITGA3:ITGB1, ITGA5:ITGB1, ITGA3:ITGB1 and ITGA6:ITGB4 and with CD9 and CD181. Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3.
Palmitoylated. Palmitoylation by ZDHHC2 regulates CD151 expression, association with other tetraspanin family proteins and function in cell adhesion.
Belongs to the adaptor complexes small subunit family.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits.
The zeta subunit may be involved in regulating the coat assembly and, hence, the rate of biosynthetic protein transport due to its association-dissociation properties with the coatomer complex.
Belongs to the potassium channel family. S (TC 1.A.1.2) subfamily. Kv9.3/KCNS3 sub-subfamily.
Expressed in myocytes (PubMed:9362476). Detected in lung, spleen, brain and heart (PubMed:9704029).
Heterotetramer with KCNB1 (PubMed:9362476). Does not form homomultimers (By similarity).
Inhibited by 4-aminopyridine (4-AP). Channel activity is reversibly inhibited by hypoxia and down-regulated in the absence of intracellular ATP.
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 (By similarity). 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 (PubMed:9362476).
Expressed at high levels in brain, followed by testis and spleen. Expressed at very low levels, in kidney. Detected abundantly in brain and testis and at lower levels in adrenal gland, kidney, lung and spleen (at protein level). In adrenal gland it is mostly found in the medulla but not in the cortex. In brain, it is found in the cerebellum and the CA2-CA3 regions of the hippocampus.
Expressed at high levels in developing forebrain. This expression decreases slightly in embryonic and early postnatal days.
Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements (PubMed:9819351). Regulates Rho by stimulating it's GTPase activity in neurons (PubMed:9819351). Required for the regulation of neurite branching and motor neuron axon guidance (By similarity).
Phosphorylated by ALPK1 following monosodium urate monohydrate (MSU)-induced inflammation.
Represents an unconventional myosin. This protein should not be confused with the conventional myosin-9 (MYH9).
At embryonic day 16 (16 dpc) can be detected in the hippocampal anlage, thalamus, cortex and olfactory bulb. At perinatal stages (20 dpc to P1) shows a strong expression in the cortex and hippocampus and subsequently declines at later postnatal stages.
Belongs to the PA-phosphatase related phosphoesterase family.
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.
Highly expressed in the brain. Also found in the liver, kidney and testis. In the brain shows a strongest expression in the hippocampus and cerebellum.
May play a role in neurite outgrowth and neurogenesis.
Shows a transient down-regulation due to overexcitation of neurons induced by kainic acid.
Belongs to the DEAD box helicase family. DDX46/PRP5 subfamily.
Plays an essential role in splicing, either prior to, or during A complex formation.
Induces disassembly of actin filaments in conjunction with ADF/cofilin family proteins. Enhances cofilin-mediated actin severing. Involved in cytokinesis. Involved in chemotactic cell migration by restricting lamellipodial membrane protrusions. Involved in myocardium sarcomere organization. Required for cardiomyocyte growth and maintenance. 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. Involved in assembly and maintenance of epithelial apical cell junctions and plays a role in the organization of the perijunctional actomyosin belt (By similarity).
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. Acts by binding to angiotensin receptors AGTR1 and AGTR2 (By similarity). Also binds the DEAR/FBXW7-AS1 receptor (PubMed:9508787).
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. Angiotensin-1 is a substrate of ACE (angiotensin converting enzyme) that removes a dipeptide to yield the physiologically active peptide angiotensin-2. Angiotensin-1 and angiotensin-2 can be further processed to generate angiotensin-3, angiotensin-4. 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. Angiotensin 1-7 has also been proposed to be cleaved from angiotensin-2 by ACE2 or from angiotensin-1 by MME (neprilysin) (By similarity).
Is a ligand for the G-protein coupled receptor MAS1 (By similarity). Has vasodilator and antidiuretic effects (By similarity). Has an antithrombotic effect that involves MAS1-mediated release of nitric oxide from platelets (PubMed:18026570).
The disulfide bond is labile. Angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized disulfide-bonded form, which preferentially interacts with receptor-bound renin.
Interacts (via C-terminus) with microtubules. Interacts with LCA5, CEP290 and SDCCAG8. Interacts with FAM161B. Interacts with POC1B. Interacts with CEP78.
Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.
Belongs to the phospholipase B-like family.
Glycosylated; contains mannose 6-phosphate sugars.
In neuronal cells, but not as specifically as VILIP-1 or VILIP-2.
May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.
Probably binds two or three calcium ions.
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 (By similarity). Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA (By similarity).
Tetramer (By similarity). Encodes coiled-coil structures that mediate homo- and heteromultimerization. Interacts with NFATC2; interaction is calcium independent; interaction competes with PPP3CA for NFATC2 binding; interaction is reduced by AKT activation. Interacts with NFATC1 and NFATC4. Interacts with SHANK1; forms a high-order complex at least composed of SHANK1 and HOMER3; the complex formation is regulated by CAMK2A-mediated phosphorylation (By similarity).
The WH1 domain interacts with the PPXXF motif in GRM1, GRM5, RYR1, RYR2, ITPR1, SHANK 1 and SHANK3.
Adapter protein that binds F-actin and DNM1, and thereby plays a role in receptor-mediated endocytosis. Required for the formation of organized podosome rosettes. 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 (By similarity). 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.
Detected in brain (at protein level). Widely expressed in brain with highest levels in hippocampus and cerebral cortex. Located primarily in dendrites and, in moderate amounts, in cell bodies. Isoform 1 and isoform 3 are the predominant isoforms in brain.
Interacts with FGD1, MAP4K1 and PRAM1 (By similarity). Interacts with ANKRD54. Interacts with WASL and WIPF1 (By similarity). Interacts with SHANK2 and SHANK3. Interacts with both COBL and PACSIN1. Interacts with DNM1 and SYN1.
The SH3 domain mediates interaction with SHANK2, SHANK3 and PRAM1.
May act as a scaffolding protein within caveolar membranes. Interacts directly with G-protein alpha subunits and can functionally regulate their activity.
Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair (By similarity). 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 (By similarity). Involved in ER-Golgi transport (PubMed:27276012). Regulates ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes (By similarity). 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 (By similarity). 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 (By similarity). Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway (By similarity). Promotes localization and polymerization of TFG at endoplasmic reticulum exit site (By similarity). 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 (By similarity). 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 (By similarity).
EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium-binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity. 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 (By similarity). 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 (By similarity). 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. Interacts with RBM22. Interacts with PLSCR4. Interacts with ANXA7 and TSG101. Interacts with DAPK1. Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A. Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent. Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent. Interacts with MCOLN1; the interaction is calcium-dependent. Interacts with KDR; the interaction is calcium-dependent. Interacts with HEBP2; the interaction is calcium-dependent. Interacts with TFG. Isoform 1: Interacts with SHISA5, leading to stabilize it. Isoform 2: Does not interact with SHISA5. Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11 (By similarity).
Interacts with different set of proteins thanks to 3 different hydrophobic pockets. 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). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3).
Class I metallothioneins contain 2 metal-binding domains: four divalent ions are chelated within cluster A of the alpha domain and are coordinated via cysteinyl thiolate bridges to 11 cysteine ligands. Cluster B, the corresponding region within the beta domain, can ligate three divalent ions to 9 cysteines.
Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
Belongs to the TNF receptor-associated factor family.
Belongs to the WD repeat striatin family.
Binds calmodulin in a calcium dependent manner. May function as scaffolding or signaling protein.
Interacts with protein phosphatase 2A (PP2A) (Potential). Interacts with CTTNBP2; this interaction may regulate dendritic spine distribution of STRN. Activation of glutamate receptors weakens the interaction with CTTNBP2.
Mainly expressed in the central nervous system. Mostly confined in dendrites, not in axons, and is most abundant in dendritic spines.
Autophosphorylated on tyrosine residues between pH 7.9 and pH 10.5.
Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.
Expressed preferentially in the kidney. Also found in stomach and thymus but not in skeletal muscle, brain, intestine, and uterus.
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 (By similarity).
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.
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.
Belongs to the ROX family. MINA53 subfamily.
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' (By similarity). 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.
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.
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 (By similarity).
Fibronectin type-II domain mediates collagen-binding.
Interacts directly with PLAUR/UPAR and PLAU/pro-UPA to form a tri-molecular complex. Interacts with collagen V (By similarity). Interacts with C-terminal region of type I collagen/COL1A1.
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 (By similarity). May participate in remodeling of extracellular matrix cooperating with the matrix metalloproteinases (MMPs) secreted by hepatic stellate cells. May mediate endocytosis of partially degraded collagens and glycoproteins produced in the extracellular matrix by MMPs.
Ricin B-type lectin domain contacts with the second C-type lectin domain.
Probable substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
Belongs to the inositol 3,4-bisphosphate 4-phosphatase family.
Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate (PubMed:7608176). Catalyzes also inositol 1,3,4-trisphosphate and inositol 1,4-bisphosphate (PubMed:7608176). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (By similarity). May protect neurons from excitotoxic cell death by regulating the synaptic localization of cell surface N-methyl-D-aspartate-type glutamate receptors (NMDARs) and NMDAR-mediated excitatory postsynaptic current (By similarity).
Widely expressed. Expressed at highest levels in the brain, heart and skeletal muscle.
Associates with the intermediate 315 kDa subcomplex of incompletely assembled complex I. Interacts with TMEM70 (By similarity).
Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). Participates in constructing the membrane arm of complex I (By similarity).
Nucleolin is the major nucleolar protein of growing eukaryotic cells. It is found associated with intranucleolar chromatin and pre-ribosomal particles. It induces chromatin decondensation by binding to histone H1. It is thought to play a role in pre-rRNA transcription and ribosome assembly. May play a role in the process of transcriptional elongation. Binds RNA oligonucleotides with 5'-UUAGGG-3' repeats more tightly than the telomeric single-stranded DNA 5'-TTAGGG-3' repeats.
Activated by insulin. Inhibited by diphenylene iodonium. Inhibited by plumbagin. Activated by phorbol 12-myristate 13-acetate (PMA) (By similarity).
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.
Interacts with TLR4 (By similarity). Interacts with, relocalizes and stabilizes CYBA/p22phox. Interacts with protein disulfide isomerase. Interacts with PPP1R15A (By similarity).
N-glycosylation is required for the function.
Up-regulated in diabetic kidney (at protein level).
In the embryo, preferentially expressed in the developing nervous system.
Interacts with stathmin and CDKN1B/p27Kip1 (By similarity) Interacts with PAM.
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).
Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters (By similarity). Enhances ligand-dependent transcriptional activation by nuclear hormone receptors (By similarity). Plays an important role in neural progenitor cell proliferation and self-renewal through the regulation of specific genes involved brain development, including REST (By similarity). Also controls the expression of genes involved in somatic development and regulates, for instance, lymphoblast proliferation (By similarity).
Interacts with NCOA6; may enhance ligand-dependent transcriptional activation by nuclear hormone receptors (By similarity). Interacts with CNOT6 (By similarity). 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 (By similarity). Within the complex interacts with EMSY and interacts (via C-terminus) with CCAR2 (By similarity). Interacts with members of histone H3'Lys4'(H3K4) methyltransferase complexes ASCL2, CXXC1, KMT2A/MLL1, RBBP5, SETD1A 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 (By similarity). Interacts with RBBP5 and WDR5 (By similarity). Interacts with ASHL2 (By similarity). 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 (By similarity). Within this complex also interacts with HCFC1 and MKI67 (By similarity).
Activated by threonine and tyrosine phosphorylation.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. MAP kinase subfamily.
Binds PPP1CA and/or PPP1CC. Binds F-actin in an ATP-sensitive manner (PubMed:11588169). 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). Interacts with KIRREL3 (By similarity).
Highest level of isoform 1 found in brain. Also found in bladder, kidney and lung. Very low or undetectable levels of isoform 2 in all tissues tested.
In the C-terminal section; belongs to the NYAP family.
In the N-terminal section; belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Myosin family.
Isoform 1 is expressed at all developmental stages with highest levels during the first two weeks after birth when migration of neurons and formation of dendrites and axons is highest. Within the developing brain the highest level is found in granule neurons in the initial stages of migration. Also found in soma and dendrites of developing Purkinje cells.
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). May be involved in targeting of the catalytic subunit of protein phosphatase 1 during brain development. Activates PI3K and concomitantly recruits the WAVE1 complex to the close vicinity of PI3K and regulates neuronal morphogenesis (By similarity).
Phosphorylated on tyrosine residues by FYN upon stimulation with CNTN5.
Dimer. Forms a ternary complex with NFE2L2 and KEAP1. Interacts with BCL2L1 and MAP3K5 (By similarity). Upon TNF-induced necrosis, forms in complex with RIPK1, RIPK3 and MLKL; the formation of this complex leads to PGAM5 phosphorylation (By similarity). Interacts with DNM1L; this interaction leads to DNM1L dephosphorylation and activation and eventually to mitochondria fragmentation (By similarity).
Displays phosphatase activity for serine/threonine residues, and, dephosphorylates and activates MAP3K5 kinase. Has apparently no phosphoglycerate mutase activity. May be regulator of mitochondrial dynamics. Substrate for a KEAP1-dependent ubiquitin ligase complex. Contributes to the repression of NFE2L2-dependent gene expression (By similarity). Acts as a central mediator for programmed necrosis induced by TNF, by reactive oxygen species and by calcium ionophore.
Phosphorylated by the RIPK1/RIPK3 complex under necrotic conditions. This phosphorylation increases PGAM5 phosphatase activity (By similarity).
The N-terminal 35 amino acids, including the potential transmembrane alpha-helix, function as a non-cleaved mitochondrial targeting sequence that targets the protein to the cytosolic side of the outer mitochondrial membrane.
Found in a complex with PUF60 and far upstream element (FUSE) DNA segment. Interacts with PUF60 and JTV1 (By similarity).
Regulates MYC expression by binding to a single-stranded far-upstream element (FUSE) upstream of the MYC promoter. May act both as activator and repressor of transcription (By similarity).
Ubiquitinated. This targets the protein for proteasome-mediated degradation (By similarity).
Abundant in the skeletal muscle, spleen and fetal liver.
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. Interacts with RRP1B.
Belongs to the TALE/MEIS homeobox family.
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.
Belongs to the phosphatase 2A regulatory subunit B56 family.
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. Interacts with SGO1. Interacts with AKT1.
Ubiquitinated by CUL3-KLHL15 complex; this modification leads to proteasomal degradation.
Widely expressed at the mRNA level, with highest levels in cerebellum and lung.
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. Plays a role in lipoprotein assembly and dietary cholesterol absorption. Utilizes oleoyl-CoA ((9Z)-octadecenoyl-CoA) preferentially as susbstrateb 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.
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.
May form homo- or heterodimers. Interacts with UBIAD1.
Belongs to the queuine tRNA-ribosyltransferase family. QTRT2 subfamily.
Heterodimer of a catalytic subunit QTRT1 and an accessory subunit QTRT2.
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).
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). The SRP complex interacts with the signal sequence in nascent secretory and membrane proteins and directs them to the membrane of the ER.
Responsible for the reduction of the oxo group on the C-3 of 5alpha-androstane steroids. Catalyzes the conversion of 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. Does not function as an isomerase.
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. Positively regulates IL31RA expression in macrophages. Stimulates autophagy in dendritic cells by interfering with mTORC1 signaling and through the induction of RUFY4.
Heterooligomer of MSH4 and MSH5. Interacts with HJURP (By similarity).
Involved in DNA mismatch repair and meiotic recombination processes. Facilitates crossovers between homologs during meiosis (By similarity).
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.
Belongs to the terpene cyclase/mutase family.
Hypomorphic mutations in this gene and the Fdft1 gene were identified, as well as a null mutation in this gene. Cataract onset is associated with the specific combination of Lss and Fdft1 mutant alleles that decrease cholesterol levels in cataractous lenses to about 57% of normal. Cholesterol insufficiency may cause the deficient proliferation of lens epithelial cells in Shumiya cataract rats, resulting in the loss of homeostatic epithelial cell control of the underlying fiber cells and ultimately cataractogenesis.
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:7568116). Through the production of lanosterol may regulate lens protein aggregation and increase transparency (By similarity).
Forms heteromeric complexes with LRFN1 and LRFN2. Can form heteromeric complexes with LRFN3 and LRFN5 (By similarity). Unable to form homophilic interactions across cell junctions (By similarity). Interacts with DLG1, DLG2, DLG3 and DLG4 (By similarity).
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 and interaction with DLG1, DLG3- and DLG4.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-independent O-methyltransferase family.
Catalyzes the transfer of a methyl group onto N-acetylserotonin, producing melatonin (N-acetyl-5-methoxytryptamine).
Exhibits very slight night/day variation, if any.
Expressed predominantly in the pineal gland (at protein level). Very low expression, if any, in the retina.
Pineal melatonin synthesis is severely compromised in most inbred strains. In many inbred strains, genetic defects in ASMT have been identified. Melatonin production may have an impact on gonadal development, testis development being significantly promoted in melatonin-deficient C57BL/6J x Mus musculus molossinus animals.
Identified in a complex composed of ACTA1, COBL, GSN AND TMSB4X (By similarity). Identified in a complex composed of COBL, PACSIN1 and WASL. Interacts with PACSIN1, PACSIN2 and PACSIN3. Interacts (via WH2 domains) with actin monomers. Interacts with both PACSIN1 and DBNL.
Plays an important role in the reorganization of the actin cytoskeleton. 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. Regulates dendrite branching in Purkinje cells (By similarity). Regulates neuron morphogenesis and increases branching of axons and dendrites.
Interacts with CHD4/Mi-2; the interaction is direct.
Transcription repressor that specifically binds the 5'-GGAG[GA]A[GA]A-3' consensus sequence. Represses transcription by recruiting the chromatin multiprotein complex NuRD to target promoters. Negatively regulates expression of EGFR, a gene involved in cell proliferation, survival and migration. Its ability to repress genes of the EGFR pathway suggest it may act as a tumor suppressor (By similarity).
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).
Interacts with EXOC2/Sec5 and EXOC8/Exo84. Interacts (via effector domain) with RALBP1.
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. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles (PubMed:17202486). Required both to stabilize the assembly of the exocyst complex and to localize functional exocyst complexes to the leading edge of migrating cells (PubMed:16382162). Required for suppression of apoptosis (By similarity). In late stages of cytokinesis, upon completion of the bridge formation between dividing cells, mediates exocyst recruitment to the midbody to drive abscission (By similarity). Involved in ligand-dependent receptor mediated endocytosis of the EGF and insulin receptors (By similarity).
Prenylation is essential for membrane localization.
The farnesylated form confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of some geranylgeranyltransferase I inhibitors.
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 dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A1 subfamily.
Expressed to a high extent in brain and kidney, and to a lower extent in heart, lung and skeletal muscle.
Homotrimer (Probable). Interacts with ARL6IP5/PRAF3 (PubMed:11242046). Interacts with RTN2 (via N-terminus); the interaction promotes cell surface expression of SLC1A1 (PubMed:19720795). 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:9011753, PubMed:11242046). Can also transport L-cysteine. 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. Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli (By similarity). 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 (PubMed:11242046).
Bifunctional enzyme which acts as both a sphingolipid delta(4)-desaturase and a sphingolipid C4-monooxygenase.
Homotetramer. Interacts with TNFAIP6 (via Link domain).
O-linked glycan consists of Gal-GalNAc disaccharide which is modified with sialic acid residues (microheterogeneity).
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.
Detected in heart atrium and ventricle, aorta and skeletal muscle (PubMed:11738816). Detected in heart left ventricle (PubMed:21127204).
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.
Expressed in the brain, heart, lung, liver and stomach. Expressed in the granular layer of the cerebellum. Expressed in Purkinje cells. Expressed in cortical neurons and coronary artery smooth muscle cells (at protein level). Expressed ubiquitously in the brain.
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 or not. 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 (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 (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). Interacts with CDH1, CTNNB1 and TJP1 (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 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.
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 (By similarity).
Ubiquitinated by NEDD4, leading to proteasomal degradation.
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 (By similarity). 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.
Binds two Mg(2+), but the interaction with the protein is mostly indirect.
Highly expressed in kidney, and at lower levels in hippocampus, brain cortex, cerebellum, heart and lung.
Inositol phosphate kinase with a broad substrate specificity. Phosphorylates inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) first to inositol 1,3,4,5-tetrakisphosphate and then to inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) (PubMed:11226235). Phosphorylates inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4) (By similarity). Phosphorylates glycero-3-phospho-1D-myo-inositol 4,5-bisphosphate to glycero-3-phospho-1D-myo-inositol 3,4,5-trisphosphate (PubMed:16123124). Plays an important role in MLKL-mediated necroptosis via its role in the biosynthesis of inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6). Binding of these highly phosphorylated inositol phosphates to MLKL mediates the release of an N-terminal auto-inhibitory region, leading to activation of the kinase. Essential for activated phospho-MLKL to oligomerize and localize to the cell membrane during necroptosis (By similarity). Required for normal embryonic development, probably via its role in the biosynthesis of inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P5) and inositol hexakisphosphate (InsP6) (By similarity).
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).
Homopentamer (By similarity). Interacts (via C-terminus) with GRASP55/GORASP2 (By similarity). Interacts with CUL3 and with ubiquitinated proteins (By similarity). Interacts with CRY1 (By similarity).
Its interaction with CUL3 suggests that it may act as a substrate adapter in some E3 ligase complex (By similarity). Does not affect the function of Kv channel Kv2.1/KCNB1, Kv1.2/KCNA2, Kv4.2/KCND2 and Kv3.4/KCNC4 (By similarity).
The BTB (POZ) domain is atypical and mediates the formation of a homopentamer instead of a homotetramer (By similarity). Homopentamerization is due to the presence of 4 residues in the BTB (POZ) domain: Leu-56, Gly-100, Val-112 and Ala-118 (By similarity).
Interacts with ACTN2. Interacts with F-actin (By similarity).
Protects actin filaments from depolymerization.
Activated by manganese or magnesium ions (PubMed:9874775). In the presence of magnesium ions, the enzyme is activated by bicarbonate (PubMed:12609998). Calcium mildly increases the enzyme activity, also in the presence of magnesium ions.
Binds 2 magnesium ions per subunit (By similarity). Is also active with manganese (in vitro) (PubMed:9874775).
Catalyzes the formation of the signaling molecule cAMP (PubMed:9874775). May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels (By similarity). 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 (By similarity).
Cleavage may occur to generate the active 48 kDa form.
Detected in testis (at protein level). Preferentially expressed in testis.
The N-terminal guanylate cyclase domains are required for enzyme activity. Fragments containing the first 470 amino acid residues are fully active.
Binds two calcium ions per molecule with an affinity similar to that of the S100 proteins.
Homodimer. Preferentially exists as a heterodimer or heterotetramer with S100A9 known as calprotectin (S100A8/A9). S100A8 interacts with AGER, ATP2A2 and with the heterodimeric complex formed by TLR4 and LY96. Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes. S100A8 and calprotectin (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin (S100A8/9) interacts with CYBA and CYBB (By similarity). Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex (By similarity).
S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. 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. 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. The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory activity includes 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 pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. 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. 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. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. The iNOS-S100A8/A9 transnitrosylase complex is proposed to direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as GAPDH, ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity (By similarity).
Interacts with GOLGA3. Interacts with ZDHHC9 (By similarity).
May be involved in protein transport from Golgi to cell surface. The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS (By similarity).
Palmitoylated on Cys-69 and Cys-72; which is required for Golgi localization and interaction with GOLGA3.
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).
Testis, and in a lower level in brain, heart and adrenal glands.
Belongs to the nucleotide-sugar transporter family. SLC35B subfamily.
Binds to ECMV-D capsid proteins and acts as a receptor for this virus.
Expressed in aortic endothelial cells, with low expression in the descending thoracic aorta and the outer curvature of the aortic arch, where pulsatory shear stress exists, and high in the inner curvature of the aortic arch, where oscillatory shear stress prevails (at protein level) (PubMed:28167758). Expressed on inflamed vascular endothelium, as well as on macrophage-like and dendritic cell types in both normal and inflamed tissue (PubMed:1371918).
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.
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 beta subunit family.
Highly expressed in kidney, heart, white adipose tissue, lung and spleen.
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.
Uncoupling protein which may catalyze the physiological 'proton leak' in liver.
Catalyzes the ferrous insertion into protoporphyrin IX.
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 (By similarity). Interacts with APLP1 (via NPXY motif) (By similarity). Interacts with DAB2IP (PubMed:11812785).
Phosphorylated on Tyr-198 and Tyr-220 upon reelin induction in embryonic neurons. Also phosphorylated on Ser-491 independently of reelin signaling.
The PID domain specifically binds to the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins.
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. Homooligomer. Interacts with PPM1F and PHTF1. Interacts with the death domain of FAS/TNFRSF6 and TNFRSF1A. Interacts with CHEK1 (By similarity). Interacts with NKX3-1 (By similarity).
In testis, it is first observed in leptotene and early pachytene spermatocytes. Present at high level in pachytene spermatocytes at stage IX-X and persists throughout spermiogenesis. At spermiation, most of the protein is associated with the residual bodies, but some protein persists in the queues of mature spermatids.
Present in adult testis (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. 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. The CRL2(FEM1B) complex specifically recognizes proteins ending with -Gly-Leu-Asp-Arg, such as CDK5R1, leading to their ubiquitination and degradation (By similarity). 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 (By similarity). Promotes ubiquitination and degradation of ANKRD37 (By similarity). Promotes ubiquitination and degradation of SLBP. Involved in apoptosis by acting as a death receptor-associated protein that mediates apoptosis (By similarity). 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 (By similarity).
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, ADGRB1, LPAR2/EDG4, FZD4, FZD7, GRIN2B, TGFA and VANGL2 (By similarity). Interacts with PTEN. Interacts with ADRB1, PTPRB and unidentified tyrosine phosphorylated proteins. Interacts with DLL1 (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (By similarity).
Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion. Integrin alpha-4/beta-1 is a receptor for VCAM1 and recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. 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. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. When associated with alpha-7/beta-1 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis (By similarity). ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGA4:ITGB1 and ITGA5:ITGB1 bind to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1. ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1. ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (By similarity). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (By similarity). Plays an important role in myoblast differentiation and fusion during skeletal myogenesis (By similarity).
Interacts with seprase FAP (seprase); the interaction occurs at the cell surface of invadopodia membrane in a collagen-dependent manner (By similarity). Heterodimer of an alpha and a beta subunit. Beta-1 associates with either alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-8, alpha-9, alpha-10, alpha-11 or alpha-V. ITGA6:ITGB1 is found in a complex with CD9; interaction takes place in oocytes and is involved in sperm-egg fusion. Binds LGALS3BP and NMRK2, when associated with alpha-7, but not with alpha-5. Interacts with FLNA, FLNB, FLNC and RANBP9. Interacts with KRT1 in the presence of RACK1 and SRC. Interacts with JAML; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization. Interacts with RAB21. Interacts (via the cytoplasmic region) with RAB25 (via the hypervariable C-terminal region). Interacts with MYO10. Interacts with ITGB1BP1 (via C-terminal region); the interaction is a prerequisite for focal adhesion disassembly. Interacts with TLN1; the interaction is prevented by competitive binding of ITGB1BP1. Interacts with ACAP1; required for ITGB1 recycling. Interacts with ASAP3. Interacts with FERMT2; the interaction is inhibited in presence of ITGB1BP1. Interacts with DAB2. Interacts with FGR and HCK. Isoform 2 interacts with alpha-7A and alpha-7B in adult skeletal muscle. Isoform 2 interacts with alpha-7B in cardiomyocytes of adult heart. Interacts with EMP2; the interaction may be direct or indirect and ITGB1 has a heterodimer form (By similarity). ITGA5:ITGB1 interacts with CCN3 (By similarity). ITGA4:ITGB1 is found in a ternary complex with CX3CR1 and CX3CL1 (By similarity). ITGA5:ITGB1 interacts with FBN1 (By similarity). ITGA5:ITGB1 interacts with IL1B. Interacts with MDK. ITGA4:ITGB1 interacts with MDK; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation. ITGA6:ITGB1 interacts with MDK; this interaction mediates MDK-induced neurite-outgrowth (By similarity). ITGA5:ITGB1 interacts with ACE2 (By similarity). Interacts with TMEM182 and LAMB1 (By similarity).
The cysteine residues are involved in intrachain disulfide bonds.
Autoubiquitinated, undergoes 'Lys-6'-linked polyubiquitination. 'Lys-6'-linked polyubiquitination does not promote degradation.
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. 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 (By similarity). Interacts with EXD2 (By similarity). Interacts (via C-terminus) with DHX9; this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme (By similarity).
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.
Phosphorylated in response to IR, UV, and various stimuli that cause checkpoint activation, probably by ATM or ATR. Phosphorylation at Ser-975 by CHEK2 regulates mitotic spindle assembly. Phosphorylation by AURKA regulates centrosomal microtubule nucleation.
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 RING-type zinc finger domain interacts with BAP1.
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.
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. Phosphorylates CLSPN (By similarity).
Belongs to the G-protein coupled receptor Fz/Smo family.
Expressed predominantly in neonatal tissues, at lower levels in adult.
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. 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 (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. Activation by Wnt5A stimulates PKC activity via a G-protein-dependent mechanism.
The FZ domain is involved in binding with Wnt ligands.
Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.
Widely expressed. Most abundant in kidney, liver, uterus, ovary and heart. Lower levels seen in brain and intestine. Extremely low in calvaria, mammary glands and testis.
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.
Belongs to the protein-tyrosine phosphatase family. Receptor class 5 subfamily.
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. Binds calmodulin. Interacts with PLXNB3 (By similarity).
Shows rapid uncatalyzed guanine nucleotide dissociation rates, which are much faster than those of most Ras subfamily members.
Cleavage of precursor form by UCHL3 or SENP8 is necessary for function.
Interacts with AHR; interaction is direct. Interacts with NUB1; interaction is direct.
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. 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. Attachment of NEDD8 to p53/TP53 inhibits p53/TP53 transcriptional activity. Covalent attachment to its substrates requires prior activation by the E1 complex UBE1C-APPBP1 and linkage to the E2 enzyme UBE2M.
Belongs to the SNF2/RAD54 helicase family. ISWI subfamily.
Expressed exclusively in meiotic prophase cells.
Major component of the transverse filaments of synaptonemal complexes, formed between homologous chromosomes during meiotic prophase (PubMed:1464329). 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. 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 (By similarity). 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 region exhibits a prominent seven-residues periodicity.
Belongs to the spermidine/spermine synthase family.
Detected in spleen, lung, muscle, liver, kidney, heart, testis and brain.
Expressed at 14.5 dpc in cerebral cortex; expression increases over time in cultured neural stem/progenitor cells.
Interacts with PPARD and PPARG (By similarity). Interacts with SCOC (By similarity). Interacts with PPARA. Interacts with THRB, RARA, RARG and RXRA in the presence of bound ligand. Associates with the PI3K complex I (PI3KC3-C1); the direct binding partner in the complex is reported variably as PIK3R4 or ATG14 (By similarity).
Involved in starvation-induced autophagy probably by its association with PI3K complex I (PI3KC3-C1). However, effects has been described variably. Involved in the induction of starvation-induced autophagy. Stabilzes PI3KC3-C1 assembly and enhances ATG14-linked lipid kinase activity of PIK3C3. Proposed to negatively regulate basal and starvation-induced autophagy and to inhibit PIK3C3 activity by modulating interactions in PI3KC3-C1. May be involved in autophagosome biogenesis. May play a role in neural progenitor cell survival during differentiation (By similarity).
May modulate transcriptional activation by target nuclear receptors. Can act as transcriptional activator (in vitro).
Belongs to the ubiquitin conjugation factor E4 family.
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. May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates 'Lys-48'-linked polyubiquitination of substrates.
ADP-ribosylated by SIRT4, leading to inactivate glutamate dehydrogenase activity. Stoichiometry shows that ADP-ribosylation occurs in one subunit per catalytically active homohexamer.
Belongs to the Glu/Leu/Phe/Val dehydrogenases family.
By water maze training in the hippocampus and in other regions of the brain including the laterodorsal nucleus of the thalamus and the cingulate cortex.
Homohexamer (By similarity). Interacts with HADH; this interaction inhibits the activation of GLUD1 (By similarity).
Mitochondrial glutamate dehydrogenase that converts L-glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle (By similarity). Plays a role in insulin homeostasis (By similarity). May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (PubMed:9275181).
Subject to allosteric regulation. Activated by ADP. Inhibited by GTP and ATP. ADP can occupy the NADH binding site and activate the enzyme. Inhibited by SIRT4 (By similarity). Inhibited by HADH (By similarity).
Widely expressed throughout the hippocampus. After induction by training, highly expressed in the dentate gyrus, pyrimidal layer and lacunosum moleculare.
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.
Component of the ribosomal small subunit (SSU) processome.
Involved in nucleolar processing of pre-18S ribosomal RNA.
Homodimer; disulfide-linked (By similarity). Monomer (By similarity). Homooligomer (By similarity).
Perchlorate inhibits iodide transport activity.
Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland (PubMed:8559252, PubMed:9341168, PubMed:32084174). Can also mediate the transport of chlorate, thiocynate, nitrate and selenocynate (PubMed:9341168).
Forms homooligomers; homo-oligomerization is essential for the roles in membrane tethering and enhancement of SNARE-mediated fusion. 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. PI3KC3-C1 displays a V-shaped architecture with PIK3R4 serving as a bridge between PIK3C3 and the ATG14:BECN1 subcomplex. PI3KC3-C1 can associate with further regulatory subunits. Interacts with PIK3CB. Interacts (via coiled-coil domain) with BECN2 (via coiled-coil domain); this interaction is tighter than BECN2 self-association (By similarity). Interacts with the STX17-SNAP29 binary t-SNARE complex (By similarity). Interacts with NRBF2 (By similarity). Interacts with PIK3C3 and BECN1; this interaction is increased in the absence of TMEM39A (By similarity). Interacts with STEEP1; the interaction is required for trafficking of STING1 from the endoplasmic reticulum (By similarity).
Required for both basal and inducible autophagy. Determines the localization of the autophagy-specific PI3-kinase complex. Plays a role in autophagosome formation and MAP1LC3/LC3 conjugation to phosphatidylethanolamine. Promotes BECN1 translocation from the trans-Golgi network to autophagosomes. Enhances PIK3C3 activity in a BECN1-dependent manner. Essential for the autophagy-dependent phosphorylation of BECN1. Stimulates the phosphorylation of BECN1, but suppresses the phosphorylation PIK3C3 by AMPK. Binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion. 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.
Detected only after the second postnatal week.
Forms a complex with CASK and CASKIN1. 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. Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C) (By similarity). Interacts with MARCHF11.
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.
Ubiquitously expressed in brain and detected in lung, liver and testis (at protein level). Expression was detected only in brain.
Up-regulated by cell depolarization and calcium entry through L-type calcium channels.
Could serve as a target-derived trophic factor for sensory and sympathetic neurons.
Expressed in thymus, muscle, ovary, brain, heart, stomach and kidney. Expressed in both embryo and adult tissues.
Belongs to the threonine synthase family.
Adaptor protein complex 4 (AP-4) is a heterotetramer composed of two large adaptins, a medium adaptin and a small adaptin.
Belongs to the adaptor complexes large subunit family.
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.
Belongs to the universal ribosomal protein uL6 family.
Belongs to the 2-oxoacid dehydrogenase family.
Reduces a broad range of aliphatic and aromatic aldehydes to the corresponding alcohols (PubMed:21048316). Reduces prostaglandins (By similarity). May play a role in the metabolism of xenobiotic aromatic aldehydes.
Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle (PubMed:8042990). Calcium ions are bound by clusters of acidic residues at the protein surface, especially at the interface between subunits. Can bind around 60 Ca(2+) ions. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR2; this plays an important role in triggering muscle contraction. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats (By similarity).
Detected in stomach and vas deferens (at protein level).
Monomer, homodimer and homooligomer. Mostly monomeric in the absence of calcium. Forms higher oligomers in a calcium-dependent manner. Dimers associate to form tetramers, that then form linear homomer chains. Interacts with ASPH and TRDN (By similarity).
Phosphorylation in the C-terminus, probably by CK2, moderately increases calcium buffering capacity.
Belongs to the lambda interferon family.
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 (By similarity). 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 (By similarity). Required for recruiting and activating RAB18 at the endoplasmic reticulum (ER) membrane where it maintains proper ER structure (By similarity). 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 (PubMed:9733780). The Rab3 GTPase-activating complex interacts with DMXL2 (PubMed:11809763). Interacts with LMAN1 (By similarity).
Cdca7 expression is correlated with MYC expression in fibroblasts and is much higher in attached cells tham in non-attached cells.
Interacts with MYC (via C-terminus), YWHAE and YWHAZ.
Participates in MYC-mediated cell transformation and apoptosis; induces anchorage-independent growth and clonogenicity in lymphoblastoid cells. Insufficient to induce tumorigenicity when overexpressed but contributes to MYC-mediated tumorigenesis. May play a role as transcriptional regulator (By similarity).
Phosphorylation at Thr-166 promotes interaction with YWHAE and YWHAZ, dissociation from MYC and sequestration in the cytoplasm.
Involved in the presentation of foreign antigens to the immune system.
Belongs to the cyclin family. Cyclin D subfamily.
Interacts with the CDK4 and CDK6 protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Interacts with ATF5. Interacts with EIF3K. Component of the ternary complex cyclin D/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity. Can form similar complexes with either CDKN1A or CDKN2A.
Phosphorylation at Thr-284 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex.
Regulatory component of the cyclin D3-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. 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. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Component of the ternary complex, cyclin D3/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Shows transcriptional coactivator activity with ATF5 independently of CDK4.
Ubiquitinated by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-284 phosphorylation. The DCX(AMBRA1) complex represents the major regulator of CCND3 stability during the G1/S transition (By similarity). Polyubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation (By similarity).
Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint. The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies. The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner. 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. In the complex, it mediates the interaction with microtubules.
Component of the SKA1 complex, composed of SKA1, SKA2 and SKA3. Forms a heterodimer with SKA2; 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 with microtubules; the interaction is direct. Interacts with SKA2. Interacts with SKA3.
Belongs to the DNA polymerase type-X family.
Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ).
Belongs to the peptidase S8 family. Furin subfamily.
Expressed abundantly in the testis. High levels seen in germ cells but not in Leydig, Sertoli or peritubular cells. Expressed in the pachytene spermatocytes and the round spermatids but not in the elongating spermatids. May be expressed within hormonally stimulated ovaries.
First expressed postnatally between days 19 and 22 coinciding with the early stages of spermiogenesis. The levels increase up to postnatal day 60.
Proprotein convertase involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. 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). Plays also 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 (By similarity). 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.
Belongs to the glycosyl hydrolase 38 family.
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.
Belongs to the WD repeat DDB2/WDR76 family.
Belongs to the cysteine dioxygenase family.
Binds 1 Fe cation per subunit (PubMed:16611640). Ni(2+) and Zn(2+) can be used to a lesser extent (By similarity).
By increase of sulfur amino acid intake.
Catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen.
Highest levels in liver. Significant expression also in kidney, lung and brain.
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.
Dual phosphorylation of Thr-197 and Thr-202 activates the kinase. Phosphorylation of Thr-332 activates the kinase. MAPK3/ERK1 is one of the kinases which activate MKNK1/MNK1. Phosphorylation by PAK2 leads to a reduced phosphorylation of EIF4G1 (By similarity).
Interacts with the C-terminal regions of EIF4G1 and EIF4G2. Also binds to dephosphorylated ERK1 and ERK2, and to the p38 kinases (By similarity).
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 (By similarity).
Phosphorylated and activated by the p38 kinases and kinases in the Erk pathway.
Hydrolyzes UDP-glucose to glucose 1-phosphate and UMP and UDP-galactose to galactose 1-phosphate and UMP. Preferred substrate is UDP-glucose.
By phytohemagglutinin (PHA) in spleen T-cells.
Interacts with TRAF1, TRAF2, TRAF3 and TRAF5.
Receptor for TNFSF8/CD30L. May play a role in the regulation of cellular growth and transformation of activated lymphoblasts (By similarity). Regulates gene expression through activation of NF-kappa-B (PubMed:8982082).
Very low level of expression. Detected in spleen, thymus and lung. Highly expressed in HTLV-1 infected T-cell lines.
Phosphorylates D-xylulose to produce D-xylulose 5-phosphate, a molecule that may play an important role in the regulation of glucose metabolism and lipogenesis.
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.
In cochlea, it is expressed in pillar cells from postnatal day 2 to adulthood.
In neurons degenerating after kainate-induced seizures, likely in a zinc-dependent manner.
May be a signaling adapter molecule involved in p75NTR-mediated apoptosis induced by NGF. Plays a role in zinc-triggered neuronal death.
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.
Ubiquitinated (Probable). Degraded by the proteasome.
Belongs to the glycosyltransferase 29 family.
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). 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).
Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family.
Inhibited by N-ethylmaleimide and high concentrations of zinc chloride.
Monomer and homodimer (PubMed:9642256, PubMed:10899106). 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 (By similarity). Interacts with ALDH1A1; the interaction is direct, inhibits ALDH1A1 aldehyde dehydrogenase activity and is independent of the methyltransferase activity of PRMT3 (PubMed:15334060).
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 (PubMed:9642256, PubMed:15334060, PubMed:10899106). May regulate retinoic acid synthesis and signaling by inhibiting ALDH1A1 retinal dehydrogenase activity (By similarity).
The C2H2-type zinc-finger is responsible for substrate specificity.
Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Responsible for cross-linking epidermal proteins during formation of the stratum corneum. Involved in cell proliferation (By similarity).
The membrane anchorage region possesses a cluster of five cysteines within which fatty acid(s) may become thioester-linked. It is subject to phorbol ester-stimulated phosphorylation and is hypersensitive to proteolysis, which releases the enzyme in a soluble form.
Belongs to the ADP-ribosyl cyclase family.
Catalyzes both the synthesis of cyclic ADP-beta-D-ribose (cADPR) from NAD(+), and its hydrolysis to ADP-D-ribose (ADPR). Cyclic ADPR is known to serve as an endogenous second messenger that elicits calcium release from intracellular stores, and thus regulates the mobilization of intracellular calcium. May be involved in pre-B-cell growth.
Pancreatic islets, kidney, spleen, heart, thymus, intestine and salivary gland.
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 (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).
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 tenascin (PubMed:7512960). Interacts with N-CAM and NG-CAM (PubMed:7528221). The carbonic-anhydrase like domain interacts with CNTN1 (contactin) (PubMed:7628014). Interacts with PTN (PubMed:16814777). Interaction with PTN promotes formation of homooligomers; oligomerization impairs phosphatase activity (PubMed:16814777). Interacts (via chondroitin sulfate chains) with MDK (via C-terminal); this interaction is inhibited by PTN; this interaction promotes neuronal migration (PubMed:10212223).
Isoform 3 (phosphacan), previously designated 3F8 chondroitin sulfate proteoglycan or 3H1 keratan sulfate proteoglycan depending on the glycosylation status, is a soluble nervous tissue-specific proteoglycan. It is synthesized by glia and binds to neurons and to the neural cell adhesion molecules tenascin, N-CAM or NG-CAM but not to laminin and fibronectin. Phosphacan acts as a potent inhibitor of cell adhesion and neurite outgrowth.
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).
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 (PubMed:8995428, PubMed:9298990). 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 (PubMed:17640868). In cerebellar granule cells the inhibition is mediated primarily via binding to neuronal gangliosides (PubMed:17640868). In sensory neurons, inhibition of neurite extension depends only partially on RTN4R, RTN4RL2 and gangliosides (PubMed:19367338). Inhibits axon longitudinal growth (PubMed:9298990). Inhibits axon outgrowth by binding to RTN4R (By similarity). Preferentially binds to alpha-2,3-linked sialic acid (PubMed:8995428). Binds ganglioside Gt1b (PubMed:8995428).
Belongs to the immunoglobulin superfamily. SIGLEC (sialic acid binding Ig-like lectin) family.
Detected in myelin (PubMed:17640868). Detected in olfactory bulb and throughout the brain (at protein level) (PubMed:4020419). Detected in brain (PubMed:2432614).
Monomer and homodimer (By similarity). Interacts (via the first three N-terminal Ig-like domains) with RTN4R and RTN4RL2 (PubMed:19420245). Interacts with isoform 2 of BSG (By similarity).
The C-terminal cytoplasmic region found only in isoform L-MAG is required for normal myelination in the central nervous system (CNS), but is apparently not required for normal myelination in the peripheral nervous system (PNS).
The extracellular domain is required to protect against axon degeneration (By similarity). The first three Ig-like domains mediate interaction with RTN4R and RTN4RL2, but are not sufficient to inhibit neurite outgrowth (PubMed:19420245). The two C-terminal extracellular Ig-like C2-type domains are required for inhibition of axon longitudinal growth (PubMed:9298990, PubMed:19420245, PubMed:19367338). Besides, the two C-terminal extracellular Ig-like C2-type domains are required for protection against apoptosis after nerve injury (By similarity).
Ubiquitinated, leading to proteasomal degradation.
Homodimer. Interacts with HOOK1. Interacts with HOOK2. Interacts with HOOK3.
Microtubule-binding protein that localizes to the microtubular manchette of elongating spermatids.
Belongs to the UNC119-binding protein family.
Belongs to the immunoglobulin superfamily. TIM family.
Probable receptor for SEMA4A involved in the regulation of T-cell function. The interaction with SEMA4A enhances T-cell activation (By similarity).
Acrosomal membrane-anchored protein involved in the process of fertilization and in acrosome biogenesis.
Highly N- and O-glycosylated; contains sialic acid.
Highly expressed in testis and epididymis. Low expression in other tissues.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family.
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.
Mainly expressed in ovary and testis. Alpha- and beta-B-subunits are the predominant forms found in testis. Also found in placenta, pituitary, adrenal gland, bone marrow, kidney, spinal cord and brain.
Proteolytic processing yields a number of bioactive forms, consisting either solely of the mature alpha chain, of the most N-terminal propeptide linked through a disulfide bond to the mature alpha chain, or of the entire proprotein.
Belongs to the phenylalanyl-tRNA synthetase beta subunit family. Type 2 subfamily.
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 (By similarity). 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 (By similarity). Interacts with COPB1 (By similarity). Interacts with TMED10 (via C-terminus). Interacts with TMED2, TMED3, TMED7 and TMED9 (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. 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).
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. 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.
Was originally thought to be part of the complex AP-2.
Belongs to the protein-tyrosine phosphatase family. Receptor class 4 subfamily.
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.
Expressed in brain, heart, lung and spleen. Low level in liver and testis.
Homodimer, and heterodimer with SH3GLB2. Binds BAX; induction of apoptosis augments BAX binding. Binds DNM1, HTT, AMPH, BIN1 and ARFGAP1. Interacts with UVRAG; UVRAG bridges the interaction to BECN1 indicative for an association with the PI3K complex II (PI3KC3-C2) (By similarity).
May be required for normal outer mitochondrial membrane dynamics. Required for coatomer-mediated retrograde transport in certain cells. May recruit other proteins to membranes with high curvature. May promote membrane fusion. Involved in activation of caspase-dependent apoptosis by promoting BAX/BAK1 activation. Involved in caspase-independent apoptosis during nutrition starvation and involved in the regulation of autophagy. Activates lipid kinase activity of PIK3C3 during autophagy probably by associating with the PI3K complex II (PI3KC3-C2). Associated with PI3KC3-C2 during autophagy may regulate the trafficking of ATG9A from the Golgi complex to the peripheral cytoplasm for the formation of autophagosomes by inducing Golgi membrane tubulation and fragmentation. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (By similarity).
Phosphorylated at Thr-145 by CDK5; this phosphorylation is required for autophagy induction in starved neurons and facilitates homodimerization.
Belongs to the secreted frizzled-related protein (sFRP) family.
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. 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. 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). 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. 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 (By similarity). Plays a role in the inhibition of microRNAs (miRNAs) biogenesis (By similarity). 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 (By similarity). 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 (By similarity). Affects the overall ubiquitination of cellular proteins. 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. 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 (By similarity). Prevents stress granules (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock, and energy deprivation. Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state. May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (By similarity). Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway (By similarity). 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).
Oligomer. 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. Interacts with IKBKG; this interaction increases in response to DNA damage. 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. Interacts with TRAF6; this interaction increases in response to DNA damage and is stimulated by TANK. 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. Interacts with ZC3H12D. Interacts with TNRC6A. Interacts with IKBKB/IKKB. Interacts with IKBKB/IKKB. Interacts with IKBKB/IKKB. Interacts with BTRC; the interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner. Interacts with IRAK1; this interaction increases the interaction between ZC3H12A and IKBKB/IKKB. 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. Associates with ribosomes. Interacts with ubiquitin.
Phosphorylated by IRAK1; phosphorylation is necessary for subsequent phosphorylation by the I-kappa-B-kinase (IKK) complex. Phosphorylated by I-kappa-B-kinases (IKKs) at Ser-435 and Ser-439 upon lipopolysaccharide (LPS) or IL1B stimulation in macrophages through the MyD88-dependent signaling pathway; these phosphorylations promote rapid ubiquitin proteasome-mediated degradation of ZC3H12A in macrophages and hence allows its target mRNAs, such as IL6, to escape from degradation and accumulate during the inflammatory response.
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. The C-terminal region and proline-rich domain are necessary for oligomerization.
Ubiquitinated; ubiquitination is induced in response to interleukin IL1 receptor stimuli in a IKBKB/IKKB and IRAK1-dependent manner, leading to proteasome-mediated degradation.
Brain-specific. Expression restricted to the pyramidal neurons of the cerebral cortex and in the Purkinje cells of the cerebellum.
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.
Belongs to the protein-tyrosine phosphatase family. Receptor class 2B subfamily.
May function as a chaperone that inhibits aggregation of misfolded proteins. Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling. May also regulate the UPR via the EIF2AK3 UPR sensor. Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin.
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 MICA on the surface of tumor cells, leading to MICA disulfide bond reduction which is required for its release from tumor cells. Interacts with ITGB3 following platelet stimulation. Interacts with ERN1; the interaction is direct. Interacts with EIF2AK3.
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 (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. 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.
O-GlcNAcylation at Thr-84 reduces transcriptional activity in adipocytes.
PDPK1 activates its transcriptional activity independently of its kinase activity.
Phosphorylated at basal conditions and dephosphorylated when treated with the ligand. May be dephosphorylated by PPP5C. The phosphorylated form may be inactive and dephosphorylation at induces adipogenic activity (By similarity).
Phosphorylated by MAPK. The phosphorylation inhibits PPAR gamma activity.
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. Involved in an early step of the formation of preautophagosomal structures. 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. Mediates ER-isolation membranes contacts by interacting with the ULK1:RB1CC1 complex and PtdIns3P. Once activated, WIPI2 recruits at phagophore assembly sites the ATG12-ATG5-ATG16L1 complex that directly controls the elongation of the nascent autophagosomal membrane.
Interacts with TECPR1. Interacts with ATG16L1. Interacts with ATG5. Interacts with WIPI1. Interacts with WDR45. May interact with NUDC. Interacts with ULK1 and RB1CC1.
The L/FRRG motif is required for recruitment to PtdIns3P.
Acts as an important p53/TP53-apoptotic effector. Regulates TNF-alpha-mediated apoptosis in a p53/TP53-dependent manner.
The LITAF domain is stabilized by a bound zinc ion. The LITAF domain contains an amphipathic helix that mediates interaction with lipid membranes.
Interacts with ASPN (By similarity). 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 (By similarity). 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).
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:32165585). 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:32165585).
Catalyzes the cleavage of 2'-deoxyuridine 5'-triphosphate (dUTP) into 2'-deoxyuridine 5'-monophosphate (dUMP) and inorganic pyrophosphate and through its action efficiently prevents uracil misincorporation into DNA and at the same time provides dUMP, the substrate for de novo thymidylate biosynthesis (By similarity). Inhibits peroxisome proliferator-activated receptor (PPAR) activity by binding of its N-terminal to PPAR, preventing the latter's dimerization with retinoid X receptor (PubMed:8910358). Essential for embryonic development (By similarity).
Each trimer binds three substrate molecules. The ligands are bound between subunits, and for each substrate molecule, residues from adjacent subunits contribute to the binding interactions.
Expressed in all tissues examined. Higher levels in heart and kidney.
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 (By similarity).
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 (By similarity).
Expressed at high levels in glioblastoma cell lines. Up-regulated in GBM (glioblastoma multiforme) tumors. Significantly increased in both the tumor core as well as the contralateral striatum and cortex in gliomas.
Phosphorylated by PLK1 at Thr-73, creating a self-tethering site that specifically interacts with the polo-box domain of PLK1.
Binds to the ATPase domain of HSP/HSP70 chaperones. Binds PRKN (By similarity). Interacts with HSPA8 and JPH2 (By similarity).
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 (By similarity). 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 (PubMed:15603737).
Detected in brain, lung, stomach, liver, kidney and testis.
Belongs to the class I-like SAM-binding methyltransferase superfamily. DOT1 family.
Histone methyltransferase that specifically trimethylates histone H3 to form H3K79me3. This methylation is required for telomere silencing and for the pachytene checkpoint during the meiotic cell cycle by allowing the recruitment of RAD9 to double strand breaks. Nucleosomes are preferred as substrate compared to free histone.
Histone methyltransferase. Methylates 'Lys-79' of histone H3.
In contrast to other lysine histone methyltransferases, it does not contain a SET domain, suggesting the existence of another mechanism for methylation of lysine residues of histones.
Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Responsible for the synthesis of complex-type N-linked oligosaccharides in many glycoproteins as well as the carbohydrate moieties of glycolipids.
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 (By similarity).
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 (By similarity).
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 TPR motif-containing C-terminal of kinesin light chain. Binds the cytoplasmic tails of LRP1 and LRP2 (Megalin). Interacts with DCLK2. Interacts with FGF13; enables the interaction with MAPK13 and may regulate the MAPK8IP2 scaffolding activity. Interacts with TIAM1 and TIAM2 (By similarity). Interacts with SH3RF2 (PubMed:22128169).
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.
Belongs to the DDOST 48 kDa subunit family.
Component of the oligosaccharyltransferase (OST) complex (By similarity). 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 (By similarity). 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. Interacts with SMIM22 (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 (By similarity). 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 (By similarity).
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 miochondrial matrix. Required during erythropoiesis.
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.
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).
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.
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.
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.
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. Interacts with AURKB. Interacts with CDKN1A. Interacts with MDM2 and RB1. Interacts with the C-terminus of TBXA2R isoform 2. Interacts with DNAJB2.
Interacts (preferentially in its GTP-bound form) with GCC2 (via its GRIP domain) (PubMed:16885419). Interacts (GTP-bound form) with SGSM1; the GDP-bound form has much lower affinity for SGSM1. Interacts with SGSM2. 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 (By similarity).
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.
Hydrolyzes DNA under acidic conditions. Does not require divalent cations for activity. Participates in the degradation of nuclear DNA during lens cell differentiation.
Inhibited by aurintricarboxylic acid and Zn(2+).
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:11042118). 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:11042118).
Might be cleaved at the N-terminus, retained in an intracellular membrane compartment and in addition be released into the extracellular medium.
Strongly and equally activated by either Ca(2+) or Mg(2+).
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 (By similarity).
Component of ribonuclease P, a protein complex that generates mature tRNA molecules by cleaving their 5'-ends.
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. In contrast, filament nucleation by the Arp2/3 complex is not affected.
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.
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins. Has depalmitoylating activity towards DLG4/PSD95. Has depalmitoylating activity towards GAP43. Has depalmitoylating activity towards MAP6. Has depalmitoylating activity towards NRAS.
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.
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.
First detected at birth, after which expression level is steadily increasing until it reaches a plateau at P15.
Isoform 1 is ubiquitously expressed. Isoform 2 is expressed in brain, predominantly in cerebral cortex, hippocampus and striatum.
Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-depending refilling of readily releasable vesicle pool (RRP) (By similarity). Essential for synaptic vesicle maturation in a subset of excitatory/glutamatergic but not inhibitory/GABA-mediated synapses (By similarity). In collaboration with UNC13A, facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release (By similarity).
The C2 domains are not involved in calcium-dependent phospholipid binding.
Binds RPS6KA3, MAPK3 and MAPK1. Interacts with CASP8 and FADD. Transient interaction with PLD1 and PLD2 (By similarity).
Blocks Ras-mediated inhibition of integrin activation and modulates the ERK MAP kinase cascade. Inhibits RPS6KA3 activities by retaining it in the cytoplasm. 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 (By similarity).
Phosphorylated by protein kinase C and calcium-calmodulin-dependent protein kinase. These phosphorylation events are modulated by neurotransmitters or hormones (By similarity).
Belongs to the prokaryotic/mitochondrial release factor family.
Belongs to the PDGF/VEGF growth factor family.
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.
Highly expressed in the lung, ovary, preputial gland and the adrenal gland. Expressed in the post-pubertal mammary glands.
Homodimer; non-covalent and antiparallel. Interacts with FLT4/VEGFR3; the interaction is required for FLT4/VEGFR3 homodimarization and activation.
Increases moderately during pregnancy (2.8-fold increase on day 4) and lactation (1.9-fold increase on day 2).
Indolinones; MAE87, MAE106 and MAZ51 inhibit VEGF-C induced activation of VEGFR-3.
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-223 and Ser-224 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 (By similarity).
Expressed in the central nervous system, in most motor and sensory axons of the ventral and dorsal roots, as well as in the large motor neurons of the ventral horn (at protein level).
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.
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 (PubMed:17283221, PubMed:19339511, PubMed:23532852). Interacts with regulatory subunit FXYD3 (PubMed:15743908). Interacts with SLC35G1 and STIM1 (By similarity). Interacts with SIK1 (PubMed:17939993). Interacts with CLN3; this interaction regulates the sodium/potassium-transporting ATPase complex localization at the plasma membrane (By similarity).
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.
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 (By similarity).
OAS domain 3 is catalytically active. OAS domain 1 has no catalytic activity but is essential for recognition of long dsRNAs.
Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection. Strongly activated by long dsRNAs at least 50 nucleotides in length. ssRNA does not activate the enzyme.
Belongs to the complex I subunit 4 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. Essential for the catalytic activity and assembly of complex I.
Interacts with TIMELESS, which impairs TIMELESS self-association. Associates with the MCM2-7 complex. Interacts with RPA2, PRDX2.
Plays an important role in the control of DNA replication and the maintenance of replication fork stability. Important for cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. 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.
(Microbial infection) Interacts with rabies virus phosphoprotein.
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).
As DLC8 is commonly used to refer to both DLC1 and DLC2 proteins, it is preferable to adopt the following nomenclature (see PubMed:11602781) where DLC8a and DLC8b corresponds respectively to DLC1 and DLC2.
Belongs to the dynein light chain family.
Homodimer (PubMed:12904292). 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. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. Dynein ICs and LICs bind directly to the HC dimer and the LCs assemble on the IC dimer (PubMed:11746667). Interacts with DYNC1I1 (By similarity). Interacts with GPHN (PubMed:12097491). Component of the myosin V motor complex (By similarity). Interacts with BMF (By similarity). Interacts with BCAS1 (PubMed:16133941). Interacts with Basson/BSN (By similarity). Interacts with Basson/BSN (By similarity). Interacts with AMBRA1 (via TQT motifs); tethering AMBRA1 to the cytoskeleton (By similarity).
Belongs to the apolipoprotein A1/A4/E family.
Homodimer (By similarity). Interacts with APOA1BP and CLU. Component of a sperm activating protein complex (SPAP), consisting of APOA1, an immunoglobulin heavy chain, an immunoglobulin light chain and albumin. Interacts with NDRG1. Interacts with SCGB3A2 (By similarity). Interacts with NAXE and YJEFN3 (By similarity).
Major protein of plasma HDL, also found in chylomicrons.
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.
Phosphorylation sites are present in the extracellular medium.
Belongs to the glycosyltransferase 2 family.
Belongs to the TFIIE beta subunit family.
Tetramer of two alpha and two beta chains.
Component of the heterotetramer complex KAR (3-ketoacyl-[acyl carrier protein] reductase or 3-ketoacyl-[ACP] reductase) that forms part of the mitochondrial fatty acid synthase (mtFAS). Beta-subunit of the KAR heterotetramer complex, responsible for the 3-ketoacyl-ACP reductase activity of the mtFAS, reduces 3-oxoacyl-[ACP] to (3R)-hydroxyacyl-[ACP] in a NADPH-dependent manner with no chain length preference, thereby participating in mitochondrial fatty acid biosynthesis. The homotetramer has NADPH-dependent quinone reductase activity (in vitro), hence could play a role in protection against cytotoxicity of exogenous quinones. As a heterotetramer, it can also reduce 9,10-phenanthrenequinone, 1,4-benzoquinone and various other o-quinones and p-quinones (in vitro).
Homotetramer (in vitro). Heterotetramer with HSD17B8; contains two molecules each of HSD17B8 and CBR4. Does not form homotetramers when HSD17B8 is coexpressed, only heterotetramers (in vitro).
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.
Part of the heterotrimeric IPP complex composed of integrin-linked kinase (ILK), LIMS1 or LIMS2, and PARVA.
Belongs to the peroxisomal membrane protein PXMP2/4 family.
Belongs to the flavin monoamine oxidase family.
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.
The SWIRM domain may act as an anchor site for a histone tail.
Belongs to the peptidase C12 family. BAP1 subfamily.
Component of the PR-DUB complex, at least composed of BAP1 and ASXL1. Interacts with BRCA1 (via the RING finger). Interacts (via HBM-like motif) with HCFC1. Interacts (when phosphorylated at Thr-491) with FOXK1. Interacts (when phosphorylated at Thr-491) with FOXK2; leading to recruit the PR-DUB complex and repress FOXK2 target genes.
Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1. Catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1). Does not deubiquitinate monoubiquitinated histone H2B. Acts as a regulator of cell growth by mediating deubiquitination of HCFC1 N-terminal and C-terminal chains, with some specificity toward 'Lys-48'-linked polyubiquitin chains compared to 'Lys-63'-linked polyubiquitin chains. Deubiquitination of HCFC1 does not lead to increase stability of HCFC1. Interferes with the BRCA1 and BARD1 heterodimer activity by inhibiting their ability to mediate ubiquitination and autoubiquitination. It however does not mediate deubiquitination of BRCA1 and BARD1. Able to mediate autodeubiquitination via intramolecular interactions to couteract monoubiquitination at the nuclear localization signal (NLS), thereby protecting it from cytoplasmic sequestration. Acts as a tumor suppressor.
Ubiquitinated: monoubiquitinated at multiple site of its nuclear localization signal (NLS) BY UBE2O, leading to cytoplasmic retention. Able to mediate autodeubiquitination via intramolecular interactions to couteract cytoplasmic retention.
Acts as histone chaperone in nucleosome assembly.
Interacts with core (H2A, H2B, H3, H4) and linker (H1) histones.
Phosphorylated at the G0/G1 boundary but it is not phosphorylated in S-phase. Phosphorylated protein remains in the cytoplasm in a complex with histones during the G0/G1 transition, whereas dephosphorylation triggers its transport into the nucleus at the G1/S-boundary.
Polyglutamylated and polyglycylated. These 2 modifications occur exclusively on glutamate residues and result in either polyglutamate or polyglycine chains on the gamma-carboxyl group. Both modifications can coexist on the same protein on adjacent residues, and lowering polyglycylation levels increases polyglutamylation, and reciprocally. Polyglutamylated by TTLL4.
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Dynamin/Fzo/YdjA family.
Interacts with MYOF (By similarity). Interacts with CTTN and ACTN1 (PubMed:21210813). Interacts with SHANK1, SHANK2 and NOSTRIN (By similarity). Interacts with SH3BP4 (PubMed:16325581). Interacts with SNX9 (By similarity). Interacts with SNX18 (By similarity). Interacts with SNX33 (via SH3 domain) (By similarity). Interacts with MYO1E (via SH3 domain) (PubMed:17257598). Interacts with PSTPIP1 (By similarity). Interacts with CTNND2 (By similarity). May interact with PIK3C3 (By similarity). May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity). Interacts with BIN1 (By similarity).
Localized to numerous punctate spots on the plasma membrane.
Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones (PubMed:21210813). Plays an important role in vesicular trafficking processes, in particular endocytosis (PubMed:19995918). Involved in cytokinesis (PubMed:21195118). Regulates maturation of apoptotic cell corpse-containing phagosomes by recruiting PIK3C3 to the phagosome membrane (By similarity).
Phosphorylation at Ser-764 by CDK1 is greatly increased upon mitotic entry. It regulates cytokinesis downstream of calcineurin, and does not affect clathrin-mediated endocytosis. Dephosphorylated by calcineurin/PP2. Phosphorylated on tyrosine residues after activation of SRC (PubMed:19995918).
Sequestered to clathrin-coated pits and vesicles at the plasma membrane and the Golgi apparatus.
Ubiquitously expressed. Brain expression is restricted to glial cells and fibroblasts. Highest levels in the testis.
Amidation of Leu-98 is essential for obestatin activity.
Ghrelin is broadly expressed with higher expression in the stomach. Very low levels are detected in the hypothalamus, heart, lung, pancreas, intestine and adipose tissue. Obestatin is most highly expressed in jejunum, and also found in duodenum, stomach, pituitary, ileum, liver, hypothalamus and heart. Expressed in low levels in pancreas, cerebellum, cerebrum, kidney, testis, ovary colon and lung.
Ghrelin is the ligand for growth hormone secretagogue receptor type 1 (GHSR). Induces the release of growth hormone from the pituitary. Has an appetite-stimulating effect, induces adiposity and stimulates gastric acid secretion. Involved in growth regulation.
O-octanoylated by GOAT/MBOAT4 (By similarity). O-octanoylation is essential for ghrelin activity. The replacement of Ser-26 by aromatic tryptophan preserves ghrelin activity (PubMed:10604470, PubMed:10801861).
Obestatin may be the ligand for GPR39. May have an appetite-reducing effect resulting in decreased food intake. May reduce gastric emptying activity and jejunal motility.
PubMed:16284174 reports obestatin as ligand of GPR39. However, PubMed:17289961 and others are unable to reproduce these results. It also seems to be unclear whether obestatin has opposite effects on food intake compared with ghrelin.
May bind zinc and other divalent cations and recruit them to vesicular organelles.
Strongly expressed in brain. Also detected in lung, liver, kidney and spleen. Mainly expressed in the glutaminergic neuron subpopulations.
Binds 2 magnesium or manganese ions per subunit.
Enzyme with a broad specificity. Negatively regulates TGF-beta signaling through dephosphorylating SMAD2 and SMAD3, resulting in their dissociation from SMAD4, nuclear export of the SMADs and termination of the TGF-beta-mediated signaling (By similarity). Dephosphorylates PRKAA1 and PRKAA2. Plays an important role in the termination of TNF-alpha-mediated NF-kappa-B activation through dephosphorylating and inactivating IKBKB/IKKB (By similarity).
Monomer (By similarity). Interacts with SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal SXS motif resulting in disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and termination of the TGF-beta-mediated signaling. Interacts with SMAD2; the interaction dephosphorylates SMAD2 in its C-terminal SXS motif resulting in disruption of the SMAD2/SMAD4 complex, SMAD2 nuclear export and termination of the TGF-beta-mediated signaling (By similarity). Interacts with the phosphorylated form of IKBKB/IKKB (By similarity).
N-myristoylation is essential for the recognition of its substrates for dephosphorylation.
Found in CD45+ but not in the CD45- fetal liver cells.
Heterodimer with TCRB; disulfide linked. This heterodimer assembles with CD3 proteins into a signaling-competent pre-T-cell receptor complex. Interacts with RHBDD1 (By similarity).
The pre-T-cell receptor complex (composed of PTCRA, TCRB and the CD3 complex) regulates early T-cell development.
Heterodimer with ALG13 to form a functional enzyme.
Involved in protein N-glycosylation. Essential for the second step of the dolichol-linked oligosaccharide pathway. Anchors the catalytic subunit ALG13 to the ER (By similarity).
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.
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).
The protein kinase domain is predicted to be catalytically inactive.
Monomer. Interacts with ATG3, ATG7, ATG13 and ULK1. Interacts with TP53INP1 and TP53INP2. Interacts with TBC1D25. Directly interacts with SQSTM1 and BNIP3. Interacts with TECPR2 and PCM1. Interacts with TBC1D5. Interacts with TRIM5. Interacts with MEFV and TRIM21. Interacts with WDFY3. Interacts with UBA5; promoting recruitment of UBA5 to the endoplasmic reticulum membrane. Interacts with GOSR1. Interacts with KBTBD6 and KBTBD7; the interaction is direct. Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3.
Phosphorylation at Ser-87 and Ser-88 by TBK1 prevents interaction with ATG4 (ATG4A, ATG4B, ATG4C or ATG4D). Phosphorylation by TBK1 on autophagosomes prevents their delipidation by ATG4 and premature removal from nascent autophagosomes.
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. 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. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms required for GABARAPL2 recycling when autophagosomes fuse with lysosomes. In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy. ATG4B constitutes the major protein for proteolytic activation (By similarity). ATG4D is the main enzyme for delipidation activity (By similarity).
Ubiquitin-like modifier involved in intra-Golgi traffic. Modulates intra-Golgi transport through coupling between NSF activity and SNAREs activation. It first stimulates the ATPase activity of NSF which in turn stimulates the association with GOSR1 (By similarity). Involved in autophagy. 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. Whereas LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation (By similarity).
Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.
Belongs to the immunoglobulin superfamily. Turtle family.
Expressed in hippocampal neurons (at protein level).
Functions in dendrite outgrowth and synapse maturation.
Interacts with SHANK1 and probably with MAGI2.
The PDZ-binding motif mediates interactions with MAGI2 and SHANK1.
Citrate synthase is found in nearly all cells capable of oxidative metabolism.
Expressed in the head region and flagellum of epididymal sperm.
Methylated. Trimethylation at Lys-395 by CSKMT decreases citrate synthase activity.
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.
Already detected in embryonic stages, peaks at postnatal day 7, and decreases thereafter to adult levels.
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:7512349, PubMed:21522138, PubMed:23625947). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:7512349, PubMed:23625947).
Expressed in brain, mainly in the subcortical region.
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:21522138, PubMed:23625947). In vivo, the subunit composition may depend on the expression levels of the different subunits (Probable). Interacts with PDZ domains of PATJ and DLG4 (PubMed:7569905, PubMed:9647694).
EF-1 binds magnesium constitutively under physiological conditions, EF-3 and EF-4 bind calcium cooperatively and EF-2 binds neither calcium nor magnesium.
Interacts ITPR1, ITPR2 and ITPR3. The strength of this interaction inversely correlates with calcium concentration. Interacts with CACNA1A (via C-terminal CDB motif) in the pre- and postsynaptic membranes. Interacts with CACNA1C. Interacts with CACNA1D (By similarity). Interacts (via EF-hands 1 and 2) at microtubules with MAP1LC3B. Interacts (via EF-hands 1 and 2) with NSMF (via the central NLS-containing motif region), the interaction occurs in a calcium dependent manner after synaptic NMDA receptor stimulation and prevents nuclear import of NSMF. Interacts with MYO1C and TRPC5. Interacts with SPACA9 (By similarity).
Its expression is regulated differentially in retinal cell types during development.
Modulates calcium-dependent activity of inositol 1,4,5-triphosphate receptors (ITPRs). Inhibits agonist-induced intracellular calcium signaling (By similarity). Enhances inactivation and does not support calcium-dependent facilitation of voltage-dependent P/Q-type calcium channels (PubMed:11865310). Causes calcium-dependent facilitation and inhibits inactivation of L-type calcium channels by binding to the same sites as calmodulin in the C-terminal domain of CACNA1C, but has an opposite effect on channel function. Suppresses the calcium-dependent inactivation of CACNA1D. Inhibits TRPC5 channels. Prevents NMDA receptor-induced cellular degeneration. Required for the normal transfer of light signals through the retina (By similarity).
Phosphorylated. The phosphorylation regulates the activity (By similarity).
Somatodendritic compartment of neurons (PubMed:11906216). Restricted expression in retina to a subpopulation of amacrine, bipolar, and ganglion cells (PubMed:11906216). According to PubMed:11906216, expression is heterogeneous within brain regions and their major cell types and does not match with those of marker proteins for characterized neuronal subpopulations (PubMed:11906216). Isoform 2: Minor isoform expressed in the brain, in the granule cell layer of the cerebellum, at low level. Not developmentally regulated (PubMed:11906216). Isoform 3: Minor isoform expressed in the brain, in the granule cell layer (PubMed:11906216). of the cerebellum, at low level. Not developmentally regulated.
Isoform 1 and isoform 2 are expressed in the esophagus, tongue and trachea. Isoform 2 is also highly expressed in the adrenal cortex and heart.
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. Preferentially cleaves the C-terminal side of arginine residues at the P1 position of certain peptides (By similarity). Isoform 2 may play a key role in regulating adrenal proliferation by specifically cleaving N-POMC.
Secreted and retained on the cell surface after secretion.
Belongs to the DEAD box helicase family. DEAH subfamily. DDX15/PRP43 sub-subfamily.
Activated by forskolin (PubMed:9391159). Inhibited by calcium ions, already at micromolar concentrations (By similarity). Inhibited by adenosine, AMP and their analogs (By similarity). Activated by GNAS (PubMed:9391159, PubMed:17110384). Is further activated by the complex formed by GNB1 and GNG2 (PubMed:17110384). Phosphorylation by RAF1 results in its activation (PubMed:15385642).
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:1409703, PubMed:15385642, PubMed:17110384, PubMed:21606183). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:21606183). 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 (PubMed:21606183). 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 (By similarity). Contributes to bone cell responses to mechanical stimuli (By similarity).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
Detected in brain and kidney (PubMed:1409703). Detected in vascular smooth muscle cells (PubMed:21606183).
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 (By similarity).
Phosphorylation by RAF1 increases enzyme activity (PubMed:15385642). Phosphorylation by PKA on Ser-660 inhibits the GNAS-mediated increase in catalytic activity (PubMed:9391159). Phosphorylation by PKC on Ser-554, Ser-660 and Thr-917 inhibits catalytic activity (PubMed:11877398).
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.
Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (via cytoplasmic N-termini); this interaction leads to mutual protein stabilization. Interacts with ADAM17; this interaction is indirect and mediated by iRhom proteins (By similarity). Interacts with LRP6; this interaction affects LRP6-binding to AXIN1 (By similarity).
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 (By similarity). Negatively regulates Wnt signaling, possibly by antagonizing the recruitment of AXIN1 to LRP6 (By similarity).
Belongs to the steroid 5-alpha reductase family.
Binds to TRAF2. Interacts with BMX. Interacts (activated form) with XPNPEP3.
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 (By similarity).
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.
Divalent metal cations. Prefers magnesium or manganese.
Binds 1 heme c group covalently per subunit.
Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain.
Found in embryos and in adult liver and heart.
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 (By similarity).
Interacts with YIPF6; this interaction may stabilize YIPF1. May also form a ternary complex with YIPF2 and YIPF6.
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.
Calcium-dependent cell-adhesion protein. Mediates functions in neuroprogenitor cell proliferation and differentiation (By similarity).
Heterophilic interaction with FAT4; this interaction affects their respective protein levels.
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. Seems to act as a coregulatory factor of ER-alpha (By similarity).
Belongs to the Mediator complex subunit 15 family.
Acetylated at Lys-29 by EP300, the acetylation enhances the interaction with CEBPB, DNA-binding and transactivation activity.
Binds DNA as a dimer. Interacts with PTP4A1/PRL-1 (By similarity). Interacts with CCND3, but not with CCND1 or CCND2. Interacts with HSPA1A or HSPA1B; the interaction protects ATF5 from degradation via proteasome-dependent and caspase-dependent processes. Interacts (via C-terminal region) with NPM1 (via C-terminal region); the interaction leads to loss of association between HSPA1A or HSPA1B and ATF5 and promotes ATF5 degradation via proteasome-dependent and caspase-dependent processes. Interacts with NLK; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner. Interacts with alpha-tubulin, gamma-tubulin members TUBGCP2 and TUBGCP4, PCNT; the ATF5:PCNT:polyglutamylated tubulin (PGT) tripartite unites the mother centriole and the pericentriolar material (PCM) in the centrosome (By similarity). Interacts with CEBPB and EP300; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity) (PubMed:21791614).
Down-regulated during neuronal differentiation. Down-regulated by pro-apoptotic stimuli (PubMed:21212266).
Expressed in embryonic nasal epithelium, dorsal root, trigeminal ganglia, brain and liver. Within the brain, expression is highest in the ventricular zone and decreased in structures containing migrating and postmitotic neurons (at protein level).
Phosphorylated by NLK, probably at Ser-92 and Ser-126.
Transcription factor that either stimulates or represses gene transcription through binding of different DNA regulatory elements such as cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), ATF5-specific response element (ARE) (consensus: 5'-C[CT]TCT[CT]CCTT[AT]-3') but also the amino acid response element (AARE), present in many viral and cellular promoters. Critically involved, often in a cell type-dependent manner, in cell survival, proliferation, and differentiation. Its transcriptional activity is enhanced by CCND3 and slightly inhibited by CDK4 (By similarity) (PubMed:19531563, PubMed:21212266). Important regulator of the cerebral cortex formation, functions in cerebral cortical neuroprogenitor cells to maintain proliferation and to block differentiation into neurons. Must be down-regulated in order for such cells to exit the cycle and differentiate (By similarity) (PubMed:12805299). Participates in the pathways by which SHH promotes cerebellar granule neuron progenitor cells proliferation. Critical for survival of mature olfactory sensory neurons (OSN), directs expression of OSN-specific genes (By similarity). May be involved in osteogenic differentiation. Promotes cell proliferation and survival by inducing the expression of EGR1 sinergistically with ELK1. Once acetylated by EP300, binds to ARE sequences on target genes promoters, such as BCL2 and EGR1 (By similarity) (PubMed:21791614). Plays an anti-apoptotic role through the transcriptional regulation of BCL2, this function seems to be cell type-dependent (By similarity). Cooperates with NR1I3/CAR in the transcriptional activation of CYP2B6 in liver. In hepatic cells, represses CRE-dependent transcription and inhibits proliferation by blocking at G2/M phase. May act as a negative regulator of IL1B transduction pathway in liver. Upon IL1B stimulus, cooperates with NLK to activate the transactivation activity of C/EBP subfamily members. Besides its function of transcription factor, acts as a cofactor of CEBPB to activate CEBPA and promote adipocyte differentiation. Regulates centrosome dynamics in a cell-cycle- and centriole-age-dependent manner. Forms 9-foci symmetrical ring scaffold around the mother centriole to control centrosome function and the interaction between centrioles and pericentriolar material (By similarity).
Ubiquitinated by CDC34 and UBE2B in order to be degraded by the proteasome.
Ubiquitinated by CDC34 and UBE2B in order to be degraded by the proteasome. Cisplatin inhibits ubiquitination and proteasome-mediated degradation by inhibiting the interaction with CDC34. Ubiquitination and degradation by the proteasome are inhibited by NLK in a kinase-independent manner.
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 (PubMed:10574704, PubMed:10788476). 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. Interacts with KLHL12 (By similarity).
Monoubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex, leading to regulate the size of COPII coats.
The ALG-2-binding site motif-2 (ABS-2) contains a PXPGF sequence that binds hydrophobic pocket 3 of PDCD6.
Lysophospholipid O-acyltransferase (LPLAT) that catalyzes the reacylation step of the phospholipid remodeling process also known as the Lands cycle. Catalyzes transfer of the fatty acyl chain from fatty acyl-CoA to 1-acyl lysophospholipid to form various classes of phospholipids. Converts 1-acyl lysophosphatidylcholine (LPC) into phosphatidylcholine (PC) (LPCAT activity), 1-acyl lysophosphatidylserine (LPS) into phosphatidylserine (PS) (LPSAT activity) and 1-acyl lysophosphatidylethanolamine (LPE) into phosphatidylethanolamine (PE) (LPEAT activity). Favors polyunsaturated fatty acyl-CoAs as acyl donors compared to saturated fatty acyl-CoAs (By similarity). Has higher activity for LPC acyl acceptors compared to LPEs and LPSs. Can also transfer the fatty acyl chain from fatty acyl-CoA to 1-O-alkyl lysophospholipid or 1-O-alkenyl lysophospholipid with lower efficiency. Acts as a major LPC O-acyltransferase in liver and intestine. As a component of the liver X receptor/NR1H3 or NR1H2 signaling pathway, mainly catalyzes the incorporation of arachidonate into PCs of endoplasmic reticulum (ER) membranes, increasing membrane dynamics and enabling triacylglycerols transfer to nascent very low-density lipoprotein (VLDL) particles. Promotes processing of sterol regulatory protein SREBF1 in hepatocytes, likely by facilitating the translocation of SREBF1-SCAP complex from ER to the Golgi apparatus. Participates in mechanisms by which the liver X receptor/NR1H3 or NR1H2 signaling pathway counteracts lipid-induced ER stress response and inflammation. Down-regulates hepatic inflammation by limiting arachidonic acid availability for synthesis of inflammatory eicosanoids, such as prostaglandins. In enterocytes, acts as a component of a gut-brain feedback loop that coordinates dietary lipid absorption and food intake. Regulates the abundance of PCs containing linoleate and arachidonate in enterocyte membranes, enabling passive diffusion of fatty acids and cholesterol across the membrane for efficient chylomicron assembly. In the intestinal crypt, acts as a component of dietary-responsive phospholipid-cholesterol axis, regulating the biosynthesis of cholesterol and its mitogenic effects on intestinal stem cells (By similarity).
The di-lysine motif confers endoplasmic reticulum localization.
Cell adhesion molecule that mediates both heterotypic cell-cell contacts via its interaction with CD6, as well as homotypic cell-cell contacts. Promotes T-cell activation and proliferation via its interactions with CD6 (By similarity). Contributes to the formation and maturation of the immunological synapse via its interactions with CD6 (By similarity). Mediates homotypic interactions with cells that express ALCAM. Mediates attachment of dendritic cells onto endothelial cells via homotypic interaction. Inhibits endothelial cell migration and promotes endothelial tube formation via homotypic interactions. Required for normal organization of the lymph vessel network. Required for normal hematopoietic stem cell engraftment in the bone marrow. Plays a role in hematopoiesis; required for normal numbers of hematopoietic stem cells in bone marrow. Promotes in vitro osteoblast proliferation and differentiation (By similarity). Promotes neurite extension, axon growth and axon guidance; axons grow preferentially on surfaces that contain ALCAM (By similarity). Mediates outgrowth and pathfinding for retinal ganglion cell axons (By similarity).
Homodimer. Interacts (via extracellular domain) with CD6 (via extracellular domain). Homodimerization and interaction with CD6 involve the same region and cannot occur simultaneously. The affinity for CD6 is much higher than the affinity for self-association. Interacts (via glycosylated extracellular domain) with LGALS1 and LGALS3. Interaction with LGALS1 or LGALS3 inhibits interaction with CD6.
Strongest expression in the lung, then brain, liver, and kidney. Present in the somatosensory system, basal ganglia, cortex, olfactory system, and circumventricular organs.
The CD6 binding site is located in the N-terminal Ig-like domain.
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.
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. 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.
Component of the gamma-secretase complex. 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 PEN2. Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP). Interacts with PSEN1 and PSEN2.
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). 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.
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 (By similarity).
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 (By similarity).
Highly expressed in testis, ovary and spleen. A much lower mRNA level is found in brain and lung, and no expression is detected in liver, kidney, heart, muscle, pituitary gland, prostate, epididymis and seminal vesicle.
Sumoylated. Sumoylated form can be polyubiquitinated by RNF4, leading to its degradation. Desumoylation by SENP6 prevents its degradation (By similarity).
Catalyzes the NADPH-dependent reduction of 1,5-anhydro-D-fructose (AF) to 1,5-anhydro-D-glucitol.
Inhibited by p-chloromercuribenzoic acid and alkyliodines.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.3/KCNA3 sub-subfamily.
Heterotetramer of potassium channel proteins (By similarity). Binds PDZ domains of DLG1, DLG2 and DLG4.
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.
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.
Belongs to the glycosyl hydrolase 23 family.
Belongs to the cyclophilin-type PPIase family. PPIL2 subfamily.
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 (By similarity).
In kidney epithelial tissues, the shorter form predominates in young (1 day old) rats while the longer form becomes more prevalant during aging.
The long form contains a basic insert which acts as a cell retention signal.
Belongs to the eukaryotic ribosomal protein eS21 family.
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. Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80 (By similarity).
Putative regulatory component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair.
Ubiquitously expressed. Abundant in the brain.
Found in tumor tissues and not detected in normal tissues.
Has some calmodulin-like activity with respect to enzyme activation and growth regulation. Binds two calcium ions.
Chaperone specifically assisting the folding of beta-propeller/EGF modules within the family of low-density lipoprotein receptors (LDLRs). Acts as a modulator of the Wnt pathway through chaperoning the coreceptors of the canonical Wnt pathway, LRP5 and LRP6, to the plasma membrane. 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. May regulate phagocytosis of apoptotic retinal pigment epithelium (RPE) cells.
Monomer. Interacts with LRP5; the interaction prevents LRP5 from forming aggregates and chaperones LRP6 to the plasma membrane. Interacts with LRP6; the interaction prevents LRP6 from forming aggregates and chaperones LRP6 to the plasma membrane. Interacts with LRP4; the interaction promotes glycosylation of LRP4 and its cell-surface expression.
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.
Cleaves and degrades bioactive peptides, including angiotensin, Leu-enkephalin and Met-enkephalin (By similarity). Also cleaves Arg-Arg-beta-naphthylamide.
Inhibited by spinorphin, an opioid peptide derived from hemoglobin.
Acetylated: autoacetylation is required for optimal acetyltransferase activity.
Belongs to the acetyltransferase family. NAA60 subfamily.
Monomer and homodimer; monomer in presence of substrate and homodimer in its absence.
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. 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. Required for normal chromosomal segregation during anaphase. May also show histone acetyltransferase activity; such results are however unclear in vivo and would require additional experimental evidences.
Component of the distal appendage region of the centriole involved in the initiation of primary cilium assembly. May collaborate with IFT20 in the trafficking of ciliary membrane proteins from the Golgi complex to the cilium during the initiation of primary cilium assembly (By similarity).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which hydrolyzes the 61-Lys-|-Leu-62 bond and inhibits neurotransmitter release (PubMed:8175689). This is a poor substrate for BoNT/D, high concentrations are required to cleave it in vitro (PubMed:8175689).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 60-Gln-|-Lys-61 bond and inhibits neurotransmitter release (PubMed:8505288).
Expressed in brain and spleen (at protein level). Isoform 1 expressed at very high level in brain. Even higher level found in spinal cord. Isoform 3 expressed in kidney, spleen and liver. Isoforms 2 and 3 expressed in osteoblasts of trabecular bone. Also expressed in heart.
Involved in the targeting and/or fusion of transport vesicles to their target membrane.
Is not targeted by C.botulinum neurotoxin type B (BoNT/B) or by C.tetani toxin (tetX) as their target sequence is not conserved in this protein (PubMed:1331807, PubMed:8175689).
Cytotoxin and helminthotoxin with ribonuclease activity. Possesses a wide variety of biological activities (By similarity).
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 CHEK2; mediates CDC25A phosphorylation and degradation in response to infrared-induced DNA damages (By similarity). Interacts with PIM1. Interacts with HSP90AB1; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (By similarity).
Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-283, Ser-296 and Thr-508 during checkpoint mediated cell cycle arrest. Also phosphorylated by CHEK2 on Ser-124, Ser-283, and Ser-296 during checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and Thr-508 creates binding sites for YWHAE/14-3-3 epsilon which inhibits CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-283 and Ser-296 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 (By similarity).
Stimulated by B-type cyclins. Stimulated by PIM1-mediated phosphorylation (By similarity).
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 (By similarity).
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 (By similarity). Phosphorylation by PIM1 leads to an increase in phosphatase activity.
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 (By similarity).
May be involved in the control of excitability of cortical neurons.
Catalyzes the reversible hydration of carbon dioxide (By similarity). Involved in the regulation of fluid secretion into the anterior chamber of the eye (By similarity). Essential for bone resorption and osteoclast differentiation (PubMed:9665810). Contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption (By similarity). Stimulates the chloride-bicarbonate exchange activity of SLC26A6 (By similarity).
Interacts with SLC4A4 and SLC26A6. Interaction with SLC4A7 regulates SLC4A7 transporter activity (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 (By similarity). Interacts with KCNT1.
Detected in heart, brain, liver, kidney and testis (at protein level). Ubiquitous.
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. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. 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. Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1 (By similarity). May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (By similarity).
Ubiquitinated, ubiquitination is mediated by its own DCX protein ligase complex.
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 to 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.
Interacts with GLRX3 (via N-terminus). Interacts with ECT2.
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.
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 (By similarity).
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.
Brain, restricted to the oligodendrocyte-containing cell layers of cerebrum and cerebellum.
Catalyzes the transfer of galactose to ceramide, a key enzymatic step in the biosynthesis of galactocerebrosides, which are abundant sphingolipids of the myelin membrane of the central nervous system and peripheral nervous system. Galactosylates both hydroxy- and non-hydroxy fatty acid-containing ceramides and diglycerides (PubMed:8713090).
Heterodimer with GPN1. Binds to RNA polymerase II (RNAPII). Interacts directly with subunits RPB4 and RPB7 and the CTD of RPB1.
Small GTPase required for proper localization of RNA polymerase II (RNAPII). May act at an RNAP assembly step prior to nuclear import.
May play a role in cell growth and maintenance of cell morphology.
Belongs to the immunoglobulin superfamily. MyBP family.
Binds to myosin; probably involved in interaction with thick myofilaments in the A-band.
Thalamus, hypothalamus, and the hippocampal rudiments.
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. This receptor is implicated in the regulation of mammalian circadian rhythms.
Neurotensin may play an endocrine or paracrine role in the regulation of fat metabolism. It causes contraction of smooth muscle.
Megakaryocyte-potentiating factor (MPF) may potentiate megakaryocyte colony formation.
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.
Specifically expressed in lung. Overexpressed in hereditary renal carcinoma developed by Eker rats.
Binds calmodulin in a calcium dependent manner. May function as scaffolding or signaling protein (By similarity).
Interacts with protein phosphatase 2A (PP2A). Interacts with CDC42BPB.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a p18 subunit and a p12 subunit. Forms a complex named the PIDDosome with PIDD1 and CRADD (By similarity). Interacts with NOL3 (via CARD domain); inhibits CASP2 activity in a phosphorylation-dependent manner (PubMed:16639714).
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 (By similarity). Associates with PIDD1 and CRADD to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis in response to genotoxic stress (By similarity).
The CARD domain mediates a direct interaction with CRADD.
The mature protease can process its own propeptide, but not that of other caspases.
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 (PubMed:19265014). Interacts with AP4M1 and GRIA1; associates GRIA1 with the adaptor protein complex 4 (AP-4) to target GRIA1 to the somatodendritic compartment of neurons (By similarity).
Cytokine that stimulates the proliferation of T-lymphocytes. Stimulation by IL15 requires interaction of IL15 with components of the IL2 receptor, including IL2RB and probably IL2RG but not IL2RA (By similarity). In neutrophils, stimulates phagocytosis probably by signaling through the IL15 receptor, composed of the subunits IL15RA, IL2RB and IL2RG, which results in kinase SYK activation (By similarity).
Abundant in the bone matrix (PubMed:2070682). Expressed in cardiomyocytes (PubMed:26858265).
Homodimer; disulfide-linked. Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction.
Homodimer; disulfide-linked. 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. May interact with THSD4; this interaction may lead to sequestration by FBN1 microfibril assembly and attenuation of TGFB signaling. Interacts with CD109, DPT and ASPN. Interacts with EFEMP2. Interacts with TSKU; the interaction contributes to regulation of the hair cycle.
Homodimer; disulfide-linked. 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. Interacts with LTBP1; leading to regulation of TGF-beta-1 activation. Interacts with LRRC32/GARP; leading to regulation of TGF-beta-1 activation on the surface of activated regulatory T-cells (Tregs). Interacts with LRRC33/NRROS; leading to regulation of TGF-beta-1 activation in macrophages and microglia. Interacts (via cell attachment site) with integrins ITGAV and ITGB6 (ITGAV:ITGB6), leading to release of the active TGF-beta-1. Interacts with NREP; the interaction results in a decrease in TGFB1 autoinduction. Interacts with HSP90AB1; inhibits latent TGFB1 activation.
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 (By similarity). 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. 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 (By similarity). Once activated following release of LAP, TGF-beta-1 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (By similarity). 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' (PubMed:2070682). Plays an important role in bone remodeling: acts as a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts (PubMed:2070682). 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). Mediates SMAD2/3 activation by inducing its phosphorylation and subsequent translocation to the nucleus. Can induce epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types (By similarity).
N-glycosylated. 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.
Required to maintain the Transforming growth factor beta-1 (TGF-beta-1) chain in a latent state during storage in extracellular matrix. 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. Interaction with LRRC33/NRROS regulates activation of TGF-beta-1 in macrophages and microglia. Interaction with LRRC32/GARP controls activation of TGF-beta-1 on the surface of activated regulatory T-cells (Tregs). 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.
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). The motif locates to a long loop in the arm domain called the bowtie tail. Integrin-binding stabilizes an alternative conformation of the bowtie tail. 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.
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.
Homooligomer and heterooligomer. Interacts with TRIM63 and probably with TRIM55. Interacts with tubulin (By similarity).
May bind and stabilize microtubules during myotubes formation.
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. As a type I receptor, forms heterotetrameric receptor complexes with the type II receptors AMHR2, ACVR2A ors ACVR2B. Upon binding of ligands such as BMP7 or GDF2/BMP9 to the heteromeric complexes, type II receptors transphosphorylate ACVR1 intracellular domain. In turn, ACVR1 kinase domain is activated and subsequently phosphorylates SMAD1/5/8 proteins that transduce the signal. 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 (By similarity). Besides canonical SMAD signaling, can activate non-canonical pathways such as p38 mitogen-activated protein kinases/MAPKs (By similarity).
Interacts with FKBP1A. Interacts with FCHO1. Interacts with CLU. Interacts with type II receptors AMHR2 and ACVR2A. Interacts with BMP7. Interacts with GDF2/BMP9. Interacts with BMP6.
Urogenital ridge, testis, ovary, brain and lungs.
Biosynthesis of L-glutamate from L-aspartate or L-cysteine. 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 liver and kidney, by glucocorticod hormones. Levels in the liver also increase 2-fold on animals fed on a high protein diet or during fasting. By hypoxia during cerebral ischemia.
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.
Interacts with nephrin/NPHS1, KIRRL1 and CD2AP (By similarity). Interacts with DDN.
Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton.
Belongs to the JARID1 histone demethylase family.
Belongs to the glucosamine/galactosamine-6-phosphate isomerase family.
Monomer (By similarity). Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (By similarity). Interacts with RANBP9/RANBPM (By similarity). Interacts with BRCA2 (By similarity). Interacts with CHUK/IKKA (By similarity). Interacts with NFKBIA (By similarity). Interacts with SPRY3, RAE1, MYCBP2/PAM, and KCTD6 (By similarity).
Protease that can remove conjugated ubiquitin from target proteins and polyubiquitin chains. Inhibits the degradation of target proteins by the proteasome. 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). Plays a role in the regulation of pathways leading to NF-kappa-B activation. Plays a role in the regulation of DNA repair after double-stranded DNA breaks. 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 comple. Promotes cell proliferation by deubiquitinating phosphorylated E2F1x.
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.
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. Interacts with AICDA; the interaction is important for the antibody diversification activity of AICDA. Interacts with PRPF31 (via its NLS). Interacts (via its N-terminal NLS) with KPNA1 and KPNA2 (By similarity).
The surface residues of the concave side of the superhelical ARM repeat region contribute to, but are not essential for NLS binding.
Interacts with CFAP45 and CFAP52; CFAP45 and AK8 dimerization may create a cavity at the interface of the dimer that can accommodate AMP.
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.
Belongs to the tenascin family. Teneurin subfamily.
Interacts with NLRX1. Interacts with ATG16L1.
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. Promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
Component of a PRC1-like complex. Interacts with BMI1/PCGF4, RING1 and RNF2. Interacts with KDM5D. Interacts with CBX4, CBX6, CBX7 and CBX8.
Transcriptional repressor. May modulate the levels of histone H3K4Me3 by activating KDM5D histone demethylase. Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity.
Belongs to the SLC35F solute transporter family.
By high fat and high carbohydrate diets.
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:8978480, PubMed:10198260, PubMed:10749848, PubMed:28209804). Preferentially uses palmitoleate, oleate and linoleate (By similarity). Preferentially activates arachidonate than epoxyeicosatrienoic acids (EETs) or hydroxyeicosatrienoic acids (HETEs) (PubMed:28209804).
Inhibited at high temperature and by arachidonate.
Levels remain constant during development.
Liver, heart, epididymal adipose and to a lesser extent brain, small intestine and lung.
Belongs to the krueppel C2H2-type zinc-finger protein family. ZBTB18 subfamily.
Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development. 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. 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. May also play a role in the organization of chromosomes in the nucleus (By similarity).
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 (By similarity).
The SH3 domain mediates interaction with SMN1.
Androgen dependent, as shown by the decrease in the level of the protein following castration.
Associated with the mammalian reproductive process. Plays an important role in the formation of the seminal coagulum through the cross-linking of specific proteins present in the seminal plasma. Transglutaminase is also required to stabilize the copulatory plug.
Expressed in the coagulating gland, the dorsal part of the prostate and in semen (at protein level). Expressed at low levels in the lateral prostate and seminal vesicle. Not expressed in the epididymis, kidney, liver, serum, sperm plug, testes and ventral prostate.
N-glycosylated on 2 Asn residues by a high mannose oligosaccharide consisting of five mannose residues and a fucosylated biantennary complex glycan.
Probably linked to the cell membrane via a lipid-anchor, possibly a GPI-anchor.
Acetylated during keratinocyte differentiation. Acetylation at Ser-799 and Ser-803 regulates subcellular localization. Can be deacetylated by SIRT1.
Belongs to the retinoblastoma protein (RB) family.
N-terminus is methylated by METTL11A/NTM1. Monomethylation at Lys-802 by SMYD2 enhances phosphorylation at Ser-799 and Ser-803, and promotes cell cycle progression. Monomethylation at Lys-852 by SMYD2 promotes interaction with L3MBTL1 (By similarity).
Phosphorylated by CDK6 and CDK4, and subsequently by CDK2 at Ser-560 in G1, thereby releasing E2F1 which is then able to activate cell growth. Dephosphorylated at the late M phase. Phosphorylation of threonine residues in domain C promotes interaction between the C-terminal domain C and the Pocket domain, and thereby inhibits interactions with heterodimeric E2F/DP transcription factor complexes. CDK3/cyclin-C-mediated phosphorylation at Ser-799 and Ser-803 is required for G0-G1 transition (By similarity). Dephosphorylated at Ser-787 by calcineruin upon calcium stimulation.
The hypophosphorylated form interacts with and sequesters the E2F1 transcription factor. 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, ATAD5, 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, LIMD1 and USP4. Interacts with PRMT2. Interacts (when methylated at Lys-852) with L3MBTL. Interacts with CHEK2; phosphorylates RB1 (By similarity). Interacts with SMARCA4/BRG1 and HDAC1. Binds to CDK1 and CDK2. P-TEFB complex interacts with RB1; promotes phosphorylation of RB1 (By similarity). Interacts with RBBP9; the interaction disrupts RB1 binding to E2F1 (PubMed:9697699). Interacts with KAT2B/PCAF and EP300/P300 (By similarity). Interacts with PAX5 (By similarity).
Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle. The hypophosphorylated form binds transcription regulators of the E2F family, preventing transcription of E2F-responsive genes. Both physically blocks E2Fs transactivating domain and recruits chromatin-modifying enzymes that actively repress transcription. 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. RB1 also promotes the G0-G1 transition upon phosphorylation and activation by CDK3/cyclin-C. 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 (PubMed:19081374). 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).
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 (By similarity).
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) (By similarity).
Homodimer. Interacts with CSTF2 (By similarity).
Belongs to the immunoglobulin superfamily. ROBO family.
Expressed in embryonal brain and spinal chord.
Homodimer. Dimerization is mediated by the extracellular domain and is independent of SLIT liganding (By similarity). Interacts with SLIT1 (By similarity). Interacts with SLIT2. Interacts with FLRT3. Interacts with MYO9B (via Rho-GAP domain) (By similarity).
In the developing spinal cord expressed at 11 dpc and 13 dpc dorsally in the region of the commissural and association neuron cell bodies and ventrally in subpopulations in the motor column. In the brain detected between 15 dpc and 18 dpc, between P0 and P10, and in adult in regions of the hippocampal system and the basal ganglia. Detected at 18 dpc, between P0 and P10, and in adult in anterior olfactory nuclei, regions of the cortex and basal telencephalon.
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. Interaction with the intracellular domain of FLRT3 mediates axon attraction towards cells expressing NTN1 (By similarity). 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 (By similarity). May be required for lung development (By similarity).
Ubiquitinated. May be deubiquitinated by USP33.
Belongs to the universal ribosomal protein uS11 family.
Expressed predominantly in embryonic neural lineage cells.
Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator (By similarity).
Binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes. Transactivates both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element (By similarity).
Composed by a short N-terminal domain followed by the DNA binding, hinge, and ligand binding/dimerization domains.
Heterodimer of NR1I3 and RXR. Interacts with PSMC4. Interacts with ECT2. Directly interacts with DNAJC7; this complex may also include HSP90 (By similarity). Interacts with CRY1 (By similarity). Interacts with CRY2 in a ligand-dependent manner (By similarity).
Phosphorylated at Thr-48 by PKC, dephosphorylation of Thr-48 is required for nuclear translocation and activation.
Belongs to the cytochrome c oxidase subunit 5B family.
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. 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. May also promote XRCC6 acetylation thus facilitating cell apoptosis in response to DNA damage.
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.
Anorexigenic peptide. Increases the pigmentation of skin by increasing melanin production in melanocytes.
Stimulates the adrenal glands to release cortisol.
Belongs to the eukaryotic ribosomal protein eS7 family.
Binds IPO9 with high affinity (By similarity). Interacts with NEK6 (By similarity). Interacts with DESI2 (By similarity). Interacts with IPO5, IPO7 and KPNB1; these interactions may be involved in RPS7 nuclear import for the assembly of ribosomal subunits (By similarity).
Ubiquitinated. Deubiquitinated by DESI2, leading to its stabilization.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interaction with SKP1 does not occur. Interacst with ANAPC2; the ineraction is direct, ANAPC4, CDC16, CDC23; the ineraction is direct; ANAPC10; the ineraction is direct and CDC26, during spermatogenesis (By similarity). Interacts with CDC20 (By similarity).
Phosphorylated on Thr-190 and Ser-289 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 (By similarity). Plays a vital role in modulating the ubiquitilation of CCNB1 and CDK1 during gametogenesis.
Ubiquitinated in response to calcium, which promotes proteasomal degradation.
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. Thereby, may negatively regulate the function of ETFB in electron transfer from Acyl-CoA dehydrogenases to the main respiratory chain.
Belongs to the FAD-dependent oxidoreductase family.
Functions both as NADH oxidoreductase and as regulator of apoptosis (By similarity). 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. Release into the cytoplasm is mediated upon binding to poly-ADP-ribose chains. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Binds to DNA in a sequence-independent manner (By similarity). Interacts with EIF3G, and thereby inhibits the EIF3 machinery and protein synthesis, and activates caspase-7 to amplify apoptosis (By similarity). Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells (By similarity). 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 (By similarity).
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. Also dimerizes with isoform 3 preventing its release from mitochondria. Interacts with XIAP/BIRC4. Interacts (via N-terminus) with EIF3G (via C-terminus). Interacts with PRELID1. Interacts with CHCHD4; the interaction increases in presence of NADH. 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.
Ubiquitination by XIAP/BIRC4 does not lead to proteasomal degradation. Ubiquitination at Lys-254 by XIAP/BIRC4 blocks its ability to bind DNA and induce chromatin degradation, thereby inhibiting its ability to induce cell death.
Under normal conditions, a 54-residue N-terminal segment is first proteolytically removed during or just after translocation into the mitochondrial intermembrane space (IMS) by the mitochondrial processing peptidase (MPP) to form the inner-membrane-anchored mature form (AIFmit). During apoptosis, it is further proteolytically processed at amino-acid position 101 leading to the generation of the mature form, which is confined to the mitochondrial IMS in a soluble form (AIFsol). AIFsol is released to the cytoplasm in response to specific death signals, and translocated to the nucleus, where it induces nuclear apoptosis in a caspase-independent manner.
Catalyzes the conversion of sulfated steroid precursors, such as dehydroepiandrosterone sulfate (DHEA-S) and estrone sulfate to the free steroid.
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. Associates with internalized 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). Interacts with DUSP29 (By similarity).
Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, 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. 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 (By similarity).
Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:14511394). 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 (By similarity). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (By similarity). 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:2369897, PubMed:9029219). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (By similarity). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (PubMed:11069105, PubMed:11598104, PubMed:12065600). Involved in insulin receptor/INSR internalization (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:11724780, PubMed:12740371). 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 (By similarity). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (By similarity). In that process also activates WDR45/WIPI4 (By similarity). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (By similarity). 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 (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:10025949, PubMed:14709557, PubMed:17341212). 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).
Lacks the sequence parts essential for kinase activity and is therefore inactive.
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) (By similarity).
Skeletal muscle, lower levels in liver, heart and kidney.
The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.
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.
Belongs to the uracil-DNA glycosylase (UDG) superfamily. UNG family.
Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine.
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.
Interacts with the Trk receptors in a phosphotyrosine-dependent manner and MEGF12. Once activated, binds to GRB2 (By similarity).
Phosphorylated on tyrosine by the Trk receptors.
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.
Catalyzes the formation of fatty acid-cholesterol esters, which are less soluble in membranes than cholesterol. Plays a role in lipoprotein assembly and dietary cholesterol absorption. Utilizes oleoyl-CoA ((9Z)-octadecenoyl-CoA) and linolenoyl-CoA ((9Z,12Z,15Z)-octadecatrienoyl-CoA) as substrates. May provide cholesteryl esters for lipoprotein secretion from hepatocytes and intestinal mucosa.
May form homo- or heterodimers (By similarity). Interacts with INSIG1; the interaction is direct and promotes association with AMFR/gp78 (By similarity).
Oxidized at Cys-279: high concentration of cholesterol and fatty acid induce reactive oxygen species, which oxidizes Cys-279, preventing ubiquitination at the same site, and resulting in protein stabilization.
Polyubiquitinated by AMFR/gp78 at Cys-279, leading to its degradation when the lipid levels are low. Association with AMFR/gp78 is mediated via interaction with INSIG1. High concentration of cholesterol and fatty acid results in Cys-279 oxidation, preventing ubiquitination at the same site, resulting in protein stabilization.
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.
Belongs to the prickle / espinas / testin family.
Expressed abundantly 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. 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.
Heteromer composed of three CRYAA and one CRYAB subunits. Aggregates with homologous proteins, including the small heat shock protein HSPB1, to form large heteromeric complexes. Inter-subunit bridging via zinc ions enhances stability, which is crucial as there is no protein turn over in the lens (By similarity). Interacts with HSPBAP1 (PubMed:10751411). Interacts with TTN/titin. Interacts with TMEM109. Interacts with DES; binds rapidly during early stages of DES filament assembly and a reduced binding seen in the later stages. Interacts with TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion (By similarity). Interacts with ATP6V1A and with MTOR, forming a ternary complex (By similarity).
Levels are low in both the slow-twitch soleus and fast-twitch rectus femoris muscles at prenatal day 2, then increase slowly until postnatal day 3. At 2 weeks, levels in the rectus femoris muscle then decrease while those in the soleus muscle increase sharply, reaching adult levels by 4 weeks.
May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions. In lens epithelial cells, stabilizes the ATP6V1A protein, preventing its degradation by the proteasome (By similarity).
Interacts with DRG2 (By similarity). Interacts with androgen receptor.
Protects DRG2 from proteolytic degradation.
Factor involved in transcription-coupled nucleotide excision repair (TC-NER), a mechanism that rapidly removes RNA polymerase II-blocking lesions from the transcribed strand of active genes. Facilitates the ubiquitination of the elongating form of RNA polymerase II (RNA pol IIo) at DNA damage sites, thereby promoting RNA pol IIo backtracking and access by the TC-NER machinery to lesion sites. Acts by promoting stabilization of ERCC6 by recruiting deubiquitinating enzyme USP7 to TC-NER complexes, preventing UV-induced degradation of ERCC6 by the proteasome. Also facilitates transfer of TFIIH to RNA polymerase II. Not involved in processing oxidative damage.
Interacts with the elongating form of RNA polymerase II (RNA pol IIo) during transcription stress. Interacts with the TFIIH complex during transcription stress. Interacts with ERCC6. Interacts with ERCC8. Interacts with USP7.
Monoubiquitinated at Lys-419 in response to transcription stress; this promotes efficient transfer of TFIIH to stalled RNA polymerase II.
May play a role in the regulation of pre-mRNA splicing.
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins. 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. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C15alpha and C16alpha positions (By similarity). Displays different regioselectivities for polyunsaturated fatty acids (PUFA) hydroxylation (By similarity). Catalyzes the epoxidation of double bonds of certain PUFA (PubMed:20972997). Converts arachidonic acid toward epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, that function as lipid mediators in the vascular system. Displays an absolute stereoselectivity in the epoxidation of eicosapentaenoic acid (EPA) producing the 17(R),18(S) enantiomer (By similarity). May play an important role in all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (By similarity). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (By similarity).
Both Cytochrome P450MT2A and Cytochrome P450MT2B interact with cytosolic chaperones HSP70 and HSP90; this interaction is required for initial targeting to mitochondria. P450MT2B interacts (via mitochondrial targeting signal) with TOMM40 (via N-terminus); this interaction is required for translocation across the mitochondrial outer membrane.
By 3-methylcholanthrene (3MC) and beta-naphthoflavone (BNF).
Contains a chimeric signal that facilitates targeting of the protein to both the endoplasmic reticulum and mitochondria. A 12 amino acid sequence between 33 and 44 functions as a putative mitochondrial-targeting signal. The removal of the first 4- or 32-amino acid residues from the intact protein positions the mitochondrial targeting signal for efficient binding to the mitochondrial import receptors. The membrane-free P4501A1 seems to be more sensitive to proteolysis.
Two forms; MT2A (long form) and MT2B (short form); are produced by NH2-terminal proteolytic cleavage. This cleavage activates a cryptic mitochondrial targeting signal.
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). Interacts with ARRB1. Interacts with SNX17. Interacts with the full-length immature form of PCSK9 (via C-terminus) (By similarity).
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.
ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. Seems to contact the pointed end of the daughter actin filament. In podocytes, required for the formation of lamellipodia downstream of AVIL and PLCE1 regulation. 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. 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). Plays a role in ciliogenesis.
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. Interacts with WHDC1. Interacts weakly with MEFV. Interacts with AVIL.
Detected in brain and kidney glomeruli (at protein level) (PubMed:18064521). Detected in kidney, lung and spleen (PubMed:18064521).
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 ATP5MPL.
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 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.
Acetylation at Lys-318 and Lys-322 in proximity of the cofactor-binding sites strongly reduces catalytic activity. These sites are deacetylated by SIRT3.
Inhibited by crotonyl-CoA, 2-octenoyl-CoA and 2-hexadecenoyl-CoA.
Long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats (PubMed:3968063). 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:3968063). 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:3968063, PubMed:15466478).
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.
Autoinhibited (By similarity). Activated by diacylglycerol and calcium binding, which induces a conformational change releasing the autoinhibitory state (PubMed:9582122). Regulated by DGKA. Regulated by DGKZ. Regulated by PLC gamma and F-actin polymerization (By similarity).
Expression appears in neurons of the hippocampus during the first 2 weeks after birth (at protein level).
Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP (PubMed:9789079, PubMed:9582122). Activates the Erk/MAP kinase cascade. Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras. Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways (By similarity). Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses. May also function in differentiation of other cell types. Proto-oncogene, which promotes T-cell lymphomagenesis when its expression is deregulated (By similarity).
Homodimer. Forms a signaling complex with DGKZ and HRAS. Interacts with F-actin. Interacts with SKAP1 (By similarity).
Specifically expressed in brain with higher density in hippocampal CA1 and CA3 fields. Detected in interneurons and projection neurons with no restriction to any neuronal type or neurotransmitter phenotype but not detected in glial cells. Expressed in the hematopoietic system. Expressed in several neuronal types of the hippocampus and entorhinal cortex (at protein level).
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.
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 (By similarity).
Interacts with DCTN1. Interacts with APC (via C-terminal). Interacts with monomeric and polymerized tubulin. Interacts with SLAIN1.
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).
Adapter involved in the TLR2 and TLR4 signaling pathways in the innate immune response.
Belongs to the ammonium transporter (TC 2.A.49) family. Rh subfamily.
Expressed in kidney by connecting segments and collecting tubules (at protein level).
Functions as a specific ammonium transporter.
Interacts (via C-terminus) with ANK2 and ANK3; required for targeting to the basolateral membrane.
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 (Probable). Isoform 2: Constitutively active (PubMed:8378304).
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 (By similarity).
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 (By similarity).
Induced during synaptic long term potentiation.
Interacts with PARD6A, PARD6B and PARD6G. Part of a complex with PARD3, PARD6A or PARD6B or PARD6G and CDC42 or RAC1. Interacts with ADAP1/CENTA1 (By similarity). Forms a ternary complex with SQSTM1 and KCNAB2. Forms another ternary complex with SQSTM1 and GABRR3. Forms a complex with SQSTM1 and MAP2K5. 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) (By similarity). Interacts with VAMP2 (By similarity). Forms a complex with WDFY2 and VAMP2 (By similarity). Interacts with APPL1 (By similarity).
Involved in late synaptic long term potentiation phase in CA1 hippocampal cells and long term memory maintenance.
Isoform 1: In brain, expressed in hippocampus, neocortex and cerebellum (at protein level) (PubMed:8378304, PubMed:12857744). Also expressed in lung, liver, kidney, testis and to a lesser extent in pancreas, intestine and skin (at protein level) (PubMed:12857744). Isoform 2: Specifically expressed in brain where it localizes to the hippocampus, neocortex and cerebellum (at protein level) (PubMed:8378304, PubMed:12857744, PubMed:27498875).
Isoform 2 (PKMzeta) was initially thought to be generated by proteolysis of full-length PRKCZ (PubMed:8378304). However, PKMzeta is a bona fide isoform produced by an alternative promoter in intron 4 (PubMed:12857744).
RNAi-mediated knockdown in the dorsal hippocampus impairs the late phase of long-term potentiation and the establishment of long term memory. Formation of short term memory is not affected.
The C1 domain does not bind the diacylglycerol (DAG).
The PB1 domain mediate mutually exclusive interactions with SQSTM1 and PARD6B.
Detected in sciatic nerve and in trigeminal nerve Schwann cells (PubMed:11430802). Detected in myelinating Schwann cells in sciatic nerve (at protein level) (PubMed:8155317, PubMed:10671475).
Has a remarkable domain of repetitive pentameric units sometimes followed by a tripeptide spacer, it may separate two functional basic and acidic domains.
Homodimer (via PDZ domain) (PubMed:11430802). Interacts with SCN10A. Found in a complex with SCN10A (PubMed:12591166). Interacts with DRP2 (PubMed:11430802). Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity). Detected in a complex composed of at least EZR, AHNAK, PPL and PRX (By similarity). Identified in a complex with EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, VIM and spectrin (By similarity).
Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells. Required for the maintenance of the peripheral myelin sheath that is essential for normal transmission of nerve impulses and normal perception of sensory stimuli. Required for normal transport of MBP mRNA from the perinuclear to the paranodal regions. Required for normal remyelination after nerve injury. Required for normal elongation of Schwann cells and normal length of the internodes between the nodes of Ranvier. The demyelinated nodes of Ranvier permit saltatory transmission of nerve impulses; shorter internodes cause slower transmission of nerve impulses. Required for the formation of appositions between the abaxonal surface of the myelin sheath and the Schwann cell plasma membrane; the Schwann cell cytoplasm is restricted to regions between these appositions. Required for the formation of Cajal bands and of Schmidt-Lanterman incisures that correspond to short, cytoplasm-filled regions on myelinated nerves. Recruits DRP2 to the Schwann cell plasma membrane. Required for normal protein composition of the eye lens fiber cell plasma membrane and normal eye lens fiber cell morphology.
The Arg/Lys-rich basic domain functions as a tripartite nuclear localization signal.
The PDZ domain contains the signal for export from the nucleus (By similarity). The N-terminal region including the PDZ domain is required for the formation of Cajal bands on myelinated nerves (By similarity).
mRNA and protein levels peak in the sciatic nerve between posnatal days 8 and 20; thereafter they decline precipitously.
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 (By similarity).
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.
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).
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. May play a role in keratin cytoskeleton disassembly and thereby, it may regulate epithelial cell migration (By similarity).
Interacts with the Axin complex (By similarity). Interacts with TUT1, leading to TUT1 phosphorylation (By similarity). Interacts with FAM83H; recruits CSNK1A1 to keratin filaments (By similarity). Interacts with FAM83D (via N-terminus); in mitotic cells (By similarity).
Heterodimer with RBM8A. Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A. Interacts with PYM1; the interaction is direct and dissociates the EJC from spliced mRNAs. Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro). Identified in the spliceosome C complex.
Required for pre-mRNA splicing as component of the spliceosome. Plays a redundant role with MAGOHB as core component of the exon junction complex (EJC) and in the nonsense-mediated decay (NMD) pathway. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms; the function is different from the established EJC assembly.
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 (By similarity). Interacts with SH3GL3 (By similarity). Interacts with AMPH (By similarity). Interacts with ITSN1 (via SH3 domains) (By similarity). Interacts with and REPS1 (By similarity).
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.
Specifically expressed in brain (at protein level).
Belongs to the immunoglobulin superfamily. ICAM family.
Belongs to the distal-less homeobox family.
Interacts (when monoubiquitinated at Lys-15 and Lys-24) with PCNA. Interacts with isoform 2/p33ING1b of ING1. Interacts with BRCA1 (By similarity).
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 (By similarity).
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 (By similarity).
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.
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 (By similarity).
Interacts with TSPOAP1. Interacts with MOST-1. May interact with STAR.
Promotes the transport of cholesterol across mitochondrial membranes and may play a role in lipid metabolism, but its precise physiological role is controversial. It is apparently not required for steroid hormone biosynthesis (By similarity). Can bind protoporphyrin IX and may play a role in the transport of porphyrins and heme. Was initially identified as peripheral-type benzodiazepine receptor; can also bind isoquinoline carboxamides (PubMed:2555358).
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 (By similarity). Promotes translocation of NDUFS1 into mitochondria to regulate mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) activity (By similarity).
By thyroid stimulating hormone (TSH) and cAMP or cAMP-analog.
Interacts with SLC8A3. Interacts with CFAP91. Interacts with CLPB (By similarity). Interacts with NDUFS1 (By similarity).
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.
Homodimer. Interacts with DNM1L (PubMed:23792689). Interacts with C11orf65/MFI; the interaction inhibits MFF interaction with DNM1L (By similarity).
Plays a role in mitochondrial and peroxisomal fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface. May be involved in regulation of synaptic vesicle membrane dynamics by recruitment of DNM1L to clathrin-containing vesicles.
Autophosphorylated at multiple residues, Thr-347 being the major site. Phosphorylated by AMP-activated protein kinase AMPK at Ser-397 leading to EEF2K activation and protein synthesis inhibition. Phosphorylated by TRPM7 at Ser-77 resulting in improved protein stability, higher EE2F phosphorylated and subsequently reduced rate of protein synthesis. Phosphorylation by other kinases such as CDK1 and MAPK13 at Ser-358 or RPS6KA1 and RPS6KB1 at Ser-365 instead decrease EEF2K activity and promote protein synthesis (By similarity).
Belongs to the protein kinase superfamily. Alpha-type protein kinase family.
Monomer or homodimer (Probable). Interacts with Calmodulin/CALM1; this interaction is strictly required for phosphorylation activity (By similarity).
The catalytic domain is located to N-terminal region. The neighbor region contains the calmodulin-binding domain (By similarity).
Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced (By similarity).
Undergoes calcium/calmodulin-dependent intramolecular autophosphorylation, and this results in it becoming partially calcium/calmodulin-independent.
Widely expressed, with high levels in reticulocytes and skeletal muscle.
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. This includes the von Hippel-Lindau ubiquitination complex CBC(VHL). 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. 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 (By similarity). 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 (By similarity). 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 (By similarity). 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. Interacts with VHL. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with SPSB1. Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component. May also interact with DCUN1D1, DCUN1D2, DCUN1D3 and DCUN1D5 (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) (By similarity). 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).
Catalytically inactive protein kinase that acts as a scaffold protein (PubMed:29503074). Functions as an effector of the small GTPase RND2, which stimulates RhoA activity and inhibits NGF-induced neurite outgrowth (PubMed:16481321). Promotes Src family kinase (SFK) signallig by regulating the subcellular localization of CSK, a negative regulator of these kinases, leading to the regulation of cell morphology and motility by a CSK-dependent mechanism (PubMed:27116701, PubMed:21873224). Acts as a critical coactivator of Notch signaling (By similarity).
Despite of the presence of a putative ATP-binding motif, this protein does not bind ATP, suggesting that it has no protein kinase activity (PubMed:29503074).
Highly-expressed in brain, including cortical and hippocampal pyramidal neurons, as well as in kidney, spleen, colon and small intestine (PubMed:16481321).
Homodimer (PubMed:29503074). Dimerization leads to the catalytic activation of CSK (PubMed:29503074). Interacts (via C-terminus) with RND2 (PubMed:16481321). Interacts with CSK (via SH2 domain) in a Tyr-391 phosphorylation-dependent manner; this interaction potentiates kinase activity of CSK (PubMed:29503074, PubMed:21873224, PubMed:27116701). Interacts with NOTCH1 intracellular domain (N1ICD) (By similarity). Forms a complex with N1ICD and MAML1, in a MAML1-dependent manner (By similarity).
Phosphorylated by CSK on Tyr-238, Tyr-343, and Tyr-391; Tyr-391 is a primary site of phosphorylation.
The dimerization region encompasses helices both from the N- and C-terminal of the protein kinase domain.
Associates with the RNA polymerase II complex. Interacts with transcribing RNA polymerase II phosphorylated on 'Ser-7' on CTD (By similarity).
Associates with the RNA polymerase II complex. Interacts with transcribing RNA polymerase II phosphorylated on 'Ser-7' on CTD.
Protein phosphatase that displays CTD phosphatase activity and regulates transcription of snRNA genes. Recognizes and binds phosphorylated 'Ser-7' of the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit POLR2A, and mediates dephosphorylation of 'Ser-5' of the CTD, thereby promoting transcription of snRNA genes.
Belongs to the GST superfamily. Pi family.
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 (By similarity). Interacts with SP1; the interaction is inhibited by glycosylation of SP1. Interacts (via N-terminus) with ZHX2 (via homeobox domain). Interacts with ZFX3. Interacts with ZHX1 (By similarity).
Belongs to the methyltransferase superfamily.
Highly expressed in liver and kidney. No expression in testis, heart, lung, brain, spleen or cultured fibroblasts.
Thiol S-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-l-methionine to hydrogen sulfide and other thiol compounds including dithiothreitol, 7alpha-thiospironolactone, L-penicillamine, and captopril.
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 bacterial ribosomal protein bL28 family.
May act as a specific coactivator for the mammalian TEFs.
Binds DNA via bZIP domain; DNA-binding is under control of cellular redox homeostasis (in vitro) (By similarity). 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) (By similarity).
Heterodimer; binds DNA as a heterodimer (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 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 (By similarity). Interacts (via MBM motif) with MEN1; this interaction represses transcriptional activation (By similarity). Interacts with MAPK10; this interaction is inhibited in the presence of MEN1 (By similarity).
Phosphorylated by MAP kinases MAPK8 and MAPK10; phosphorylation is inhibited in the presence of MEN1.
Transcription factor binding AP-1 sites (By similarity). 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 (By similarity).
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.
Belongs to the GST superfamily. Theta family.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Also binds steroids, bilirubin, carcinogens and numerous organic anions. Has dichloromethane dehalogenase activity.
In liver, highest expression found in central vein limiting plate hepatocytes. In lung, expressed mainly in club cells of the bronchiolar epithelium and, at low levels, in type II alveolar cells.
Belongs to the C/M/P thioester hydrolase family.
Adapter protein involved in endocytic machinery. Involved in the synaptic vesicle recycling. May facilitate clathrin-coated vesicle uncoating (By similarity).
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 and ubiquitinated; leading to its degradation and inhibited by TOR1A and COPS4.
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).
Detected in liver, kidney and placenta, and at lower levels in lung.
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 activation of receptor kinases. Phosphorylated on tyrosine residues by TEK/TIE2. Phosphorylated on tyrosine residues by PTK2/FAK1, and possibly also other kinases. Phosphorylation is enhanced by activation of receptor kinases by a cognate ligand. Tyrosine phosphorylation is essential for activation of down-stream protein kinases. Phosphorylation decreases affinity for target mRNA molecules (By similarity).
The PH domain mediates interaction with membranes containing phosphoinositides.
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 (By similarity).
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 (By similarity).
Belongs to the universal ribosomal protein uS9 family.
Belongs to the potassium channel HCN family.
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 (By similarity).
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.
Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (By similarity). In association with LDAF1, defines the sites of LD formation in the ER (By similarity). Also required for growth and maturation of small nascent LDs into larger mature LDs (By similarity). 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 (By similarity). Regulates the maturation of ZFYVE1-positive nascent LDs and the function of the RAB18-ZFYVE1 complex in mediating the formation of ER-LD contacts (By similarity). Binds anionic phospholipids including phosphatidic acid (By similarity). Plays an important role in the differentiation and development of adipocytes (By similarity).
Undecamer (an oligomer having eleven subunits) (By similarity). Oligomerization is important for its function in lipid droplet formation (By similarity). Interacts with LDAF1 to form an oligomeric complex (By similarity). Interacts with RAB18 (By similarity). Interacts with ZFYVE1 in a RAB18-dependent manner (By similarity).
Belongs to the protein kinase superfamily. RIO-type Ser/Thr kinase family.
Belongs to the paired homeobox family. Bicoid subfamily.
Brain: restricted regions of the developing rostral brain including the presumptive cerebral cortex and olfactory bulbs; expressed in the developing olfactory, auricolar and ocular systems, including the covering of the optic nerve.
Expressed throughout the forebrain and midbrain during development, and in addition is also seen in discrete spatial and temporal domains in the developing cerebral cortex and cerebellum. Confined to a subpopulation of neurons in layers 5 and 6 within the adult cerebral cortex and during development expression is high in the progenitors of these deep-layer cells. Expressed in the developing cerebellum in spatially restricted regions of the external granular layer.
Probably plays a role in the development of the brain and the sense organs. Can bind to the BCD target sequence (BTS): 5'-TCTAATCCC-3' (By similarity). May play a role in the specification or differentiation of neurons in the deep layers of the cerebral cortex, and also in cerebellar regionalization during early development.
Detected in lung, liver, testis, and at lower levels in kidney and brain.
Inhibited by warfarin (coumadin) (PubMed:23928358). Warfarin locks VKORC1 in both redox states into the closed conformation (By similarity).
Involved in vitamin K metabolism. Can reduce inactive vitamin K 2,3-epoxide to active vitamin K, and may contribute to vitamin K-mediated protection against oxidative stress. Plays a role in vitamin K-dependent gamma-carboxylation of Glu residues in target proteins.
Belongs to the DEAD box helicase family. DECD subfamily.
Binds ALYREF/THOC4 and DDX39B/BAT1 (By similarity). Interacts with SARNP (By similarity). Interacts with MX1 (By similarity). Interacts with MCM3AP (By similarity).
Involved in pre-mRNA splicing. Required for the export of mRNA out of the nucleus (By similarity).
RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion (PubMed:11118435). Binds preferentially to the 5'-[AU]UAAA-3' motif in vitro. Binds optimally to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). RNA-binding abilities are down-regulated by tyrosine kinase PTK6 (By similarity). Involved in splice site selection of vascular endothelial growth factor. In vitro regulates CD44 alternative splicing by direct binding to purine-rich exonic enhancer (PubMed:11118435). Can regulate alternative splicing of neurexins NRXN1-3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners such as neuroligins and LRRTM family members. Targeted, cell-type specific splicing regulation of NRXN1 at AS4 is involved in neuronal glutamatergic synapse function and plasticity. May regulate expression of KHDRBS2/SLIM-1 in defined brain neuron populations by modifying its alternative splicing. Can bind FABP9 mRNA (By similarity). May play a role as a negative regulator of cell growth. Inhibits cell proliferation (By similarity).
Self-associates to form homooligomers; dimerization increases RNA affinity (By similarity). Interacts with KHDRBS1/SAM68 and KHDRBS2/SLM-1; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity (PubMed:15345239). Interacts with the splicing regulatory proteins SFRS9, SAFB and YTHDC1. Interacts with HNRPL (PubMed:11118435). Interacts with RBMX, RBMY1A1, p85 subunit of PI3-kinase, SERPINB5 (By similarity).
The proline-rich site binds the SH3 domain of the p85 subunit of PI3-kinase.
Ubiquitous. Highly expressed in brain, heart, testis and in Sertoli cells at all stages of spermatogenesis. Expressed in neurons. Detected in cortical layers of the forebrain and in the CA1 to CA4 regions of the hippocampus.
Belongs to the D-isomer specific 2-hydroxyacid dehydrogenase family.
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:20493079). Preferentially degrades benzylamine and phenylethylamine (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).
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.
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. Involved in bile acid promoted GLP1R secretion (By similarity).
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.
Binds specifically to collagen. Could be involved as a chaperone in the biosynthetic pathway of collagen.
Homodimers and homomultimers. Found in a complex with RIP60 and RIP100 (By similarity).
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 (By similarity).
Belongs to the acetyltransferase family. GNAT subfamily.
Expressed in hepatocytes (at protein level) (PubMed:3121604, PubMed:11278697). Strongly expressed in liver, spleen, lung, kidney and submaxillary gland and weakly in heart and brain (PubMed:1733948, PubMed:2793863).
Homodimer (By similarity). Monomer in its soluble form (PubMed:11278697).
Produced by alternative promoter usage. The alternative promoter is active in kidney.
Produced by alternative splicing of isoform RKA.
Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates.
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.
Homodimer (By similarity). Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40 (PubMed:23041287). Within the complex, CAMLG and GET1 form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer (By similarity). Interacts with CAMLG/GET2 (via N-terminus) (PubMed:23041287). GET3 shows a higher affinity for CAMLG than for GET1 (By similarity). Interacts with SERP1 and SEC61B (By similarity).
Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter (By similarity).
Detected in kidney proximal tubule cells (at protein level).
Belongs to the chloride channel (TC 2.A.49) family.
Belongs to the chloride channel (TC 2.A.49) family. CLCNKA subfamily.
Expressed predominantly in the kidney. Expressed strongly in the cortical thick ascending limb and the distal convoluted tubule, with minor expression in the S3 segment of the proximal tubule and the cortical collecting tubule.
Homodimer. Interacts with BSND. Forms heteromers with BSND in the thin ascending limb of Henle (By similarity).
Regulated in parallel with BSND under furosemide treatment. Decreased to half in the inner medulla under furosemide treatment. In the renal cortex and outer medulla levels were weak and did not change. Regulation with BSND in inner medulla is limited to the thin limb; levels in collecting ducts were not affected by furosemide treatment. During furosemide treatment selective down-regulation with BSND in thin limb plays a role in maintaining salt and water homeostasis.
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.
Brain. Expressed in the hippocampal and dentate neuronal layers, cerebellar cortex, molecular layer of the hippocampus and dentate gyrus.
Guanine nucleotide exchange factor for ARF6 (By similarity). 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).
On embryonic day 15 (15 dpc) and 18 dpc, weakly expressed in the mantle zone throughout the neuraxis. On postnatal days 0 (P0) and P7, expression is evident in the cerebral neocortex, hippocampal pyramidal and dentate granule cell layers, olfactory granule, mitral cell layers and the striatum. A weak expression is seen in the gray matter of di-, mes- and met-encephalon and in the cerebellar Purkinje cells. On P14, expressed in the gray matter of the telencephalon such as the cerebral neocortex, olfactory bulb, hippocampus, dentate gyrus and striatum. On P21 and thereafter detected in the cerebellar granule cells.
Expressed in the eye, thyroid, prostate, kidney and liver. Abundantly expressed in the CNS, including hippocampus, olfactory bulb, cortex, cerebellum. Not detected in the white matter.
Forms PANX1/PANX2-heteromeric intercellular channels on coexpression in paired Xenopus oocytes. Does not form homomeric channels.
Structural component of the gap junctions and the hemichannels.
Essential multidomain scaffolding protein required for normal development (By similarity). Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel (By similarity). May play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. During long-term depression in hippocampal neurons, it recruits ADAM10 to the plasma membrane (By similarity).
Homotetramer (Probable). Interacts (via guanylate kinase-like domain) with DLGAP1, DLGAP2, DLGAP3, DLGAP4 and MAP1A (PubMed:9115257, PubMed:9786987). Interacts (via guanylate kinase-like domain) with KIF13B (By similarity). May interact with HTR2A (By similarity). Interacts (via PDZ domains) with GRIA1 (PubMed:9677374). Interacts (via PDZ domains) with GRIN2A (PubMed:12933808). Interacts (via PDZ domains) with KCND2 and KCND3 (PubMed:19213956). Interacts (via PDZ domains) with KCNA1, KCNA2, KCNA3 and KCNA4 (By similarity). Interacts (via PDZ domains) with ADGRA3 (By similarity). Interacts with KCNF1 (By similarity). Interacts with CAMK2 (PubMed:19213956). Interacts with cytoskeleton-associated protein EPB41 (By similarity). 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 (By similarity). Interacts with CDH1 through binding to PIK3R1 (By similarity). Forms multiprotein complexes with CASK, LIN7A, LIN7B, LIN7C, APBA1, and KCNJ12 (PubMed:11865057, PubMed:14960569). Interacts with TOPK (By similarity). Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C) (By similarity). May interact with TJAP1 (By similarity). Interacts with PTEN (PubMed:15951562). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1 and LRFN2 (PubMed:16495444, PubMed:16630835). Interacts with LRFN4 and SFPQ (By similarity). Interacts (via PDZ domains) with ADGRA2 (via PDZ-binding motif) (By similarity). Interacts with ADAM10; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (By similarity). Interacts with DGKI (via PDZ-binding motif) (PubMed:21119615). Interacts (via PDZ domains) with MARCHF2 (via PDZ domain); the interaction leads to DLG1 ubiqtuitination and degradation (By similarity).
Phosphorylated by MAPK12 (By similarity). Phosphorylation of Ser-39 modulates transport to the plasma membrane and phosphorylation of Ser-232 regulates association with GRIN2A.
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 (By similarity).
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.
Ubiquitinated; by MARCHF2 which results in its degradation.
Widely expressed. Strongly expressed in epithelial cells, in the small intestine it is only detected in the vili. Expressed in brain, heart (at protein level), muscle, lung and liver. In the brain it was detected in olfactory bulbs, cerebral cortex, hippocampus, and spinal cord (at protein level).
Belongs to the cyclin family. Cyclin G subfamily.
Induced within 3 hours after growth stimulation, remains elevated with no apparent cell cycle dependency.
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.
Belongs to the eukaryotic initiation factor 4E family.
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.
Expressed in soleus muscle. Isoform 4 is predominantly expressed in fast muscles.
Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
Belongs to the GLI C2H2-type zinc-finger protein family.
Component of the spliceosome B complex. Interacts with IK.
Highly expressed in cerebellum, midbrain and heart. Moderately expressed in brain stem, cerebral cortex and liver. Detected in dentate gyrus, pyramidal layer of the hippocampus and Purkinje and granule neurons of cerebellum.
Involved in pre-mRNA splicing as a component of the spliceosome (By similarity). Regulates alternative splicing of the HSPG2 pre-mRNA (By similarity). Required for normal accumulation of IK (By similarity). Required for normal mitotic spindle assembly and normal progress through mitosis (By similarity).
The WD repeats assemble into a seven-bladed WD propeller.
Interacts with HDAC1 and ATN1. Interaction with ATN1 is improved when the poly-Gln region of ATN1 is extended (By similarity).
Plays a role as a transcriptional repressor during development. May play a role in the control of cell survival (By similarity). Interacts with FAT1 (By similarity).
The interaction with ATN1 is mediated by the coiled domain.
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. Transports preferentially phosphatidylcholine containing short acyl chains. 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.
Highly expressed in lung, moderately expressed in stomach, intestine, and kidney and weakly expressed in thyroid, brain, liver, spleen, heart, testis, and thymus.
N-glycosylated. Localization at intracellular vesicles is accompanied by processing of oligosaccharide from high mannose type to complex type. N-linked glycosylation at Asn-124 and Asn-140 is required for stability and efficient anterograde trafficking and prevents from proteasomal degradation.
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.
Lectin-like receptor for natural killer (NK) cells (PubMed:12782717, PubMed:18713988). Can either inhibit or activate NK cell cytotoxic activity, depending on its binding partner (PubMed:18713988). Heterodimer formation with KLRI1 mediates NK cell inhibition whereas heterodimer formation with KLRI2 mediates NK cell activation (PubMed:18713988). Plays a role in allogeneic recognition by the immune system (By similarity).
Belongs to the hcp beta-lactamase family.
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.
Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. 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. 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).
Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion.
Allosterically activated by benzodiazepines and pentobarbital (PubMed:1977069). Allosterically activated by the neuroanesthetic alphaxalone (By similarity). Inhibited by the antagonist bicuculline (PubMed:1977069, PubMed:1376242).
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:18281286, PubMed:2540033). Interacts with UBQLN1 (PubMed:11528422). Interacts with TRAK1 (By similarity). Interacts with KIF21B (PubMed:25172774). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (PubMed:28279354). Interacts with LHFPL4 (PubMed:28279354). Interacts with NLGN2 (PubMed:28279354). 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:2540033, PubMed:1977069, PubMed:1376242). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (By similarity). 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 (By similarity). 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 (PubMed:18281286).
Acts as a centrosome maturation factor, probably by maintaining the integrity of the pericentriolar material and proper microtubule nucleation at mitotic spindle poles. The function seems to implicate at least in part WRAP73; the SSX2IP:WRAP73 complex is proposed to act as regulator of spindle anchoring at the mitotic centrosome (By similarity). Involved in cell movement: localizes at the leading edge of moving cells in response to PDGF and is required for the formation of the leading edge and the promotion of cell movement, possibly via activation of Rac signaling (By similarity). Belongs to an adhesion system, which plays a role in the organization of homotypic, interneuronal and heterotypic cell-cell adherens junctions (AJs). May connect the nectin-afadin and E-cadherin-catenin system through alpha-actinin and may be involved in organization of the actin cytoskeleton at AJs through afadin and alpha-actinin (PubMed:12446711). Involved in ciliogenesis (By similarity). It is required for targeted recruitment of the BBSome, CEP290, RAB8, and SSTR3 to the cilia (By similarity).
Interacts with SSX2 and SSX3 (By similarity). Does not interact with SSX1 and SSX4. Interacts with VAV2 (By similarity). Interacts with afadin and alpha-actinin (PubMed:12446711). Interacts with WRAP73 (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.
Binds and inhibits the catalytic activity of neuronal nitric oxide synthase.
Homodimer. Monomer; the monomeric form is incapable of binding to target proteins (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. 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 (PubMed:8702622, PubMed:11746667). Interacts with TXNDC17. Interacts with WWC1 and ESR1. The interaction with WWC1 is mandatory for the recruitment and transactivation functions of ESR1 or DYNLL1 to the target chromatin (By similarity). Interacts with BCL2L11 (PubMed:21478148). 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 (By similarity). 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 (PubMed:16133941). Interacts with Bassoon/BSN (By similarity). Interacts with HDAC6 (By similarity). Interacts with TPPP (By similarity). Interacts with AMBRA1 (via TQT motifs); tethering AMBRA1 to the cytoskeleton (By similarity). Interacts with FAM83D/CHICA (via C-terminus) (By similarity). Interacts with HMMR, SPAG5/Astrin and KNSTRN/Kinastrin (By similarity). Interacts with TLK2 (By similarity).
Phosphorylation at Ser-88 appears to control the dimer-monomer transition.
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 (By similarity).
Weaker expression in the cerebellum and spinal cord compared with other brain regions.
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.
Activated by magnesium and inorganic phosphate.
Belongs to the ribose-phosphate pyrophosphokinase family.
Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.
Homodimer. The active form is probably a hexamer composed of 3 homodimers (By similarity).
Homodimer. The active form is probably a hexamer composed of 3 homodimers.
Gustducin-coupled receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5 (By similarity).
Several bitter taste receptors with distinct ligand specificities are expressed in a single taste receptor cell.
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.
Interacts with CDCP1. Interacts (via C-terminus) with TIAM1 (via PDZ domain) (By similarity). Interacts with MDK (PubMed:9089390).
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 (By similarity).
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 (By similarity).
Component of the CMG helicase complex, a hexameric ring of related MCM2-7 subunits stabilized by CDC45 and the tetrameric GINS complex. Associated with ORC2. Interacts with HELB.
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.
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family.
Belongs to the SMC family. SMC1 subfamily.
Forms a heterodimer with SMC3 in cohesin complexes. Cohesin complexes are composed of the SMC1 (SMC1A or meiosis-specific SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or meiosis-specific STAG3), which interacts with RAD21. In germ cell cohesin complexes, SMC1A is mutually exclusive with SMC1B. Found in a complex with CDCA5, SMC3 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN. Interacts with STAG3, NDC80, BRAC1, BRAT1 and RPGR. Found in a complex containing POLE and SMC3. 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). Interacts with SYCP2 (PubMed:10652260).
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.
Phosphorylated upon ionizing radiation or DNA methylation. Phosphorylation of Ser-957 and Ser-966 activates it and is required for S-phase checkpoint activation (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 protein, forming a ring structure (By similarity).
Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.
Homodimer. Interacts with RTN4. Isoform 2 interacts with BACE1, BACE2, BCL2 and FADD. Interacts with ATL2. Interacts with TMEM33 (By similarity). Interacts with ATL1 (PubMed:19665976). Interacts with ZFYVE27 and with KIF5A in a ZFYVE27-dependent manner (By similarity). Interacts with RIGI. Interacts with TRIM25 (By similarity).
In the optic nerve, expressed more abundantly in the embryo than in the adult.
May be involved in membrane trafficking in the early secretory pathway. Inhibits BACE1 activity and amyloid precursor protein processing. May induce caspase-8 cascade and apoptosis. May favor BCL2 translocation to the mitochondria upon endoplasmic reticulum stress. Induces the formation of endoplasmic reticulum tubules. Acts also as an inflammation-resolving regulator by interacting with both TRIM25 and RIGI, subsequently impairing RIGI 'Lys-63'-linked polyubiquitination leading to IRF3 and NF-kappa-B inhibition.
Present in olfactory bulb, olfactory epithelium and retina (at protein level).
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:7906114). Preferentially hydrolyzes palmitoyl-CoA, but has a broad specificity acting on other fatty acyl-CoAs with chain-lengths of C8-C18 (PubMed:7906114). May play an important physiological function in brain (PubMed:7906114).
Isoform 1 is expressed constitutively in brain and testis. Isoform 2 is induced in liver by treatment with the peroxisome proliferator.
These proteins have been named according to their molecular weight (see PubMed:11755680): BACH (also called CTE-IIa and CTE-II), LACH1 (also called MTE-II) and ACT (also called CTE-IIb). It is unknown whether ACT corresponds to another isoform.
Belongs to the Mediator complex subunit 18 family.
Inhibited by 3-isobutyl-1-methylxanthine (IBMX), zaprinast and dipyridamole. cGMP acts as an allosteric activator.
Isoform 1 is expressed in brain, heart, kidney and liver, but not in prostate. Isoform 2 is specifically expressed in testis. Isoform 3 is expressed in various tissues including brain, lung, skeletal muscle, spleen, testis and prostate.
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP (PubMed:11502204). Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'-GMP, respectively (PubMed:11502204).
The tandem GAF domains bind cGMP, and regulate enzyme activity. The binding of cGMP stimulates enzyme activity.
ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. In vitro causes vesiculation of endocytic membranes (By similarity). Acts in early endocytic membrane fusion and membrane trafficking of recycling endosomes (By similarity). Recruited to endosomal membranes upon nerve growth factor stimulation, indirectly regulates neurite outgrowth (PubMed:23572513). 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 (By similarity).
Homooligomer, and heterooligomer with EHD2, EHD3 and EHD4, ATP-binding is required for heterooligomerization (By similarity). Interacts (via EH domain) with MICALL1 (via NPF1 motif); the interaction is direct and recruits EHD1 to membranes (PubMed:23572513). Interacts with RAB35; the interaction is indirect through MICALL1 and recruits EHD1 to membranes (PubMed:23572513). Interacts (via EH domain) with PACSIN2 (via NPF motifs); regulates localization to tubular recycling endosome membranes (PubMed:15930129). Interacts with PACSIN1 (PubMed:15930129). Interacts with RAB8A (By similarity). Interacts with FER1L5 (via second C2 domain) (By similarity). Interacts with MYOF (By similarity). Interacts with ZFYVE20 (By similarity). Interacts (via EH domain) with RAB11FIP2 (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 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:10195194, PubMed:11283605). 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 (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 (PubMed:16760431). Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN (By similarity). 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 (By similarity). Interacts with CNTRL, NANOS1, PUM2 and RGS7. Interacts with TOR1A; the interaction is direct and associates SNAPIN with the CSN complex (By similarity).
Strongly expressed in testis, spleen, kidney, liver and brain; lower expression in heart, fat and skeletal muscle.
A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand. Activating serine proteases include trypsin, mast cell tryptase, coagulation factors VII and Xa, myeloblastin/PRTN3 and membrane-type serine protease 1/ST14. Proposed subsequent cleavage by serine proteases is leading to receptor deactivation and include neutrophil elastase and cathepsin G. 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.
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 (By similarity).
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. 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. 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 (By similarity). Proposed to have a bronchoprotective role in airway epithelium, but also shown to compromise the airway epithelial barrier by interrupting E-cadherin adhesion. 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. 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 G 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 (By similarity).
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.
Belongs to the D-glutamate cyclase family.
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.
Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport (By similarity). Binds calcium (via the C2 domains) and translocates to sites of contact between the endoplasmic reticulum and the cell membrane in response to increased cytosolic calcium levels. Helps tether the endoplasmic reticulum to the cell membrane and promotes the formation of appositions between the endoplasmic reticulum and the cell membrane (By similarity).
Interacts with ESYT2 and ESYT3. Interacts (phosphorylated form) with SLC2A4 (By similarity).
Phosphorylated on Ser residues in insulin-treated adipocytes (in vitro); this promotes interaction with SLC2A4.
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. The third C2 domain mediates interaction with membranes enriched in phosphatidylinositol 4,5-bisphosphate and is required for translocation to the cell membrane in response to increased cytosolic calcium levels (By similarity).
The SMP-LTD domain is a barrel-like domain that binds glycerophospholipids in its interior (By similarity).
Ubiquitously expressed with a higher expression in spleen and white adipose tissue.
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 (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 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) (By similarity). 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 (By similarity). 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 (By similarity).
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.
A cytochrome P450 monooxygenase involved in the metabolism of endogenous cholesterol and its oxygenated derivatives (oxysterols) (PubMed:1694852, PubMed:2335522). 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:1694852, PubMed:2335522). Functions as a critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis. Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of cholesterol, a rate-limiting step in cholesterol catabolism and bile acid biosynthesis (PubMed:1694852, PubMed:2335522). 7-alpha hydroxylates several oxysterols, including 4beta-hydroxycholesterol and 24-hydroxycholesterol. Catalyzes the oxidation of the 7,8 double bond of 7-dehydrocholesterol and lathosterol with direct and predominant formation of the 7-keto derivatives (By similarity).
Detected in liver (at protein level). Liver.
Up-regulated by dietary cholesterol and cholestyramine. Down-regulated by dietary bile acids, such as chenodeoxycholic acid and cholic acid.
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.
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. Also forms heterodimers with S100P (By similarity). Interacts with AGER (PubMed:19910580). Interacts with CAPZA1 (PubMed:19452629). Interacts with FKBP4. Interacts with RYR1 and RYR2 (PubMed:18650434). Interacts with CACYBP in a calcium-dependent manner. Interacts with PPP5C (via TPR repeats); the interaction is calcium-dependent and modulates PPP5C activity. Interacts with ATP2A2 and PLN in a Ca(2+)-dependent manner (By similarity). 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.
Small calcium binding protein that plays important roles in several biological processes such as Ca(2+) homeostasis, chondrocyte biology and cardiomyocyte regulation. In response to an increase in intracellular Ca(2+) levels, binds calcium which triggers conformational changes. These changes allow interactions with specific target proteins and modulate their activity. 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:18650434). Facilitates diastolic Ca(2+) dissociation and myofilament mechanics in order to improve relaxation during diastole (By similarity) (PubMed:18650434).
Probable acetyltransferase, which acetylates the inositol ring of phosphatidylinositol during biosynthesis of GPI-anchor.
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.
Phosphorylation at Ser-177 is required for deubiquitinating activity.
Interacts with CACTIN (via N-terminal domain); the interaction occurs in a pro-inflammatory-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 pro-inflammatory stimuli (By similarity).
Mediates the proteolytic cleavage of HP/haptoglobin in the endoplasmic reticulum.
A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its oxygenated derivatives (PubMed:14634044, PubMed:9344476, PubMed:17418803). 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:14634044, PubMed:9344476, PubMed:17418803). 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:14634044). Hydroxylates the terminal carbon (omega-hydroxylation) of inflammatory lipid mediators, including prostaglandin (PG) A1, PGE1 and leukotriene B4 (LTB4), and may play a role in inactivation of these oxylipins during the resolution of inflammation (PubMed:14634044, PubMed:9344476, PubMed:17418803).
Expressed in hepatocytes (PubMed:17418803). High expression in liver and kidney. Lower expression in brain (PubMed:9344476).
Up-regulated in hepatocytes by pro-inflammatory cytokine IL6 and down-regulated by anti-inflammatory cytokine IL10.
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 (By similarity).
Controls PGR and ESR1 protein levels through their targeting for ubiquitination and subsequent proteasomal degradation.
The CUE domain mediates interaction with PGR and ESR1.
Expressed in striatal neurons (at protein level).
Interacts (via cytoplasmic C-terminal domain) with USP4; the interaction is direct (By similarity). May interact with DRD4 (By similarity). Interacts with NECAB2 (By similarity). Interacts (via cytoplasmic C-terminal domain) with GAS2L2; interaction enhances receptor-mediated adenylyl cyclase activity (PubMed:23994616).
Receptor for adenosine (By similarity). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (PubMed:23994616).
The cytoplasmic C-terminal domain is necessary for targeting the non-ubiquitinated form of this protein to the cell surface.
Ubiquitinated. Deubiquitinated by USP4; leading to stabilization and expression at the cell surface (By similarity).
Expressed in hippocampal neurons, with highest levels of expression in the CA4 and CA3 neurons and lower levels in CA1 neurons (PubMed:11948657, PubMed:17577668). Expressed in the dorsal root ganglion (PubMed:12957493).
Expression in dentate granule cells of the hippocampus at postnatal day P5, with disappearing expression in dentate granule cells as early as P14.
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).
Palmitoylated by ZDHHC3 (By similarity). Palmitoylation is regulated by ARF6 and is essential for plasma membrane association and axonal and dendritic filopodia induction. Deacylated by LYPLA2 (By similarity).
Phosphorylated (PubMed:1533624, PubMed:8454596, Ref.13). Phosphorylation of this protein by a protein kinase C is specifically correlated with certain forms of synaptic plasticity (PubMed:1533624, PubMed:8454596, Ref.13).
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 (By similarity).
Up-regulated by kainic acid-induced seizures (PubMed:17577668). Up-regulated after axotomy (PubMed:12957493).
Belongs to the class V-like SAM-binding methyltransferase superfamily.
May function as a transcription factor involved in cell 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.
The C-terminal phenylalanine residue is cleaved by KIAA0895L/MATCAP.
This tubulin does not have a C-terminal tyrosine; however, its C-terminal phenylalanine residue can be cleaved.
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). SRP9 together with SRP14 and the Alu portion of the SRP RNA, constitutes the elongation arrest domain of SRP. The complex of SRP9 and SRP14 is required for SRP RNA binding.
Heterodimer with SRP9; binds RNA as heterodimer. 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.
May positively contribute to the induction of apoptosis triggered by O(6)-methylguanine.
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. Calcium-binding is required for the activation of calmodulin. 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. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis.
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. Calcium-binding is required for the activation of calmodulin. 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. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. Is a regulator of voltage-dependent L-type calcium channels. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2. Forms a potassium channel complex with KCNQ1 and regulates electrophysiological activity of the channel via calcium-binding. Acts as a sensor to modulate the endoplasmic reticulum contacts with other organelles mediated by VMP1:ATP2A2.
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. Calcium-binding is required for the activation of calmodulin. 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. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. Mediates calcium-dependent inactivation of CACNA1C. Positively regulates calcium-activated potassium channel activity of KCNN2.
Interacts with CEP97, CCP110, TTN/titin and SRY (By similarity). Interacts with MYO5A and RRAD (PubMed:18056528). Interacts with USP6; the interaction is calcium dependent (By similarity). Interacts with CDK5RAP2 (By similarity). Interacts with SCN5A (By similarity). Interacts with RYR1 (By similarity). Interacts with FCHO1 (By similarity). 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 SYT7 (By similarity). Interacts with MYO10 and MYO1C (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 (PubMed:8576129). Interacts with RYR2; regulates RYR2 calcium-release channel activity (By similarity). Interacts with PCP4; regulates calmodulin calcium-binding (By similarity). 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 (By similarity).
Interacts with CEP97, CCP110, TTN/titin and SRY (By similarity). Interacts with MYO5A and RRAD (PubMed:18056528). Interacts with USP6; the interaction is calcium dependent (By similarity). Interacts with CDK5RAP2 (By similarity). Interacts with SCN5A (By similarity). Interacts with RYR1 (By similarity). Interacts with FCHO1 (By similarity). 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 (PubMed:23109337). Interacts with SYT7 (By similarity). Interacts with MYO10 and MYO1C (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 (PubMed:8576129). Interacts with RYR2; regulates RYR2 calcium-release channel activity (By similarity). Interacts with PCP4; regulates calmodulin calcium-binding (By similarity). 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 (By similarity). Interacts with SLC9A1 in a calcium-dependent manner (By similarity). 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 (By similarity). Interacts with KCNQ1 (via C-terminus); forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner (By similarity). Interacts with PIK3C3; the interaction modulates PIK3C3 kinase activity (By similarity).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.
This protein has four functional calcium-binding sites.
Ubiquitination results in a strongly decreased activity.
Homodimer (By similarity). Interacts (calcium-independent) with NCS1/FREQ (By similarity). 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:17502602). May activate the MAP kinase JNK (By similarity). Plays a role in neurite outgrowth (PubMed:18801879). 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.
Displays temperature-dependent chaperone activity.
Monomer. Interacts with HSPB1 (By similarity). Interacts with DNAJB6 (By similarity). Interacts with BAG3 (By similarity).
Cadherins are calcium-dependent cell adhesion proteins.
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).
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.
By insulin in adipocytes (at protein level).
Expressed at highest levels in the brain and testis, followed by lung, heart, kidney, skeletal muscle, spleen and liver. Also expressed in epididymal, abdominal and brown fat, small intestine and pancreas.
Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR (By similarity). mTORC1 binds to and is inhibited by FKBP12-rapamycin. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (By similarity). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts directly with MTOR and RPTOR (By similarity). Interacts with RHEB (By similarity). Interacts with MEAK7 (By similarity). Interacts with SIK3 (By similarity). Interacts with SLC38A7; this interaction mediates the recruitment of mTORC1 to the lysosome and its subsequent activation (By similarity).
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. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts directly with MTOR and RPTOR. Interacts with RHEB. Interacts with MEAK7. Interacts with SIK3.
Subunit of both mTORC1 and mTORC2, 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, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-421'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657' (By similarity).
Subunit of both mTORC1 and mTORC2, 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, which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1. mTORC2 also modulates the phosphorylation of PRKCA.
Belongs to the purine nucleoside phosphorylase YfiH/LACC1 family.
Expressed in the brain. Expressed in neurons of the hippocampus, hypothalamic paraventricular nucleus (PVN), supraoptic nucleus (SON) and the median eminence. Expressed in magnocellular neurosecretory cells (MNCs) which secrete oxytocin but not in MNCs which secrete vasopressin. Expressed in glial cells. Expressed in the nucleus ambiguous. Expressed in epithelial cells, in pachytene spermatocytes (PS) (at protein level). Expressed strongly in vascular endothelial cells and poorly in vascular smooth muscle cells (VSMC). Expressed in the brain, lung, pituitary gland, adrenal medulla, renal pelvis and ovary. Expressed in CA1 hippocampus. Expressed weakly in heart, skeletal muscle and kidney.
G-protein coupled estrogen receptor that binds to 17-beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Stimulates cAMP production, calcium mobilization and tyrosine kinase Src inducing the release of heparin-bound epidermal growth factor (HB-EGF) and subsequent transactivation of the epidermal growth factor receptor (EGFR), activating downstream signaling pathways such as PI3K/Akt and ERK/MAPK. Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. Has a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a RAMP3-dependent manner. Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. Stimulates uterine epithelial cell proliferation. Enhances uterine contractility in response to oxytocin. Contributes to thymic atrophy by inducing apoptosis. Attenuates TNF-mediated endothelial expression of leukocyte adhesion molecules. Promotes neuritogenesis in developing hippocampal neurons. Plays a role in acute neuroprotection against NMDA-induced excitotoxic neuronal death. Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. Inhibits early osteoblast proliferation at growth plate during skeletal development. Inhibits mature adipocyte differentiation and lipid accumulation. Involved in the recruitment of beta-arrestin 2 ARRB2 at the plasma membrane in epithelial cells. Functions also as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. Involved in cancer progression regulation. Stimulates cancer-associated fibroblast (CAF) proliferation by a rapid genomic response through the EGFR/ERK transduction pathway. Associated with EGFR, may act as a transcription factor activating growth regulatory genes (c-fos, cyclin D1). Promotes integrin alpha-5/beta-1 and fibronectin (FN) matrix assembly in breast cancer cells.
Homodimer (Probable). Heterodimer; heterodimerizes with other G-protein-coupled receptor (GPCRs) like CRHR1, HTR1A and PAQR8. Interacts with RAMP3. Interacts with KRT7 and KRT8. Interacts with EGFR; the interaction increases after agonist-induced stimulation in cancer-associated fibroblasts (CAF). Interacts with EGFR and ESR1 (By similarity). Interacts (via C-terminus tail motif) with DLG4 (via N-terminus tandem pair of PDZ domains); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner.
Ubiquitinated; ubiquitination occurs at the plasma membrane and leads to proteasome-mediated degradation.
Death domain is responsible for interaction with RANBP9. It also mediates interaction with ARHGDIA and RIPK2 (By similarity).
Homodimer; disulfide-linked (PubMed:27056327). Heterodimer with SORCS2 (PubMed:27457814, PubMed:22155786, PubMed:24908487). The extracellular domains of the heterodimer bind NGF (PubMed:22155786, PubMed:24908487). The cytoplasmic region of the heterodimer binds TRIO. NGF binding mediates dissociation of TRIO from the receptor complex (PubMed:22155786). Interacts with RTN4R (By similarity). Interacts with TRAF2, TRAF4 and TRAF6 (PubMed:10514511). Interacts with PTPN13 and RANBP9. Interacts through TRAF6 with SQSTM1 which bridges NGFR to NTRK1 (By similarity). Interacts with BEX1 (PubMed:16498402). Interacts with BEX3 (By similarity). Interacts with KIDINS220 and NTRK1. Can form a ternary complex with NTRK1 and KIDINS220 and this complex is affected by the expression levels of KIDINS220. An increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1 (PubMed:11150334, PubMed:15378608). Interacts (via death domain) with RAB31 (By similarity). Interacts with NTRK2; may regulate the ligand specificity of the NTRK2 receptor (PubMed:9927421). Interacts with LINGO1 (By similarity). Interacts with NRADD (PubMed:12095158). Interacts with MAGED1; the interaction antagonizes the association NGFR:NTRK1 (PubMed:10985348). Interacts (via death domain) with ARHGDIA and RIPK2 (By similarity).
Low affinity receptor which can bind to NGF, BDNF, NTF3, and NTF4 (PubMed:3027580, PubMed:15131306, PubMed:18596692). Forms a heterodimeric receptor with SORCS2 that binds the precursor forms of NGF, BDNF and NTF3 with high affinity, and has much lower affinity for mature NGF and BDNF (PubMed:24908487, PubMed:22155786). In response to proNGF binding, the heterodimeric receptor with SORCS2 activates a signaling cascade that leads to decreased Rac activity, reorganization of the actin cytoskeleton and neuronal growth cone collapse (PubMed:22155786). Plays an important role in differentiation and survival of specific neuronal populations during development (By similarity). Can mediate cell survival as well as cell death of neural cells (PubMed:10514511, PubMed:10985348, PubMed:24908487). Plays a role in the inactivation of RHOA (By similarity). Plays a role in the regulation of the translocation of GLUT4 to the cell surface in adipocytes and skeletal muscle cells in response to insulin, probably by regulating RAB31 activity, and thereby contributes to the regulation of insulin-dependent glucose uptake (By similarity). Necessary for the circadian oscillation of the clock genes BMAL1, PER1, PER2 and NR1D1 in the suprachiasmatic nucleus (SCN) of the brain and in liver and of the genes involved in glucose and lipid metabolism in the liver (By similarity).
Subject to intramembrane proteolytic cleavage by the gamma-secretase complex, giving rise to an intracellular fragment that is rapidly degraded via the proteasome.
The extracellular domain is responsible for interaction with NTRK1.
Expression restricted to the brain and pituitary gland. Not detected in the adrenal gland.
Interacts with CHGA (PubMed:12388744). Interacts with secretogranin II/SCG2 (By similarity). Interacts (via C-terminus) with CPE (By similarity).
Member of the granin protein family that regulates the biogenesis of secretory granules (PubMed:12388744, PubMed:14597614). Acts as a sorting receptor for intragranular proteins including chromogranin A/CHGA (PubMed:12388744, PubMed:14597614). May also play a role in angiogenesis. Promotes endothelial proliferation, migration and tube formation through MEK/ERK signaling pathway (By similarity).
Belongs to the thiolase-like superfamily. Thiolase family.
Homodimer (By similarity). Interacts (via PTS2-type peroxisomal targeting signal region) with PEX7; leading to its translocation into peroxisomes (By similarity).
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:10064897, PubMed:2882519). Plays an important role in fatty acid peroxisomal beta-oxidation (PubMed:10064897, PubMed:2882519). Catalyzes the cleavage of short, medium, long, and very long straight chain 3-oxoacyl-CoAs (PubMed:10064897, PubMed:2882519). Medium chain straight 3-oxoacyl-CoAs are preferred substrates (PubMed:10064897).
The PTS2-type peroxisomal targeting signal, which mediates interaction with PEX7 and localization to peroxisomes, is cleaved following import into peroxisomes.
There exist at least 2 rat liver peroxisomal 3-ketoacyl-CoA thiolases.
Catalyzes the first step in the biosynthesis of NAD from nicotinic acid, the ATP-dependent synthesis of beta-nicotinate D-ribonucleotide from nicotinate and 5-phospho-D-ribose 1-phosphate. Helps prevent cellular oxidative stress via its role in NAD biosynthesis.
Transiently phosphorylated on a His residue during the reaction cycle. Phosphorylation strongly increases the affinity for substrates and increases the rate of nicotinate D-ribonucleotide production. Dephosphorylation regenerates the low-affinity form of the enzyme, leading to product release.
Expressed in testis, brain, heart, kidney, lung, liver and muscle.
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).
Triazolodiamine 1 is a commercial name for 5-amino-3-([4-(aminosulfonyl)phenyl]amino)-N-(2,6-difluorophenyl)-1H-1,2,4-triazole-1-carbothioamide.
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).
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 (By similarity). As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes (By similarity).
Preferentially expressed in brain, heart, liver and testis.
Belongs to the alkaline phosphatase family.
Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation.
Expressed in neurons and kidney glomeruli podocytes (at protein level) (PubMed:18753381). Detected at least in colon, duodenum, adipose tissue, heart, jejenum, lung, muscle, spleen, stomac, testis and thymus (PubMed:28846099).
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) (By similarity). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas (By similarity). Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex (By similarity). 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. Interaction with GFRAL requires previous GDF15-binding to GFRAL (By similarity). Interacts with GFRA1; in the presence of SORL1, the GFRA1/RET complex is targeted to endosomes (PubMed:23333276). Interacts with GFRA1; in the presence of SORL1, the GFRA1/RET complex is targeted to endosomes (PubMed:23333276). Interacts with GDNF (By similarity).
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 (By similarity).
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 (By similarity). 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 (By similarity).
Belongs to the universal ribosomal protein uS14 family.
Interacts with DDB1, CUL4A and CUL4B. Interacts with KPNA1, KPNB1 and XPO1.
Belongs to the protease inhibitor I39 (alpha-2-macroglobulin) family.
Expressed on natural killer cells and macrophages.
May form multisubunit complex with other heteroproteins. This association is required for efficient cell-surface expression. Does not associate with CD3 zeta.
Receptor for the Fc region of complexed immunoglobulins gamma (PubMed:1692135). Low affinity receptor which binds to IgG1, IgG2a and IgG2b (By similarity). Mediates neutrophil activation by IgG complexes redundantly with Fcgr4 (By similarity).
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 (By similarity).
For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.
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. Phosphorylated ubiquitin specifically binds and activates parkin (PRKN), triggering mitophagy. 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.
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.
E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.
Belongs to the nuclear hormone receptor family.
Belongs to the complexin/synaphin family.
Binds to bile acids and is involved in enterohepatic bile acid metabolism. Required for efficient apical to basolateral transport of conjugated bile acids in ileal enterocytes (By similarity). Stimulates gastric acid and pepsinogen secretion (By similarity).
Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior. Can bind at least two ligands per molecule, however, the stoichiometry is debated.
Predominantly expressed in ileum; also expressed in ovary.
Belongs to the Mediator complex subunit 1 family.
Belongs to the ATP-dependent AMP-binding enzyme family. Bubblegum subfamily.
Catalyzes the conversion of fatty acids such as long chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation. Can activate diverse saturated, monosaturated and polyunsaturated fatty acids. Has increased ability to activate oleic and linoleic acid. May play a role in spermatogenesis.
Involved in pre-mRNA splicing as a component of the spliceosome.
Belongs to the protein-tyrosine phosphatase family.
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 (By similarity).
May play a role in cell cycle regulation. Dual specificity phosphatase active toward substrates containing either phosphotyrosine or phosphoserine residues. Dephosphorylates CDK2 at 'Thr-160' in a cyclin-dependent manner (By similarity).
Belongs to the class-I aminoacyl-tRNA synthetase family.
Belongs to the eukaryotic ribosomal protein eL21 family.
Belongs to the fatty acid desaturase type 1 family.
The histidine box domains are involved in binding the catalytic metal ions.
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC3 interacts with SNAPC1 (By similarity).
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 (By similarity).
Belongs to the adipolin/erythroferrone family.
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.
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. The SELENOK-SELENOS complex interacts with VCP. Interacts with ZDHHC6.
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 (By similarity). 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. Plays a role in protection of cells from ER stress-induced apoptosis. Protects cells from oxidative stress when overexpressed in cardiomyocytes (By similarity).
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.
Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits.
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.
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.
This protein binds beta-galactoside. Its physiological function is not yet known.
Acts as a repressor in the regulation of translation initiation of poly(A)-containing mRNAs. Its inhibitory activity on translation is mediated via its action on PABPC1. Displaces the interaction of PABPC1 with poly(A) RNA and competes with PAIP1 for binding to PABPC1. Its association with PABPC1 results in disruption of the cytoplasmic poly(A) RNP structure organization (By similarity).
Interacts with the second and third RRM domains and C-terminus regions of PABPC1 in a 2:1 stoichiometry.
Only the PABPC1-interacting motif-1 (PAM1) interferes with the binding of PABPC1 to poly(A) RNA and translation initiation.
Ubiquitinated, leading to its degradation by the proteasome.
3-alpha-hydroxysteroid dehydrogenase that converts 3-alpha-tetrahydroprogesterone (allopregnanolone) to dihydroxyprogesterone and 3-alpha-androstanediol to dihydroxyprogesterone (By similarity). Plays also role in the biosynthesis of retinoic acid from retinaldehyde (PubMed:12390888). Can utilize both NADH and NADPH (By similarity).
Highly expressed in epithelium of estrus uterus.
Expressed in tissues including spinal cord, brain, liver, kidney and lung.
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:11325967, PubMed:25137389, PubMed:25531214). Interacts with SRGAP2 (via SH3 domain) (By similarity). Interacts with GLRB (PubMed:15201864, PubMed:16511563, PubMed:25137389, PubMed:25531214). Interacts with GABARAP (PubMed:10900017). Interacts with GABRA3 (PubMed:25531214). GABRA3 and GLRB occupy overlapping binding sites (PubMed:25531214). 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 (PubMed:8264797). Acts as a major instructive molecule at inhibitory synapses, where it also clusters GABA type A receptors (By similarity).
Palmitoylated. Palmitoylation is stimulated by GABA type A receptors activity. Palmitoylation by ZDHHC12 regulates clustering at synapses.
In the N-terminal section; belongs to the FGAMS family.
In rat liver, the light chain is the major chain.
Oligomer of 24 subunits. There are two types of subunits: L (light) chain and H (heavy) chain. The major chain can be light or heavy, depending on the species and tissue type. The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited.
Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney (By similarity).
The rat light chain has an octopeptide insertion after residue 158 compared with other light chains.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome.
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.
Belongs to the glycogen phosphorylase family.
Detected in brain astrocytes, spleen and intestine (at protein level).
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 NGFR. Interacts with EGFR (By similarity). Interacts with OCRL. 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 the maturation of phagosomes that engulf pathogens, such as S.aureus and Mycobacterium (By similarity). 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.
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.
Down-regulated upon cold exposure in brown adipose tissue in Zucker lean rats. Down-regulated by dexamethasone.
Interacts with SLC2A4; the interaction is required for proper SLC2A4 reacycling after insulin stimulation.
Present in adipose tissue and undetectable in other tissues (at protein level).
Regulates insulin-mediated adipose tissue glucose uptake and transport by modulation of SLC2A4 recycling. Not required for SLC2A4 membrane fusion upon an initial stimulus, but rather is necessary for proper protein recycling during prolonged insulin stimulation.
Up-regulated during differentiation in primary cultured rat brown preadipocytes.
ATF3 alone can bind DNA, but it preferentially forms heteromeric complexes with JUN and JUNB and does not interact with FOS.
Expressed in tissues containing skeletal muscle or smooth muscle (PubMed:1902565). Expressed in cutaneous and muscular sensory neurons (PubMed:19913522).
This protein binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Represses transcription from promoters with ATF sites (By similarity). It may repress transcription by stabilizing the binding of inhibitory cofactors at the promoter (By similarity).
Up-regulated in regenerating neurons after nerve injury (PubMed:19913522). Rapidly and highly induced in regenerating liver and mitogen-stimulated cells (PubMed:1902565).
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.
Widely distributed in the central nervous system, including the olfactory bulb, the hypothalamus, the cerebral cortex, the hippocampus, and the cerebellum. In addition, intense expression is found in the motor nuclei including the oculomotor nucleus, abducens nucleus, trigeminal motor nucleus, facial nucleus, hypoglossal nucleus and ventral horn of spinal cord. Intense hybridization signals are also observed in the nuclei containing monoaminergic neurons, such as locus coeruleus, the substantia nigra pars compacta, the ventral tegmental area, the dorsal raphe nucleus and the median raphe nucleus.
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.
Microtubule-associated force-producing protein that may play a role in organelle transport (By similarity). Has ATPase activity (PubMed:27452403). Involved in synaptic transmission (By similarity). 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 (PubMed:23576431).
Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1. Interacts with TRAK1. Interacts with ZFYVE27 (By similarity). Interacts with KLC3 (PubMed:11319135).
Brain-specific (at protein level) (PubMed:17030985). Expressed in hippocampal neurons (PubMed:18519736).
Expressed in hippocampal neurons at 18 dpc (PubMed:23408951). Expressed at high level both in hippocampal neurons and in brain, during the period of axon formation and elongation. Accumulates in axonal growth cones during the stage 2/3 transition. Accumulates asymmetrically in a single neurite before polarization, while it is depleted in its sibling neurites, through competitive transport to multiple neurites. Transported anterogradely to the growth cones and diffused back to the soma (at protein level) (PubMed:17030985).
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 (By similarity). Interacts with L1CAM; this interaction occurs in axonal growth cones (PubMed:18519736). 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 (PubMed:18519736, PubMed:23453953). Interacts with RUFY3 (PubMed:17030985).
Involved in the generation of internal asymmetric signals required for neuronal polarization and neurite outgrowth (PubMed:17030985, PubMed:17439943, PubMed:18519736, PubMed:20664640). 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 (PubMed:18519736, PubMed:23453953). Plays a role in cytoskeletal organization by regulating the subcellular localization of phosphoinositide 3-kinase (PI3K) activity at the axonal growth cone (PubMed:17030985). Also plays a role in regenerative neurite outgrowth (PubMed:20664640). 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 (By similarity).
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 (PubMed:23453953). Phosphorylation on Ser-101 and Ser-249 is increased by netrin-1 (PubMed:23453953).
The N-terminus region is necessary for interaction with actin retrograde filament flow and accumulation in neuronal growth cones (PubMed:18519736).
Up-regulated by axonal regeneration (PubMed:20664640).
May have a role in the recovery or adaptation response of photoreceptors. May have a role in development (By similarity).
Belongs to the histone-like Alba family.
Component of nuclear RNase P and RNase MRP ribonucleoproteins. RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40. 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. 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. POP7 forms a heterodimer with RPP25 that binds to the P3 stem loop of the catalytic RNA.
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends. Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences.
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.
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 (By similarity).
Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes.
Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3). Monomethylation is performed by KMT5A/SET8. Trimethylation is performed by KMT5B and KMT5C and induces gene silencing. Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators.
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 (By similarity).
OGP is found in serum. A potentially OGP-specific transcript is highly expressed in spleen with lower levels in lung, liver, thymus, spinal chord, pituitary gland, adrenal gland, bone marrow and lymph nodes as well as very low levels in kidney, heart and brain.
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 (By similarity).
Stimulates osteogenesis and hematopoiesis.
Sumoylated, which is associated with 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 (By similarity). Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers (By similarity). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (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. 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) (By similarity).
Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage.
ATP-dependent RNA helicase required during spermatogenesis to repress transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Involved in the secondary piRNAs metabolic process, the production of piRNAs in fetal male germ cells through a ping-pong amplification cycle. 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.
Belongs to the DEAD box helicase family. DDX4/VASA subfamily.
Found in a mRNP complex, at least composed of TDRD1, TDRD6, TDRD7 and DDX4. Interacts with RANBP9. Interacts with RANBP10. Interacts with PIWIL2 and MAEL. Interacts with BMAL1 and CLOCK. Interacts with Tex19.1 and, probably, Tex19.2.
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.
May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.
Interacts with ARL6. 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.
Binds TCF4 (By similarity). Binds RB1. Binds the second PAH repeat of SIN3A (By similarity).
Highly expressed in liver, adipose tissue, lung, brain, spleen, kidney, skeletal muscle and heart.
Not detectable in undifferentiated preadipocytes and myogenic cells. Accumulates at high levels during the terminal stages of the differentiation process.
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 (By similarity).
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.
Up-regulated by insulin in differentiated cultured adipocytes.
Active at low pH (under pH 4.6): proton channel activity is activated by luminal side protons. Polyunsaturated fatty acids, such as arachidonic acid, also activate the channel activity. Channel activity is activated following interaction with AKT (AKT1, AKT2 or AKT3): interaction promotes activation from closed to an open state. Activation by AKT is independent of AKT serine/threonine-protein kinase activity.
Composed of two modules of six transmembranes, forming a homodimer with a tetrameric architecture. The six transmembrane regions of each module are tightly packed within each subunit without undergoing domain swapping. Forms a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues (Ile-43 in the first module and Ile-268 in the second module) in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, the same residues establish a constriction essential for potassium selectivity.
Homodimer. Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the lysoK(GF) complex, which activates the channel.
Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH (By similarity). 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 (By similarity). Regulation of lumenal pH stability is required for autophagosome-lysosome fusion (By similarity). May also act as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes (By similarity). The potassium channel activity is however unclear as it was tested in non-physiological conditions for a lysosomal channel (By similarity). Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors (By similarity). 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 (By similarity). The lysoK(GF) complex is required to protect neurons against stress-induced damage (PubMed:32799888) (Probable).
Interacts (via C-terminal cytoplasmic tail) with PI4KA.
Possible role in fasting-induced catabolism.
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. Acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (By similarity). May also play a role in fasting-induced catabolism (PubMed:10858565).
Widely expressed with higher expression in placenta, liver and kidney.
Component of the oligosaccharyltransferase (OST) complex (By similarity). 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 (By similarity). 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. 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.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Aurora subfamily.
Interacts with LMO2, possibly leading to regulate the transcriptional activity of a DNA-binding complex containing LMO2. Interacts with OMP (By similarity).
Regulator of mitochondrial apoptosis and G1 cell cycle. Regulates the level of PP2A regulatory subunit B and PP2A phosphatase activity (By similarity).
Transcriptional repressor involved in developmental processes (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 (By similarity). Probably plays a role in limb pattern formation (By similarity). Required for mammary placode induction, involved in maintenance of the mammary buds during development and branching morphogenesis in embryonic and adult glands; partially redundant with TBX2 (By similarity). Involved in modulating early inner ear development, acting independently of, and also redundantly with, TBX2 in different subregions of the developing ear (By similarity). Acts as a negative regulator of PML function in cellular senescence (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.
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 (By similarity).
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily.
Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of the PB1 domain. This domain also mediates interactions with SQSTM1 and PARD6A (By similarity).
Interacts with PARD6A, MAP3K3 and MAPK7. Forms a complex with SQSTM1 and PRKCZ or PRKCI (By similarity).
MEK5 beta is ubiquitously distributed with highest levels in the liver, whereas MEK5 alpha is expressed only in liver and brain.
Binds phosphatidylinositol 3-phosphate (PtdIns-(3)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns-(3,5)P2) in liposome-based assays. Can bind PtdIns(3,4,5)P3 in protein:lipid overlay assays, but not in liposome-based assays (By similarity).
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). 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). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity. Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptors (IGF2R, M6PR and SORT1). Plays a role in targeting ligand-activated EGFR to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi. Involvement in retromer-independent endocytic trafficking of P2RY1 and lysosomal degradation of protease-activated receptor-1/F2R. Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN. Required for endocytosis of DRD5 upon agonist stimulation but not for basal receptor trafficking (By similarity).
Predominantly forms heterodimers with BAR domain-containing sorting nexins SNX5, SNX6 and SNX32; can self-associate to form homodimers. 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. Interacts with SNX5, SNX6, SNX32, VPS26A, VPS29, VPS35, DRD5, DENND5A, KALRN, RHOG (GDP-bound form). The interaction with SNX2 is reported controversially. Interacts with DNAJC13; prevented by presence of HGS (By similarity). Interacts with HGS (PubMed:11110793).
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 (By similarity).
Phosphorylated by several kinases in vitro. In vivo, can be phosphorylated by CK2.
Present in all tissues tested, including brain, lung, spleen, kidney, liver, heart, and muscle, in decreasing order of abundance.
Different composition of the N-linked oligosaccharides appears to yield a 68-kDa and a 72-kDa form.
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) (By similarity).
Cleaved by a furin endopeptidase in the trans-Golgi network.
Expression is first detected in embryonic day 16 (16 dpc) brain, strongly increases at 20 dpc, and peaks within 24 hours of birth. The postnatal expression declines steadily to reach adult levels at P60.
Interacts (via PDZ-binding motif) with APBA3 (via PDZ domain) (By similarity). Interacts with GRIP1 and GRIP2.
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.
Predominantly expressed in the nervous system: while enriched in the central nervous system, expression is also detected in the peripheral nervous system, including the trigeminal ganglion. Expression is not restricted to the nervous system: it is also enriched in the thymus, with a lower level of expression present in the aorta. In brain, high expression is present in the brain parenchyma, particularly within the neocortex.
The PDZ-binding motif (also named EWV motif) is required for interaction with PDZ domains of APBA3 and recycling through the trans-Golgi network.
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.
Expressed in adrenal gland, aorta, brain, heart, kidney, liver, skeletal muscle and spleen.
Homodimerizes, the dimers can polymerize end-to-end to form filamentous structures. Interacts specifically with GTP-bound CDC42 and RHOQ. Interacts with AKAP9, ARHGAP17, DAAM1, DIAPH1, DIAPH2, DNM1, DNM2, 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 (By similarity). Interacts with PDE6G.
Required to coordinate membrane tubulation with reorganization of the actin cytoskeleton during endocytosis. Also acts as a link between CDC42 signaling and regulation of the actin cytoskeleton. Binds to lipids such as phosphatidylinositol 4,5-bisphosphate and phosphatidylserine and promotes membrane invagination and the formation of tubules. Also enhances actin polymerization in the vicinity of membrane tubules by recruiting WASL/N-WASP which in turn activates the Arp2/3 complex. Actin polymerization and dynamin 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. Required for translocation of GLUT4 to the plasma membrane in response to insulin signaling. May be required for the lysosomal retention of FASLG/FASL (By similarity).
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 AB hydrolase superfamily. Lipase family.
Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid (By similarity). Does not hydrolyze other phospholipids, like phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) or triacylglycerol (TG) (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mL49 family.
A cytochrome P450 monooxygenase that catalyzes omega and omega-1 hydroxylation of saturated fatty acids. Exhibits preferential omega versus omega-1 regioselectivity and (R) versus (S) stereoselectivity for hydroxylation of dodecanoic (lauric) acid. 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).
Autophosphorylated, leading to regulate its activity. IL2 promotes phosphorylation on tyrosine residues, including autophosphorylation on Tyr-781 (By similarity). Dephosphorylation of Tyr-976 and Tyr-977 by PTPN2 negatively regulates cytokine-mediated signaling (By similarity).
In contrast with the ubiquitous expression of the other JAKs, JAK3 is predominantly expressed in hematopoietic tissues.
Interacts with STAM2 and MYO18A. Interacts with SHB (By similarity).
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 (By similarity).
Possesses two phosphotransferase domains. The second one contains the catalytic domain, while the presence of a pseudokinase domain is required for suppression of basal activity of JAK3.
Homodimer. Interacts with DNM1L (By similarity).
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 (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).
Detected in brain (at protein level) (PubMed:15673660). Expressed in various regions of the brain, including the cerebral cortex, hippocampus, striatum, thalamus and cerebellum (PubMed:12694398).
Identified in a complex that contains RTN4R, RTN4RL1 and NGFR; the interaction depends on the presence of chondroitin sulfate proteoglycans (By similarity). Does not interact with MAG, OMG and RTN4 (PubMed:15673660).
Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family.
Homodimer; disulfide-linked (By similarity). 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 (By similarity). The absence of activity may be due to the inability of serine (instead of aspartate found in DPEP1/2) at position 356 to function as the acid/base catalyst and activate the nucleophilic water/hydroxide (By similarity).
Adapter protein of the Toll-like and IL-1 receptor signaling pathway that is involved in the activation of NF-kappa-B via MAP3K1. Promotes proteolytic activation of MAP3K1. Involved in the BMP signaling pathway. Required for normal embryonic development.
As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
Interacts with MAP3K1, SMAD4 and TRAF6. Interacts with SMAD1 only after BMP4-treatment (By similarity). 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 (By similarity) (PubMed:22982022). Interacts with NDUFAF1. Interacts with ACAD9 (By similarity). Interacts with TRIM59 (By similarity). Interacts with TMEM70 and TMEM242 (By similarity).
Component of a probable ECS E3 ubiquitin-protein ligase complex which contains CUL5, either RBX1 or RNF7/RBX2, Elongin BC complex (ELOB and ELOC) and ASB2. Interacts with SKP2. Through its interaction with SKP2, likely to bridge the formation of dimeric E3-ubiquitin-protein ligase complexes composed of an ECS complex and an SCF(SKP2) complex. Interacts with JAK2; the interaction targets JAK2 for Notch-mediated proteasomal degradation. Interacts with TCF3/E2A; the interaction is mediated by SKP2 and targets TCF3 for Notch-mediated proteasomal degradation (By similarity). Interacts with DES (By similarity).
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 (By similarity). Mediates Notch-induced ubiquitination and degradation of substrates including E2A and JAK2 (By similarity). Required during embryonic heart development for complete heart looping (By similarity). Required for cardiomyocyte differentiation (By similarity). Involved in myogenic differentiation and targets filamin FLNB for proteasomal degradation but not filamin FLNA (By similarity). Also targets DES for proteasomal degradation (By similarity). Acts as a negative regulator of skeletal muscle mass (By similarity).
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin-protein ligase complexes.
The UIM domain is required for monoubiquitination.
Expressed in neurons and localized in the cell body and neurites.
Interacts with RAF1, RAB2L and RAL GTPase proteins (By similarity). Interacts with DLG4 and AIP1.
May function as an adapter protein or regulator of Ras signaling pathways, in synaptic junctions.
Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.1/KCNC1 sub-subfamily.
Expressed in brain (PubMed:1378392). Expressed in globus pallidal neurons of the basal ganglia (at protein level) (PubMed:10482766). Detected on Purkinje cells in the cerebellum molecular layer (at protein level) (PubMed:20857303).
Heteromultimer with KCNG3, KCNG4 and KCNV2 (By similarity). Heteromultimer with KCNC2 (PubMed:10482766, PubMed:14679187). Heterotetramer with KCNC3 (By similarity). Interacts with the ancillary subunits KCNE1 and KCNE2; the interaction modulates channel activity (PubMed:14679187).
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:10482766, PubMed:14679187). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2, and possibly other family members as well (PubMed:10482766, PubMed:14679187). Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons (PubMed:10482766).
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 (By similarity).
Catalyzes the hydrolysis of pseudosubstrates such as p-nitrocatechol sulfate and p-nitrophenyl sulfate (By similarity). Catalyzes the hydrolysis of the 2-sulfate groups of the 2-O-sulfo-D-glucuronate residues of chondroitin sulfate, heparin and heparitin sulfate (By similarity). Acts selectively on 2-sulfoglucuronate and lacks activity against 2-sulfoiduronate (By similarity).
N-glycosylated with both high mannose and complex type sugars.
The 75-kDa precursor undergoes proteolytic processing to yield a 23 kDa form.
Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). Has prolyl 3-hydroxylase activity catalyzing the post-translational formation of 3-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts (By similarity).
Expressed in basement membranes of cardiac muscle, skeletal muscle, central nervous system, intestinal tract, trachea, ear, skin, liver and kidney. In kidney, localizes to the glomerular basement membrane, mesangial matrix and Bowman's capsule of the nephron. In the renal parenchyma, expressed in the basement membranes of tubules and blood vessels. In the ear and trachea, localizes to the perimeter of resident chondrocytes in lacunae.
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.
Probably binds two or three Mg(2+) ions per subunit.
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 COPS5. Interacts with STAMBP. Interacts with NEDD4L. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation. Interacts with WWP1 (By similarity). Interacts with PDPK1 (via PH domain) (By similarity).
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 (By similarity).
Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation. In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. BUD23/WBSCR22 family.
Forms homo- or heterooligomeric complexes (PubMed:16456539). 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 (By similarity). 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. Interacts with the cytoplasmic domain of APP (By similarity). Interacts with DCLK2, VRK2 and MAP3K7/TAK1. 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 (By similarity). Interacts with SH3RF2 (PubMed:22128169).
Highly expressed in brain and pancreatic beta-cells. Weaker expression found in kidney.
Phosphorylated by MAPK8, MAPK9 and MAPK10. Phosphorylation on Thr-103 is also necessary for the dissociation and activation of MAP3K12. Phosphorylated by VRK2. Hyperphosphorylated during mitosis following activation of stress-activated and MAP kinases (By similarity).
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 thus inhibiting the 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.
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 (By similarity).
Abundantly expressed in granule neurons at all development stages.
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 (By similarity) and neurite outgrowth. Maintains also meiotic arrest in oocytes (By similarity).
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. 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. 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. May also be involved in maintenance of normal mitochondrial structure and organization.
Interacts with WDR91; involved in early to late endosome cargo transport. Interacts with BECN1; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes. Interacts with SQSTM1; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins. Interacts with MAP1LC3C; recruits MAP1LC3C to ubiquitinated protein aggregates in the aggrephagy process.
Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures (By similarity). Binds SH2B2 (PubMed:9856458). Interacts with SQSTM1 and KIDINS220 (PubMed:12471037, PubMed:15167895). Interacts with PTPRS (PubMed:17967490). Interacts with MAPK8IP3/JIP3 (PubMed:21775604).
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 (By similarity). NTRK3 isoforms containing insertions within the kinase domain can autophosphorylate in response to NTF3/neurotrophin-3, but cannot mediate downstream phenotypic responses (PubMed:8494647, PubMed:8494648).
Widely expressed, mainly in the nervous tissue.
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 (By similarity). 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 the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Highly expressed in epithelial cells of the small intestine and its activity is essential for the absorption of dietary fats. In liver, plays a role in esterifying exogenous fatty acids to glycerol, and is required to synthesize fat for storage (By similarity). 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 (By similarity). 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 (By similarity). 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) (By similarity).
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. The reaction chamber has a tunnel to the cytosolic side and its entrance recognizes the hydrophilic CoA motif of an acyl-CoA molecule. The chamber has separate entrances for each of the two substrates, acyl-CoA and 1,2-diacyl-sn-glycerol.
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.
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 UNC5C (via cytoplasmic domain); this interaction is decreased by NTN1/Netrin-1 (By similarity). Interacts with NLRP5/MATER at cytoskeleton microtubules (By similarity). Interacts with DPYSL5 (By similarity).
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.
The highly acidic C-terminal region may bind cations such as calcium.
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. TUBB3 plays a critical role in proper axon guidance and maintenance. Binding of NTN1/Netrin-1 to its receptor UNC5C might cause dissociation of UNC5C from polymerized TUBB3 in microtubules and thereby lead to increased microtubule dynamics and axon repulsion. Plays a role in dorsal root ganglion axon projection towards the spinal cord.
The LIM domain 3 is critical for focal adhesion targeting and the suppression of paxillin (PXN) tyrosine phosphorylation. The LIM domain 3 alone or both LIM domains 3 and 4 can mediate interaction with AR.
Transcriptional coactivator for androgen receptor (AR) and serum response factor (SRF). Contributes to the regulation of cell adhesion, spreading and cell migration and acts as a negative regulator in integrin-mediated cell adhesion events. Suppresses the integrin-induced tyrosine phosphorylation of paxillin (PXN).
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).
Monomer and homodimer (PubMed:11152476). Interacts with NFASC and SDCBP2 (PubMed:11152476). Interacts with PTPRJ (PubMed:11434923). Interacts with SDC1, SDC2, SDC3, SDC4, NRXN2, EPHA7, EPHB1, NF2 isoform 1, TGFA and IL5RA (By similarity). Interacts with PDCD6IP. Forms a complex with PDCD6IP and SDC2. Interacts (via C-terminus) with TGFBR1 (By similarity). Binds to FZD7; this interaction is increased by inositol trisphosphate (IP3) (By similarity). 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. 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. In concert with SDC1/4 and PDCD6IP, regulates exosome biogenesis. Regulates migration, growth, proliferation, and cell cycle progression in a variety of cancer types. 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). May also play a role in vesicular trafficking. Seems to be required for the targeting of TGFA to the cell surface in the early secretory pathway.
Interacts with CTNNB1 (By similarity). Interacts with KATNB1. Also interacts with gamma-tubulin and KIF23.
Interacts with KATNB1. Also interacts with CTNNB1, gamma-tubulin and KIF23.
Negative regulator of katanin-mediated microtubule severing and release from the centrosome. Required for central spindle formation and the completion of cytokinesis. May negatively regulate axonal outgrowth by preventing the formation of microtubule bundles that are necessary for transport within the elongating axon. Negative regulator of the Wnt signaling pathway. Represses beta-catenin-mediated transcriptional activation by promoting the nuclear exclusion of beta-catenin.
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.
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. This form has a role in retina signal transduction.
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.
Activated by RHOA binding. Inhibited by Y-27632.
Autophosphorylated on serine and threonine residues.
Cleaved by caspase-3 during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing (By similarity).
Highly expressed in brain, spleen, lung, liver, skeletal muscle, kidney and testis.
Homodimer (By similarity). Interacts with GEM, MYLC2B, RHOE, LIMK1, LIMK2, TSG101, CHORDC1, DAPK3, PFN1, PTEN and JIP3 (By similarity). Interacts with FHOD1 in a Src-dependent manner (By similarity). Interacts with ITGB1BP1 (via N-terminus and PTB domain) (By similarity). Interacts with RHOA (activated by GTP), RHOB, RHOC and PPP1R12A. Interacts with SHROOM3 (By similarity).
May play a role in hypertension. Rock1-inhibitors lower the blood pressure in spontaneous hypertensive, renal hypertensive and deoxycorticosterone acetate-induced hypertensive rats, but not in normal rats.
Protein kinase which is a key regulator of the actin cytoskeleton and cell polarity (PubMed:19131646, PubMed:9353125). 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 DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, TPPP, PFN1 and PPP1R12A (PubMed:19131646, PubMed:9353125). Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing. Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress (By similarity). Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability (By similarity). Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Required for centrosome positioning and centrosome-dependent exit from mitosis (By similarity). Plays a role in terminal erythroid differentiation (By similarity). Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1 (By similarity). Promotes keratinocyte terminal differentiation (By similarity). Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization (By similarity). May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles (By similarity).
The C-terminal auto-inhibitory domain interferes with kinase activity. RHOA binding leads to a conformation change and activation of the kinase. Truncated ROCK1 is constitutively activated.
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) (PubMed:27907191). Interacts with CTBP1 (PubMed:25652077). Interacts with SIAH1; this interaction negatively regulates SIAH1 E3 ligase activity (PubMed:23403927). Directly interacts with GIT1 and GIT2 (PubMed:12473661).
Loss of both Bassoon/BSN and Piccolo/PCLO leads to the aberrant degradation of multiple presynaptic proteins, culminating in synapse degeneration.
Scaffold protein of the presynaptic cytomatrix at the active zone (CAZ) which is the place in the synapse where neurotransmitter is released (PubMed:22875941). 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:22875941). At the presynaptic active zone, regulates the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis (PubMed:27907191). 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 (PubMed:29194628). 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 (PubMed:23403927, PubMed:27907191). 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 (PubMed:25652077).
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC2. Interacts with CREB3; interaction is direct and specific as it does not interact with CREB1, ATF4, ATF6, JUN, FOS, CEBPA or herpes simplex virus transactivator VP16.
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. 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. The CRL2(KLHDC2) complex specifically recognizes proteins with a diglycine (Gly-Gly) at the C-terminus, leading to their ubiquitination and degradation. The CRL2(KLHDC2) complex mediates ubiquitination and degradation of truncated SELENOK and SELENOS selenoproteins produced by failed UGA/Sec decoding, which end with a diglycine. The CRL2(KLHDC2) complex also recognizes proteolytically cleaved proteins ending with Gly-Gly, such as the N-terminal fragment of USP1, leading to their degradation. May also act as an indirect repressor of CREB3-mediated transcription by interfering with CREB3-DNA-binding.
Highly expressed in mast cells and is found predominantly in the tissues of the respiratory tract and kidneys.
Receptor for alpha-ketoglutarate. Seems to act exclusively through a G(q)-mediated pathway (By similarity).
Was originally thought to be a P2Y receptor.
Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
Belongs to the cytidylyltransferase family.
Catalyzes the key rate-limiting step in the CDP-choline pathway for phosphatidylcholine biosynthesis.
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.
Part of the tectonic-like complex (also named B9 complex). Interacts with TMEM107.
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).
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 (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3/E12. Also interacts with MEF2C (By similarity).
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.
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. Active on diverse carbonyl compounds, whereas soft nucleophiles are mostly non- or poorly reactive. 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. Able to oxidize drug molecules bearing a carbonyl group on an aliphatic chain, such as nabumetone and pentoxifylline. Also, in the absence of substrates, shows slow but yet significant NADPH oxidase activity (By similarity). Acts as a positive modulator of cholesterol biosynthesis as well as glucose homeostasis, promoting metabolic aging via pleiotropic effects (By similarity).
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. HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse. Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ). 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. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (By similarity). 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).
Homodimer; dimerizes via the coiled coil domain. Interacts (via the PXDLS motif) with CTBP1; the interaction is disrupted via binding of the adenovirus E1A to CTBP1. Component of the BRCA1-RBBP8 complex. Interacts (the Ser-326 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. Interacts with RB1. Interacts with the MRN complex. Interacts directly with MRE11; the interaction is required for efficient homologous recombination (HR) and regulation of the MRN complex. Interacts directly with RAD50. Interacts directly with NBN. Interacts with LM04 (via the LIM zinc-binding 1 domain). Interacts with SIAH1. Interacts with RNF138. Interacts with EXD2. Interacts with CUL3 and KLHL15; this interaction leads to RBBP8 proteasomal degradation. Directly interacts with PIN1; this interaction depends upon RBBP8 phosphorylation. Interacts with FZR1; this interaction leads to APC/C-mediated RBBP8 proteasomal degradation. Interacts with AUNIP; leading to recruit RBBP8 to sites of DNA damage. Interacts with SAMHD1 (By similarity). Interacts with HDGFL2 (By similarity).
Hyperphosphorylation upon ionizing radiation results in dissociation from BRCA1. Phosphorylation at Thr-843 by CDK1 is essential for the recruitment to DNA and the DNA repair function. Phosphorylated on Ser-326 as cells enter G2 phase. This phosphorylation is required for binding BRCA1 and for the G2/M DNA damage transition checkpoint control (By similarity). Phosphorylation at Ser-276 may serve as a PIN1 isomerization site (By similarity).
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. Ubiquitination at multiple sites by BRCA1 (via its N-terminal RING domain) does not lead to its proteosomal degradation but instead the ubiquitinated RBBP8 binds to chromatin following DNA damage and may play a role in G2/M checkpoint control. Ubiquitinated by RNF138 at its N-terminus. Ubiquitinated through 'Lys-48' by the E3 CUL3-KLHL15 complex; this modification leads to proteasomal degradation (By similarity). Ubiquitinated by the E3 FZR1/APC/C complex; this modification leads to proteasomal degradation (By similarity).
Belongs to the SEC23/SEC24 family. SEC24 subfamily.
Interacts with ubiquitin. Interacts with UBXN6, VCP and YOD1; may form a complex involved in macroautophagy.
Plays a role in protein ubiquitination, sorting and degradation through its association with VCP (By similarity). 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 (By similarity). Plays a role in cerebellar Purkinje cell development. 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 (By similarity).
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.
Interacts with NUMA1 (via N-terminal end of the coiled-coil domain); this interaction promotes spindle formation in mitosis (By similarity). Interacts with NUP98 (By similarity). Interacts with MYCBP2 (PubMed:22357847). Interacts with USP11 (By similarity).
Plays a role in mitotic bipolar spindle formation. Binds mRNA. May function in nucleocytoplasmic transport and in directly or indirectly attaching cytoplasmic mRNPs to the cytoskeleton.
Belongs to the TNF receptor-associated factor family. A subfamily.
E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN (By similarity). Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity). Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor (By similarity). Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity). Participates also in the TCR signaling by ubiquitinating LAT (By similarity).
Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1; this interaction mediates deubiquitination of TRAF6 and inhibition of NF-kappa-B activation (By similarity). Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1. Interacts with TANK; this interaction increases in response to DNA damage. Interacts with USP10; this interaction increases in response to DNA damage. Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK (By similarity). Interacts with WDFY3 (By similarity). Interacts with TRIM13 (By similarity). Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1. Interacts with LRRC19. Interacts with IL17RA and TRAF3IP2. Interacts with TOMM70. Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1 (By similarity).
Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation with IL17A (By similarity). Polyubiquitinated; after cell stimulation with IL1B or TGFB. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form. Deubiquitinated by USP10 in a TANK-dependent manner, leading to the negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19 induces 'Lys-63' ubiquitination (By similarity).
Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1.
The MATH/TRAF domain binds to receptor cytoplasmic domains.
The coiled coil domain mediates homo- and hetero-oligomerization.
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 (By similarity).
Phosphorylation on Ser-20 relieves the inhibitory effect on Wnt signaling (By similarity). Phosphorylated on Thr-33 by CDK1 and CDK2; predominantly in G2 and M phase (By similarity).
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides (By similarity). Inhibits Wnt signaling (By similarity).
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 (By similarity).
Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex; leading to its degradation by the proteasome.
Actin cytoskeleton-organizing protein that plays a role in the formation of cell projections (By similarity). Required for actin polymerization at immunological synapses (IS) and for the recruitment of the chemokine receptor CXCR4 to IS (By similarity). 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).
Drebrins are classified into two forms of the embryonic type (E1 and E2) and one form of the adult type (A). The time course of their appearance are different from each other. Their structures are closely related. Adult rat brain expresses only drebrin A while drebrin E1 or E2 is observed in immature animals.
Interacts with RUFY (By similarity). Interacts with CXCR4; this interaction is enhanced by antigenic stimulation (By similarity). 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 (By similarity).
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 (By similarity).
N-glycosylated. The secreted form is modified by hybrid or complex type oligosaccharide chains.
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.
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. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. 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. By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes.
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 (By similarity).
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 (By similarity).
Acts as a positive regulator of ciliary hedgehog signaling. Required for cilia biogenesis.
Activated by quisqualate > glutamate > ibotenate > trans-1- aminocyclopentyl-1,3-dicarboxylate; inhibited by 2-amino-3-phosphonopropionate.
C-terminally truncated forms of isoform 1A.
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. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum (PubMed:10945991, PubMed:1438218, PubMed:1656524, PubMed:1847995). May function in the light response in the retina (By similarity).
Homodimer; disulfide-linked (PubMed:11069170, PubMed:11867751). The PPXXF motif binds HOMER1, HOMER2 and HOMER3. Interacts with TAMALIN (PubMed:11850456). Interacts with RYR1, RYR2, ITPR1, SHANK1 and SHANK3. Interacts with SIAH1 (PubMed:10469171).
Predominantly expressed in cerebellar Purkinje cells, CA2-CA3 pyramidal cells of the hippocampus, and mitral and tufted cells of the olfactory bulb.
Interacts with TFIIIB subunits BRF1 and BRF2. Interacts with Pol III subunit POLR3F. Interacts with TFIIIC subunit GTF3C1.
Phosphorylated at Ser-60, Ser-68 and Ser-75; the major sites of phosphorylation. Nuclear accumulation correlates with a concomitant dephosphorylation. Phosphorylation may attenuate its RNA polymerase III-repressive function (By similarity).
Plays a role in the repression of RNA polymerase III-mediated transcription in response to changing nutritional, environmental and cellular stress conditions to balance the production of highly abundant tRNAs, 5S rRNA, and other small non-coding RNAs with cell growth and maintenance (By similarity). Also plays a key role in cell fate determination by promoting mesorderm induction and adipocyte differentiation (By similarity). Mechanistically, associates with the RNA polymerase III clamp and thereby impairs its recruitment to the complex made of the promoter DNA, TBP and the initiation factor TFIIIB. When nutrients are available and mTOR kinase is active, MAF1 is hyperphosphorylated and RNA polymerase III is engaged in transcription. Stress-induced MAF1 dephosphorylation results in nuclear localization, increased targeting of gene-bound RNA polymerase III and a decrease in the transcriptional readout. Additionally, may also regulate RNA polymerase I and RNA polymerase II-dependent transcription through its ability to regulate expression of the central initiation factor TBP (By similarity).
Sumoylated with SUMO1 and SUMO2, mainly on Lys-35. Desumoylated by SENP1. SUMOylation promotes the ability of MAF1 to repress transcription and suppress colony formation (By similarity).
Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. Also able to mediate N-terminal lysine myristoylation of proteins: catalyzes myristoylation of ARF6 on both 'Gly-2' and 'Lys-3'. Lysine myristoylation is required to maintain ARF6 on membranes during the GTPase cycle.
Binds to the mature mitochondrial complex III dimer, after the incorporation of the Rieske protein UQCRFS1. Interacts with UQCRC1 and UQCRFS1 (By similarity). Interacts with ZFYVE26 and CHMP4B.
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. Involved in the clearance of UQCRFS1 N-terminal fragments, which are produced upon incorporation into the complex III and whose presence is detrimental for its catalytic activity.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Smok subfamily.
May play a role in sperm motility, especially in the regulation of flagellar function.
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 (By similarity).
Monomer. Interacts with TRAPPC2 and RYR2 (By similarity).
In skin fibroblasts of superficial dermis upon skin lesion with highest level between days 5-10.
May play an important role in the progression of epithelial malignancies.
The precursor is cleaved by a furin endopeptidase.
Belongs to the DNA2/NAM7 helicase family. SDE3 subfamily.
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 (By similarity).
Belongs to the Sp1 C2H2-type zinc-finger protein family.
Expressed in all tissues tested, including lung, kidney, spleen and thymus.
Interacts with ATF7IP, ATF7IP2, BAHD1, POGZ, HCFC1, AATF and PHC2. 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. 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 (By similarity). Interacts with SMARCA4/BRG1 (PubMed:19081374). Interacts with ATF7IP and TBP. Interacts with MEIS2 and PBX1. Interacts with EGR1. 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 (By similarity). Interacts with DDX3X; this interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription (By similarity).
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. Inhibited by peroxisomome proliferator receptor gamma (PPARgamma) (By similarity).
Phosphorylated on multiple serine and threonine residues. Phosphorylation is coupled to ubiquitination, sumoylation and proteolytic processing. Phosphorylation on Ser-60 enhances proteolytic cleavage. Phosphorylation on Ser-7 enhances ubiquitination and protein degradation. Hyperphosphorylation on Ser-102 in response to DNA damage has no effect on transcriptional activity. MAPK1/MAPK3-mediated phosphorylation on Thr-454 and Thr-740 enhances VEGF transcription but, represses FGF2-triggered PDGFR-alpha transcription. Also implicated in the repression of RECK by ERBB2. Hyperphosphorylated on Thr-279 and Thr-740 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-642 by PKCzeta is critical for TSA-activated LHR gene expression through release of its repressor, p107. Phosphorylation on Thr-669, Ser-671 and Thr-682 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-60 and Thr-682 can both be dephosphorylated by PP2A during cell-cycle interphase. Dephosphorylation on Ser-60 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 (By similarity).
Proteolytic cleavage in the N-terminal repressor domain is prevented by sumoylation. The C-terminal cleaved product is susceptible to degradation (By similarity).
Sumoylated with SUMO1. Sumoylation modulates proteolytic cleavage of the N-terminal repressor domain. Sumoylation levels are attenuated during tumorigenesis. Phosphorylation mediates SP1 desumoylation (By similarity).
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. Positively regulates the transcription of the core clock component BMAL1 (By similarity). Plays a role in the recruitment of SMARCA4/BRG1 on the c-FOS promoter (PubMed:19081374). 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 (By similarity).
Belongs to the type I cytokine receptor family. Type 1 subfamily.
Interacts with SMARCA1. Interacts with NEK3 and VAV2 and this interaction is prolactin-dependent.
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.
This is a receptor for the anterior pituitary hormone prolactin.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4. 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.
Arc expression is regulated at transcription, post-transcription and translation levels (PubMed:9808461, PubMed:10570490, PubMed:11226315, PubMed:18614031). Transcription is tightly coupled to encoding of information in neuronal circuits (PubMed:10570490). Expression is induced by neuronal and synaptic activity (PubMed:7777577, PubMed:7857651, PubMed:10570490). Induced at highest level in hippocampus within 30 minutes, dropping to basal levels within 24 hours (PubMed:7777577, PubMed:7857651). Arc transcripts are transported to dendrites and become enriched at sites of local synaptic activity where they are locally translated into protein (PubMed:9808461, PubMed:18614031). Arc transcripts resemble some viral RNAs and contain an internal ribosomal entry site (IRES) that allows cap-independent translation (PubMed:11226315).
Expressed during postnatal development from day 8 (PubMed:7857651). Highest expression around day 23 with moderate levels expressed to adulthood (PubMed:7857651).
Expressed exclusively in certain parts of the brain including cortex and molecular layer of the hippocampus. Typically expressed at high level in a minority of neurons. Basal expression higher in cortex than in hippocampus, highest in visual cortex.
Homooligomer; homooligomerizes into virion-like capsids (PubMed:29328916, PubMed:30028513, PubMed:31080121). Interacts with SH3GL1/endophilin-2, SH3GL3/endophilin-3 and DNM2/DYN2 (PubMed:17088211). Interacts with CAMK2B (in the kinase inactive state); leading to target ARC to inactive synapses (PubMed:22579289). Interacts with PSEN1 (By similarity). Interacts with GRIN2A and GRIN2B; inhibiting homooligomerization (PubMed:31080121).
Master regulator of synaptic plasticity that self-assembles into virion-like capsids that encapsulate RNAs and mediate intercellular RNA transfer in the nervous system (PubMed:29328916). 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 (PubMed:29328916). ARC capsids are endocytosed and are able to transfer ARC mRNA into the cytoplasm of neurons (PubMed:29328916). 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 (PubMed:10818134, PubMed:17088211, PubMed:17088212, PubMed:17088213). 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 (PubMed:17088211, PubMed:17088212). Acts as a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum by mediating elimination of surplus climbing fiber synapses (PubMed:23791196). Accumulates at weaker synapses, probably to prevent their undesired enhancement (PubMed:22579289). This suggests that ARC-containing virion-like capsids may be required to eliminate synaptic material (PubMed:29328916). Required to transduce experience into long-lasting changes in visual cortex plasticity and for long-term memory (PubMed:10818134). 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 (PubMed:29328916, PubMed:25864631). 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 (PubMed:29328916). Tetrapod and fly Arc protein-coding genes originated independently from distinct lineages of Ty3/gypsy retrotransposons (PubMed:29328916).
Transcripts enriched in dendrites may be translated locally.
Ubiquitinated by UBE3A, leading to its degradation by the proteasome, thereby promoting AMPA receptors (AMPARs) expression at synapses.
Binds to membranes enriched in phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:11161217). Modifies membrane curvature and facilitates the formation of clathrin-coated invaginations (PubMed:9723620, PubMed:12353027). Regulates receptor-mediated endocytosis (By similarity).
Monomer. Binds ITSN1 (By similarity). Binds clathrin, ZBTB16/ZNF145, AP2A1 and AP2A2. Binds ubiquitinated proteins. Interacts with RALBP1 in a complex also containing NUMB and TFAP2A during interphase and mitosis. Interacts with AP2B1. Interacts with UBQLN2 (By similarity). Interacts with REPS2; the interaction is direct (By similarity). Interacts with EPS15; the interaction is direct (By similarity). Interacts with ENTREP1 (By similarity).
Phosphorylated on serine and/or threonine residues in mitotic cells. Phosphorylation reduces interaction with REPS2, AP-2 and the membrane fraction. Depolarization of synaptosomes results in dephosphorylation.
The DPW repeat domain is involved in AP2A2 and clathrin binding.
The NPF repeat domain is involved in EPS15 binding.
The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1.
Ubiquitously expressed (PubMed:9723620). Detected in liver, spleen and testis, and weakly in lung and thymus (at protein level) (PubMed:10393179).
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. 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. Component of the U1 snRNP. 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. 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. Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. 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. 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.
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. Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes. Is also a component of the minor U12 spliceosome. May act as a charged protein scaffold to promote snRNP assembly or strengthen snRNP-snRNP interactions through non-specific electrostatic contacts with RNA.
Belongs to the 5'-3' exonuclease family. XRN2/RAT1 subfamily.
Possesses 5'->3' exoribonuclease activity. May promote termination of transcription by RNA polymerase II.
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 IFT88 (By similarity). Interacts with IFT57 and TTC30B (By similarity).
Component of the intraflagellar transport (IFT) complex B, which is essential for the development and maintenance of motile and sensory cilia.
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. Interacts with ZFP36.
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.
Chromatin-associated protein involved in DNA repair by promoting homologous recombination (HR). Binds double-stranded DNA (dsDNA) and secondary DNA structures, such as D-loop structures, but with less affinity than RAD51AP1.
Phosphorylated in an ATM-dependent manner in response to DNA damage. Phosphorylated by CDK1 and casein kinase.
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).
Pulmonary surfactant-associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces. SP-B increases the collapse pressure of palmitic acid to nearly 70 millinewtons per meter.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.3/KCNH4 sub-subfamily.
Expressed at day 18 dpc in embryonic brain.
Highly expressed in adult testis, and in adult and embryonic brain. In adult brain found in piriform cortex, olfactory tubercle, cerebral cortex, hippocampus pyramidial cells and dentate gyrus and basal ganglia of caudate/putamen and accumbens nucleus. Detected at intermediate levels in lung, spinal cord, and pituitary.
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.
Belongs to the methyltransferase superfamily. L-isoaspartyl/D-aspartyl protein methyltransferase family.
May induce apoptosis through the lysosomal-mitochondrial pathway. Translocates to the lysosome initiating the permeabilization of lysosomal membrane (LMP) and resulting in the release of CTSD and CTSL to the cytoplasm. Triggers the caspase-independent apoptosis by altering mitochondrial membrane permeabilization (MMP) resulting in the release of PDCD8 (By similarity).
PH and FYVE-type zinc finger domains are required for lysosomal location.
Heterotetramer of two alpha chains and two beta chains.
In rats there are two non-allelic alpha chains and two non-allelic beta chains.
Involved in oxygen transport from the lung to the various peripheral tissues.
Involved in the inhibition of cytokine-induced death of pancreatic beta cells (By similarity). Involved in the promotion of insulin secretion from pancreatic beta cells (By similarity). 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) (By similarity).
Acts as guanine nucleotide exchange factor (GEF) for RhoA and RhoB GTPases.
Detected in insulin-secreting beta-cells and pancreatic islets (at the protein level).
Mitochondrial glutamate/H(+) symporter (By similarity). Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton (Probable). Plays a role in the control of glucose-stimulated insulin secretion (PubMed:19584051).
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 (By similarity).
Monomer (By similarity). Interacts with phosphorylated CLDN7.
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.
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.
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.
A soluble form is produced by proteolytic processing of isoform 1 in the extracellular domain.
Acts in the early stages of hematopoiesis.
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.
The identity of N- and O-linked saccharides are not reported in PubMed:1708771. The O-linked polysaccharides are probably the mucin type linked to GalNAc.
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:2290837). The urea cycle ensures the detoxification of ammonia by converting it to urea for excretion (PubMed:2290837).
Negatively regulated by lysine acetylation.
Belongs to the immunoglobulin superfamily. LISCH7 family.
Activity is increased in the presence of K(+)or Na(+).
Belongs to the pyridoxine kinase family.
Catalyzes the phosphorylation of the dietary vitamin B6 vitamers pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) to form pyridoxal 5'-phosphate (PLP), pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP), respectively (By similarity). PLP is the active form of vitamin B6, and acts as a cofactor for over 140 different enzymatic reactions (By similarity).
Highly expressed in brain cortex in embryos (17 dpc) and newborn rats up to P7. Very low expression thereafter.
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. Interacts with UACA. Interacts with APIP (By similarity). Interacts (via CARD and NACHT domains) with NAIP/BIRC1 (via NACHT domain) (By similarity). Interacts with CIAO2A (By similarity).
Physiological concentrations of calcium ions negatively affect the assembly of apoptosome by inhibiting nucleotide exchange in the monomeric form.
Regulates programmed cell death; necessary for normal brain development. Participates with pro-caspase-9 (Apaf-3) in the cytochrome c-dependent activation of caspase-3, leading to apoptosis. This activation requires ATP (By similarity).
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).
Interacts with SRSF1 (PubMed:10564280). Interacts with SRSF2 (PubMed:10564280). Interacts with SRSF3 (By similarity). Interacts with SRSF7 (By similarity). Interacts with SRSF10 (By similarity). Interacts with CPSF6 (By similarity). Interacts with KHDRBS1/SAM68 (PubMed:10564280). Interacts with TRA2B (PubMed:10564280). Interacts with KHDRBS3 (PubMed:11118435). Interacts with EMD (By similarity). Interacts with RBMX (PubMed:19282290). Interacts with ZCCHC8 (By similarity).
Regulator of alternative splicing that specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs (PubMed:25389274). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in the efficiency of mRNA splicing, processing and stability (PubMed:25389274). Acts as a key regulator of exon-inclusion or exon-skipping during alternative splicing via interaction with mRNA splicing factors SRSF3 and SRSF10 (By similarity). Specifically binds m6A-containing mRNAs and promotes recruitment of SRSF3 to its mRNA-binding elements adjacent to m6A sites, leading to exon-inclusion during alternative splicing (By similarity). In contrast, interaction with SRSF3 prevents interaction with SRSF10, a splicing factor that promotes exon skipping: this prevents SRSF10 from binding to its mRNA-binding sites close to m6A-containing regions, leading to inhibit exon skipping during alternative splicing (By similarity). May also regulate alternative splice site selection (PubMed:10564280, PubMed:9473574). Also involved in nuclear export of m6A-containing mRNAs via interaction with SRSF3: interaction with SRSF3 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (By similarity). Involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts, probably by binding m6A-containing MAT2A mRNAs (By similarity). Also recognizes and binds m6A on other RNA molecules (By similarity). Involved in random X inactivation mediated by Xist RNA: recognizes and binds m6A-containing Xist and promotes transcription repression activity of Xist (By similarity). Also recognizes and binds m6A-containing single-stranded DNA (By similarity). Involved in germline development: required for spermatogonial development in males and oocyte growth and maturation in females, probably via its role in alternative splicing (By similarity).
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. 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 (By similarity). Plays a role in brain, heart, and eye development.
Self-associates to form homodimers and forms heterodimers with SMG8; these assembly forms may represent SMG1C intermediate forms (By similarity). Component of the SMG1C complex composed of SMG1, SMG8 and SMG9 (By similarity). Interacts with DHX34; the interaction is RNA-independent (By similarity).
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.
Homotetramer (By similarity). Homodimer (PubMed:4019513). 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. Interacts with UBIAD1 (By similarity).
N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.
Phosphorylated. Phosphorylation at Ser-871 reduces the catalytic activity.
Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (By similarity). Phosphorylation at Ser-871 down-regulates the catalytic activity (By similarity).
Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2. The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase. 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. The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase. Lys-248 is the main site of ubiquitination. Ubiquitination is enhanced by the presence of a geranylgeranylated protein.
Detected in alveolar macrophages (at protein level). Widely expressed. Expressed at highest levels in alveolar macrophages.
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:15294901). 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:15294901). Among preferred fatty acyl donors are phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols and phosphatidylserines. 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 (By similarity). 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. 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 (By similarity).
N-glycosylated. N-glycosylation is important for maturation of the enzyme and normal subcellular location.
Transacylase activity is inhibited by MJ33.
Cargo receptor involved in protein vesicular trafficking and quality control in the endoplasmic reticulum (ER) and Golgi (By similarity). The p24 protein family is a group of transmembrane proteins that bind coat protein complex I/COPI and coat protein complex II/COPII involved in vesicular trafficking between the membranes (By similarity). Acts at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and involved in vesicle coat formation at the cytoplasmic side (PubMed:10214941). Mainly functions in the early secretory pathway and cycles between the ER, ER-Golgi intermediate compartment (ERGIC) and Golgi, mediating cargo transport through COPI and COPII-coated vesicles (PubMed:10214941). In COPII vesicle-mediated anterograde transport, involved in the transport of GPI-anchored proteins by acting together with TMED2 as their cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER (PubMed:27569046). Recognizes GPI anchors structural remodeled in the ER by the GPI inositol-deacylase/PGAP1 and the metallophosphoesterase MPPE1/PGAP5 (PubMed:27569046). In COPI vesicle-mediated retrograde transport, involved in the biogenesis of COPI vesicles and vesicle coat recruitment. Involved in trafficking of amyloid beta A4 protein and soluble APP-beta release (independent from the modulation of gamma-secretase activity) (By similarity). Involved in the KDELR2-mediated retrograde transport of the toxin A subunit (CTX-A-K63)together with COPI and the COOH terminus of KDELR2 (By similarity). On Golgi membranes, acts as primary receptor for ARF1-GDP, a GTP-binding protein involved in COPI-vesicle formation. Increases coatomer-dependent GTPase-activating activity of ARFGAP2 which mediates the hydrolysis of ARF1-bound GTP and therefore modulates protein trafficking from the Golgi apparatus. Involved in the exocytic trafficking of G protein-coupled receptors F2LR1/PAR2 (trypsin and tryspin-like enzyme receptor), OPRM1 (opioid receptor) and P2RY4 (UTD and UDP receptor) from the Golgi to the plasma membrane, thus contributing to receptor resensitization. In addition to its cargo receptor activity, may also act as a protein channel after oligomerization, facilitating the post-translational entry of leaderless cytoplasmic cargo into the ERGIC. Involved in the translocation into ERGIC, the vesicle entry and the secretion of leaderless cargos (lacking the secretion signal sequence), including the mature form of interleukin 1/IL-1 family members, the alpha-crystallin B chain HSPB5, the carbohydrate-binding proteins galectin-1/LGALS1 and galectin-3/LGALS3, the microtubule-associated protein Tau/MAPT, and the annexin A1/ANXA1; the translocation process is dependent on cargo protein unfolding and enhanced by chaperones HSP90AB1 and HSP90B1/GRP9. Could also associates with the presenilin-dependent gamma-secretase complex in order to regulate gamma-cleavages of the amyloid beta A4 protein to yield amyloid-beta 40/Abeta40 (By similarity).
Ectopic expression of TMED10 alone does not result in its proper cis-Golgi network localization. Interaction of TMED10 with TMED2 is both necessary and sufficient for transport of the couple to the cis-Golgi network, and TMED3 and/or TMED9 contribute to facilitating the process.
Predominantly dimeric and to a lesser extent monomeric in the ER. Monomer and dimer in ERGIC and cis-Golgi network. Forms homooligomer (via GOLD domain); the assembly is promoted by direct binding with leaderless cargos and may form a protein channel that facilitates cargo entry into the ERGIC (By similarity). Forms heterooligomeric complexes with other members of the p24 family such as TMED2, TMED7 and TMED9 (PubMed:8663407, PubMed:10214941, PubMed:11703931). Interacts (via GOLD domain) with TMED2 (via GOLD domain); the complex is required for export of TMED10 from the ER to the cis-Golgi network; the complex is proposed to be involved in cis-Golgi network dynamics and / or biogenesis (PubMed:27569046). Associates with the COPI vesicle coat subunits (coatomer) (By similarity). Tetramerization of the cytoplasmic domain at the Golgi membrane in vitro; the complex is proposed to interact with COPI coatomer and induce budding of the vesicles (By similarity). Interacts with COPG1; the interaction involves TMED10 homodimer (By similarity). Interacts with ARF1 (GDP-bound); the interaction probably involves a TMED10 oligomer (PubMed:11703931). Interacts with SEC23A, SEC24B, SEC24C and SEC24D components of the coat protein complex II/COPII, indicative of an association of TMED10 with the COPII vesicle coat. Interacts with CD59 (PubMed:9472029). Interacts with MPPE1/PGAP5; the complex might recruit and sort GPI-anchored proteins to the ER-exit site, or the interaction might lead to recycling of PGAP5 between the ER and the Golgi. Interacts with F2LR1/PAR2 (By similarity). Interacts with KDELR2/ERD2; the interaction is disrupted by KDELR2 ligand (PubMed:11703931). Found in a complex composed at least of SURF4, TMED2 and TMED10 (By similarity). Associates with the presenilin-dependent gamma-secretase complex. Interacts with STX17; the interaction is direct (By similarity). Interacts with IL-1; the interaction is direct (PubMed:21545355). Interacts with RAB21 (active GTP-bound form); the interaction is indirect and regulates TMED10 abundance and localization at the Golgi (By similarity).
The GOLD domain is required for proper p24 heterooligomeric complex formation and efficient transport of GPI-anchored proteins.
The lumenal domain mediates localization to the plasma membrane by partially overriding the ER retention by the cytoplasmic domain.
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. Promotes pancreatic beta cell death through degradation of JUNB and inhibition of the unfolded protein response, leading to reduction of insulin secretion. Restricts the production of pro-inflammatory cytokines in effector Th17 T-cells by promoting ITCH-mediated ubiquitination degradation of RORC. 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. 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. Negatively regulates RLR-mediated antiviral response by promoting SMURF1-mediated ubiquitination and subsequent degradation of MAVS. 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. 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. Important for normal development of dendrites and dendritic spines in cortex. Enhances the ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is required for the nuclear localization of ubiquitinated BRAT1. Enhances the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-conjugating enzyme UBE2L3 to ITCH. 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. Inhibits cell proliferation by promoting PTEN nuclear localization and changing its signaling specificity.
Forms heterodimers with NDFIP2. Interacts with several E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L and WWP2. The interaction with NEDD4, NEDD4L and ITCH leads to relocalization of these proteins to exosomes and eventually to exosomal secretion. Interacts with SR1402. Interacts with SLC11A2/DMT1. Interacts with PTEN. May interact with phosphorylated EGFR. Interacts with BRAT1. Interacts with KCNH2. Interacts with MAVS. Part of a complex containing ITCH, NDFIP1 and MAP3K7. Interacts (via N-terminus) with UBE2L3; the interaction mediates recruitment of UBE2L3 to ITCH.
The PPxY motifs are required for E3 ubiquitin-protein ligase binding and activation and for ubiquitination.
Ubiquitinated by NEDD4; mono-, di- and polyubiquitinated forms are detected. Ubiquitination regulates its degradation (By similarity).
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 (By similarity).
Downstream effector protein for Rho-type small GTPases that plays a role in cell polarity and directional migration. Acts as an adapter protein, linking active Rho proteins to STK24 and STK26 kinases, and hence positively regulates Golgi reorientation in polarized cell migration upon Rho activation. Involved in the subcellular relocation of STK26 from the Golgi to cytoplasm punctae in a Rho- and PDCD10-dependent manner upon serum stimulation.
Interacts (via N-terminus) with RHOA (GTP-bound form); this interaction links active RHOA to STK24 and STK26 kinases. Interacts with RHOB. Interacts with RHOC. Interacts (via C-terminus) with PDCD10; this interaction occurs in a Rho-independent manner. Interacts (via C-terminus) with STK24; this interaction occurs in a PDCD10-dependent and Rho-independent manner. Interacts (via C-terminus) with STK26; this interaction occurs in a PDCD10-dependent and Rho-independent manner. Interacts (via N-terminus) with 14-3-3 proteins; these interactions occur in a Rho-dependent manner.
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.
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 exclusively in decidual tissue.
Expression limited to early pregnancy with abundant expression on day 7, slightly declining expression on day 9, and no detectable expression by day 11.
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.
Present in testis, at a lower level in brain, and at a very low level in ovary. Not detected in other tissues. tested. Present in Leydig cells of the adult testis and to a lesser degree in the seminiferous tubules in spermatogonia and Sertoli cells (at protein level).
Belongs to the transferase hexapeptide repeat family.
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. It has been hypothesized 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.
May serve as a regulatory subunit and allow allosteric feedback inhibition of GMPPB by GDP-mannose.
Mediates beneficial effects of muscular exercise. Induces browning of white adipose tissue by stimulating UCP1 expression, at least in part, via the nuclear receptor PPARA (By similarity).
The extracellular domain is cleaved and released from the cell membrane.
Belongs to the vinculin/alpha-catenin family.
Down-regulated by exposure to trichloroethylene (TCE) and dichloroethylene (DCE) in fetal heart.
Expressed in hippocampal and neocortical pyramidal neurons, but not in Purkinje cells.
May form homomultimers (By similarity). Interacts with G3BP1; interaction is direct and takes place in cytoplasmic RNA granules (By similarity). Interacts with PQBP1 (By similarity). Interacts with DDX3X (By similarity).
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.
O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.
Was originally thought to be a GPI-anchored membrane protein.
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.
Expressed in the sympathetic nervous system.
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. 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 (PubMed:24305827). 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 (PubMed:24412651). 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.
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.
Belongs to the peptidase C19 family. USP4 subfamily.
Deubiquitinating enzyme that removes conjugated ubiquitin from target proteins. Deubiquitinates PDPK1. Deubiquitinates TRIM21. Deubiquitinates receptor ADORA2A which increases the amount of functional receptor at the cell surface. Deubiquitinates HAS2. May regulate mRNA splicing through deubiquitination of the U4 spliceosomal protein PRPF3. This may prevent its recognition by the U5 component PRPF8 thereby destabilizing interactions within the U4/U6.U5 snRNP. May also play a role in the regulation of quality control in the ER.
Expressed in hippocampus and striatum (at protein level).
Interacts with RB1 (both dephosphorylated and hypophosphorylated forms) (By similarity). Interacts with RBL1 and RBL2 (By similarity). Interacts with ADORA2A (via cytoplasmic C-terminus); the interaction is direct. Interacts with SART3; recruits USP4 to its substrate PRPF3 (By similarity).
Monoubiquitinated by TRIM21. Ubiquitination does not lead to its proteasomal degradation. Autodeubiquitinated.
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.
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.
Binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit to form the 80S initiation complex in the cytoplasm. 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. 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. 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. Modulates cell cycle progression and global translation of pre-B cells, its activation seems to be rate-limiting in tumorigenesis and tumor growth.
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).
Phosphorylation at Ser-174 and Ser-175 by CSNK1D/CK1 promotes nuclear export.
Catalytic subunit of the phosphorylase b kinase (PHK), which mediates the neural and hormonal regulation of glycogen breakdown (glycogenolysis) by phosphorylating and thereby activating glycogen phosphorylase. In vitro, phosphorylates PYGM, TNNI3, MAPT/TAU, GAP43 and NRGN/RC3 (By similarity).
The two calmodulin-binding domains appear to act in concert to bind a single molecule of calmodulin and are pseudosubstrate/autoinhibitory domains.
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.
Protein-disulfide reductase of the endoplasmic reticulum that promotes disulfide bond formation in client proteins through its thiol-disulfide oxidase 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.
Belongs to the glycosyltransferase 8 family.
Glycosyltransferase which elongates the O-linked glucose attached to EGF-like repeats in the extracellular domain of Notch proteins by catalyzing the addition of xylose.
Synthesizes the galactose-alpha(1,3)-galactose group by catalyzing the transfer of a galactose residue, with an alpha-1,3 linkage, on terminal lactosaminide (Gal-beta-1,4-GlcNAc-R) disaccharide borne by a glycoprotein or a glycolipid.
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).
Brain-specific. Highly expressed in auditory nuclei, in Purkinje cells and in olfactory bulb mitral cells.
Probable potassium channel subunit. No channel activity observed in heterologous systems. May need to associate with another protein to form a functional channel.
Expressed only in regenerating islets, but not in normal pancreatic islets, insulinomas or regenerating liver.
Might act as an inhibitor of spontaneous calcium carbonate precipitation.
Cell surface proteoglycan that bears heparan sulfate. May fulfill a function related to the motile behaviors of developing neurons.
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 (PubMed:12084985).
Widely and transiently expressed by immature neurons, appearing around the time of final mitosis and disappearing after cell migration and axon outgrowth have been completed.
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.
Found in liver, kidney, spleen, heart and brain.
Heterodimer of an alpha and a beta subunit. Found in a complex with ADD2, DMTN and SLC2A1. Interacts with SLC2A1 (By similarity).
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 (By similarity).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1D 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.
Expressed in brain, pancreatic islets and B-lymphocytes.
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 with CABP1 and CABP4, resulting in a near elimination of calcium-dependent inactivation of the channel. 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.
Belongs to the cytidine and deoxycytidylate deaminase family.
Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.
Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates (PubMed:9482734). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors (By similarity). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (By similarity). In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:9482734). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (By similarity). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (PubMed:17242403). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). Phosphorylates MARK2, leading to inhibition of its activity (PubMed:18424437). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (By similarity). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (By similarity).
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.
Monomer (By similarity). Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation (By similarity). Interacts (via C2 domain) with PPP2CA (By similarity). Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE1 and ZBED3 (By similarity). Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction (PubMed:9482734). Interacts with and phosphorylates SNAI1 (By similarity). Interacts with DNM1L (via a C-terminal domain) (By similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (PubMed:16815997). Interacts with SGK3 (By similarity). Interacts with the CLOCK-BMAL1 heterodimer (By similarity). Interacts with the BMAL1 (By similarity). Interacts with CTNND2 (By similarity). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (By similarity). Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (By similarity). Interacts with GSKIP (By similarity). Interacts with GID8 (By similarity). Interacts with PIWIL2 (By similarity). Interacts with LMBR1L (By similarity). Interacts with DDX3X (By similarity). Interacts with BIRC2 (By similarity). Interacts with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity (By similarity).
Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 and RPS6KA3 protein kinases phosphorylate and deactivate GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (By similarity). Inactivated by phosphorylation at Ser-9 (By similarity). Phosphorylated in a circadian manner in the hippocampus (By similarity).
Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells.
Belongs to the copper transporter (Ctr) (TC 1.A.56) family. SLC31A subfamily.
High-affinity, saturable copper transporter involved in dietary copper uptake.
Almost exclusively expressed in brain, with weak expression in lung and stomach.
Prion-like protein that has PrP(C)-like neuroprotective activity. May act as a modulator for the biological actions of normal and abnormal PrP (By similarity).
Involved in the catabolism of quinolinic acid (QA).
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.
Belongs to the mitochondrion-specific ribosomal protein mS25 family.
Component of the mitochondrial ribosome small subunit (28S) which comprises a 12S rRNA and about 30 distinct proteins.
Decarboxylates ethylmalonyl-CoA, a potentially toxic metabolite, to form butyryl-CoA, suggesting it might be involved in metabolite proofreading. Also has methylmalonyl-CoA decarboxylase activity at lower level.
Belongs to the universal ribosomal protein uL29 family.
Plays an essential role in the regulation of neuronal differentiation and migration during development of the central nervous system.
Expressed more abundantly in liver and kidney of females than that of males. Equally expressed in brain, lung and heart.
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids. 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. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids. May be involved in the oxidative metabolism of xenobiotics.
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.
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 (By similarity). 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).
Nitration of Tyr-449 is irreversible and interferes with normal dynein intracellular distribution.
Tyrosination promotes microtubule interaction with CAP-Gly domain-containing proteins such as CLIP1, CLIP2 and DCTN1 (By similarity). Tyrosination regulates the initiation of dynein-dynactin motility via interaction with DCTN1, which brings the dynein-dynactin complex into contact with microtubules. 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 (MATCAP, VASH1 or VASH2) and tubulin tyrosine ligase (TTL), respectively.
Belongs to the archaeal Rpo3/eukaryotic RPB3 RNA polymerase subunit family.
Could act as a modulator of glutaredoxin biological activity (By similarity). May play a role in cytoskeleton organization (By similarity).
Expressed in heart, liver, lung, kidney, spleen, thymus, ovarian follicles, skeletal muscle, brain, lymph node and mammary epithelial and stromal cells (at protein level).
Interacts with MYO1C (via its IQ motifs); the interaction is dependent on calcium and takes place at membrane ruffles.
Belongs to the N-acylglucosamine 2-epimerase family.
Catalyzes the interconversion of N-acetylglucosamine to N-acetylmannosamine. Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway.
Homodimer (PubMed:1723410). Forms a heterodimer with renin and inhibits its activity (PubMed:1723410).
Kidney, adrenal gland, brain, lung, spleen, ovary, testis and heart.
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. 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.
Belongs to the cytochrome b5 family. MAPR subfamily.
Heme-binding protein which promotes neuronal but not astrocyte differentiation.
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 residues at position 73 and 106.
Belongs to the transcription factor STAT family.
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. May be involved in actin cytoskeleton reorganization by cleaving PTK7. Acts as a positive regulator of cell growth and migration via activation of MMP15 in association with pro-MMP2. Involved in the formation of the fibrovascular tissues in association with pro-MMP2. Cleaves ADGRB1 to release vasculostatin-40 which inhibits angiogenesis.
Interacts (via C-terminal cytoplasmic tail) with BST2. Interacts with DLL1; inhibits DLL1-induced Notch signaling.
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).
The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, possibly by interacting with phospholipids.
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. Interacts (N-terminally acetylated form) with (via DCUN1 domain) DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (By similarity).
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 universal ribosomal protein uL10 family.
P0 forms a pentameric complex by interaction with dimers of P1 and P2. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with APEX1. Interacts with FMR1.
Ribosomal protein P0 is the functional equivalent of E.coli protein L10.
Belongs to the DNA repair metallo-beta-lactamase (DRMBL) family.
Expressed in brain, spleen, kidney and testis.
May be involved in transport vesicle docking to the plasma membrane.
The first C2 domain/C2A does not mediate Ca(2+)-dependent phospholipid binding.
The second C2 domain/C2B domain binds phospholipids regardless of whether calcium is present.
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.
Hydrolyzes ADP-ribose, IDP-ribose, CDP-glycerol, CDP-choline and CDP-ethanolamine, but not other non-reducing ADP-sugars or CDP-glucose. May be involved in immune cell signaling as suggested by the second-messenger role of ADP-ribose, which activates TRPM2 as a mediator of oxidative/nitrosative stress.
Preferentially expressed in immune cells.
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 (By similarity).
Dimethylated by PRMT1 at Arg-265. The methylation may favor cytoplasmic localization. Demethylated by JMJD6 at Arg-265.
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.
Interacts with BCAS3. Binds DNA as a homodimer (By similarity). Can form a heterodimer with ESR2 (By similarity). Interacts with coactivator NCOA5. Interacts with PELP1, the interaction is enhanced by 17-beta-estradiol; the interaction increases ESR1 transcriptional activity (By similarity). Interacts with NCOA7; the interaction is ligand-inducible. Interacts with AKAP13, CUEDC2, HEXIM1, KDM5A, MAP1S, SMARD1, and UBE1C. Interacts with MUC1; the interaction is stimulated by 7 beta-estradiol (E2) and enhances ESR1-mediated transcription. Interacts with DNTTIP2, and UIMC1. Interacts with KMT2D/MLL2. Interacts with ATAD2; the interaction is enhanced by estradiol. Interacts with KIF18A and LDB1. Interacts with RLIM (via its C-terminus). Interacts with MACROD1. Interacts with SH2D4A and PLCG. Interacts with SH2D4A; the interaction blocks binding to PLCG and inhibits estrogen-induced cell proliferation. Interacts with DYNLL1. Interacts with CCDC62; the interaction requires estradiol and appears 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 EP300; the interaction is estrogen-dependent and enhanced by CITED1. Interacts with CITED1; the interaction is estrogen-dependent (By similarity). Interacts with FAM120B, FOXL2, PHB2 and SLC30A9. Interacts with coactivators NCOA3 and NCOA6. 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. 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 (By similarity). Interacts with TRIP4 (ufmylated); estrogen dependent (By similarity). 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 (By similarity). Interacts with SFR1 in a ligand-dependent and -independent manner (By similarity). Interacts with DCAF13, LATS1 and DCAF1; regulates ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation. 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 (By similarity). Interacts with UBE3A and WBP2 (By similarity). Interacts with GTF2B (By similarity). Interacts with RBM39 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (By similarity). Interacts with PI3KR1 or PI3KR2 and PTK2/FAK1 (By similarity). Interacts with SRC (By similarity).
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 (By similarity).
Palmitoylated at Cys-452 by ZDHHC7 and ZDHHC21. This modification 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 (By similarity).
Phosphorylated by cyclin A/CDK2 and CK1. Phosphorylation probably enhances transcriptional activity. Dephosphorylation at Ser-123 by PPP5C inhibits its transactivation activity (By similarity). Phosphorylated by LMTK3 (in vitro) (By similarity).
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. Deubiquitinated by OTUB1.
Strongly expressed in several brain areas including frontal cortex, cortex, mesencephalon, hippocampus, midbrain and hypothalamus. Also expressed in testis and at low levels in pituitary, liver and kidney. In brain the highest levels are detected in hippocampal pyramidal cells and raphe nuclei.
The C2 domain is required for the repression.
Transcription factor that binds specifically to the DRE (dual repressor element) and represses 5-HT1A gene transcription though this element. Mediates HDAC-independent repression of HTR1A promoter. CAMK2G inhibits CC2D1a-induced repression of the HTR1A. May play a role in the altered regulation of 5-HT1A receptors associated with anxiety and major depression. Performs essential function in controlling functional maturation of synapses (By similarity).
Belongs to the G-protein coupled receptor 1 family. Mas subfamily.
Expressed strongly in newborn dorsal root ganglia, adult dorsal root ganglia and trigeminal ganlia.
Orphan receptor. Probably involved in the function of nociceptive neurons. May regulate nociceptor function and/or development, including the sensation or modulation of pain (By similarity).
Zinc phosphodiesterase, which displays mitochondrial tRNA 3'-processing endonuclease activity. Involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
Heterotetramer of two type I and two type II keratins.
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).
Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters.
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. 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. Identified in a complex with SHMT2 and the other subunits of the BRISC complex. 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.
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 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. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates. 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. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1. 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. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination. 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.
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.
Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion.
Comprised of three regions: a N-terminal protease-resistant globular head region, a short connecting subdomain, and a protease-sensitive tail region.
Expressed in kidney, brain, spleen, liver and heart.
Expressed in renal interlobular arteries, afferent/efferent arterioles, parietal glomerular epithelial cells and microvilli of the luminal surface of the proximal tubule (at protein level) (PubMed:32830539). Expressed in podocytes (at protein level) (PubMed:32830539, PubMed:33308016) Expressed in renal cortex (at protein level) (PubMed:32830539, PubMed:32029431, PubMed:33308016). Expressed in primary vascular smooth muscle cells (VSMCs) of the kidney (at protein level) (PubMed:32029431). Expressed in tubular cells and glomeruli (at protein level) (PubMed:33308016).
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. Binds to calmodulin (By similarity). Involved in myogenic reactivity of the renal afferent arteriole (Af-art), renal interlobular arteries and middle cerebral artery (MCA) to increased perfusion pressure (PubMed:27927653, PubMed:32830539, PubMed:32029431). Involved in regulation of potassium channels in the vascular smooth muscle cells (VSMCs) of the Af-art and MCA ex vivo (PubMed:27927653, PubMed:32029431). Involved in regulation of glomerular capillary pressure, glomerular filtration rate (GFR) and glomerular nephrin expression in response to hypertension (PubMed:32830539, PubMed:33414130). Involved in renal blood flow (RBF) autoregulation (PubMed:32830539, PubMed:32029431, PubMed:33414130). 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 (PubMed:33308016). Regulates expression of profibrotics markers MMP2, MMP9, TGF beta-1, tubular tight junction protein E-cadherin, and mesenchymal markers vimentin and alpha-SMA (PubMed:33414130). 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).
Renal afferent arteriole (Af-art) of the Dicer-substrate short interfering RNA (DsiRNA) knockdown rats dilates instead of constricts as the wild-type vessel in response to an elevation in perfusion pressure. Knockdown results in impaired myogenic response in the middle cerebral artery (MCA), but vasoconstrictor response to serotonin is not affected in the presence of iberiotoxin (IBTX). Knockdown has no effect on the vasoconstrictor response of the renal Af-art to norepinephrine. Smooth muscle cells isolated from the renal microvessels or MCAs of the knockdown rats have higher peak potassium currents than the wild-type cells. A significantly higher level of IBTX-sensitive peak potassium current densities are detected in smooth muscle cells of the cerebral microvessels of the knockdown rats (PubMed:27927653). Knockout rats have elevated iberiotoxin-sensitive potassium (BK) channel current in renal vascular smooth muscle cells (VSMCs) and exhibit impairments in the myogenic response of Af-arts (PubMed:32029431). Renal blood flow (RBF) autoregulation is also impaired (PubMed:32830539, PubMed:32029431). Knockout rats have decreased glomerular capillary pressure in response to elevated blood pressure. After 1 week of DOCA-salt induced hypertension the glomerular filtration rate (GFR) increases and glomerular nephrin expression decreases while they remain unchanged in wild-type rats. Myogenic response is impaired in interlobular arteries of the knockout rats. Proteinuria, glomerulosclerosis and renal interstitial fibrosis are more pronounced in knockout rats after 3 weeks of hypertension compared to wild-type rats. Expression of macrophage-related proinflammatory cytokines, infiltrating CD68(+) macrophages and the markers of epithelial mesenchymal transition increase after hypertension. These alterations in hypertensive knockout rats lead to increased transmission of pressure to glomeruli inducing podocyte loss, and accelerated progression of chronic kidney disease (CKD) (PubMed:32830539). Acute administration of N(G)-nitro-L-arginine methyl ester (L-NAME) raises mean arterial pressure (MAP) of the knockout rats as in wild-type, but RBF and GFR are decreased less in knockout rats. However, RBF and GFR are significantly greater in knockout rats than in wild-type after the simultaneous administration of L-NAME and furosemide. Chronic administration of L-NAME with a simultaneous high-salt diet leads to impaired renal vasoconstrictor response to the blockade of nitric oxide synthase, which promotes hypertension-induced proteinuria and renal injury in knockout rats. After chronic administration of L-NAME, MAP increases in the knockout rats the same way as in wild-type, but RBF, GFR and glomerular capillary pressure are increased. They have greater loss of podocytes and glomerular nephrin expression than wild-type rats, and increased renal interstitial fibrosis. Expression of the profibrotics markers MMP9, MMP2 and TGF beta-1 increases more in L-NAME-treated knockout rats than in wild-type rats. Expression of tubular tight junction protein E-cadherin decreases more in knockout rats treated with L-NAME and high-salt diet for 3 weeks in association with greater expression of mesenchymal markers vimentin and alpha-SMA compared to wild-type (PubMed:33414130).
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.5/SCN5A subfamily.
Interacts with the PDZ domain of the syntrophin SNTA1, SNTB1 and SNTB2. Interacts with NEDD4, NEDD4L, WWP2 and GPD1L. Interacts with CALM. Interacts with FGF13; the interaction is direct and may regulate SNC5A density at membranes and function. May also interact with FGF12 and FGF14. Interacts with ANK3 (By similarity). Interacts with PKP2 (via N-terminus) (PubMed:19661460).
Lacks the cysteine which covalently binds the conotoxin GVIIJ. This cysteine (position 869) is speculated in other sodium channel subunits alpha to be implied in covalent binding with the sodium channel subunit beta-2 or beta-4.
Na(+) channels in mammalian cardiac membrane have functional properties quite distinct from Na(+) channels in nerve and skeletal muscle.
Phosphorylation at Ser-1505 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents. Regulated through phosphorylation by CaMK2D.
Strongly expressed in the heart (PubMed:19661460). Also expressed in adult and fetal brain, spinal cord, testis, and at moderate levels in kidney, adrenal gland, lung, skeletal muscle, spleen, stomach and bladder.
The IQ domain mediates association with calmodulin.
This protein 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. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.
Ubiquitinated by NEDD4L; which promotes its endocytosis. Does not seem to be ubiquitinated by NEDD4 or WWP2.
Belongs to the GST superfamily. Alpha family.
Glutathione S-transferase that catalyzes the nucleophilic attack of the sulfur atom of glutathione on the electrophilic groups of a wide range of exogenous and endogenous compounds (Probable). Involved in the formation of glutathione conjugates of both prostaglandin A2 (PGA2) and prostaglandin J2 (PGJ2). It also catalyzes the isomerization of D5-androstene-3,17-dione (AD) into D4-androstene-3,17-dione and may therefore play an important role in hormone biosynthesis. Through its glutathione-dependent peroxidase activity toward the fatty acid hydroperoxide (13S)-hydroperoxy-(9Z,11E)-octadecadienoate/13-HPODE it is also involved in the metabolism of oxidized linoleic acid (By similarity).
Homodimer (PubMed:11119643). Homodimer or heterodimer of GSTA1 and GSTA2 (By similarity).
In addition to its enzymatic activity, the homodimer of Ya chains, called ligandin, binds various organic anions, xenobiotics, and azocarcinogen dyes.
Binds to two alpha/beta-tubulin heterodimers. Interacts with KIST (By similarity).
Involved in the regulation of the microtubule (MT) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules (By similarity). Its 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 (By similarity). Phosphorylation at Ser-16 is higher in the developing axons from hippocampal neurons and seems to be required for neuron polarization.
It is uncertain whether Met-1 or Met-11 is the initiator.
May play an important role in spermatogenesis and/or testis development.
Abundantly expressed in heart and skeletal muscle and to a lower extent in brain, lung and liver. Expressed in heart, skeletal muscle and testis (at protein level).
Functions as an anchor sequestering components of the cAMP-dependent pathway to Golgi and/or centrosomes (PubMed:11134006). May participate in microtubule dynamics, promoting microtubule assembly, in an isoform-specific manner. Depending upon the cell context, may act at the level of the Golgi apparatus or that of the centrosome. 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. 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 (By similarity).
Interacts with PDE4D (PubMed:11134006). May interact with MAPRE1 and MAPRE3. May form a pericentrosomal complex with AKAP9, CDK5RAP2 and EB1/MAPRE1 in an isoform-specific manner; within this complex, may mediate MAPRE1-binding to CDK5RAP2. Interaction with AKAP9 stabilizes both proteins. May interact with CAMSAP2 in an isoform-specific manner; this interaction is much stronger in the presence of AKAP9. In complex with AKAP9, recruits CAMSAP2 to the Golgi apparatus. May interact with unglycosylated LGALS3BP in an isoform-specific manner; this interaction may connect the pericentrosomal complex to the gamma-tubulin ring complex (gamma-TuRC) to promote microtubule assembly and acetylation (By similarity).
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.
Expressed in brain, hippocampus, amygdala, Purkinje cells and single neurons in the cortex and striatum.
Heteromer with TRPC4 and/or TRPC5 (PubMed:11301024). Interacts with TRPC4 and TRPC5 (By similarity). Interacts with ITPR3 (By similarity). Interacts with MX1 and RNF24 (By similarity). Interacts with FKBP4 (By similarity). Interacts with TRPC4AP (By similarity). 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.
Acts as a transcriptional repressor. Represses the promoter activity of the CDC25C gene stimulated by NFYA. May play a role in retinal development where it regulates the composition of bipolar cell populations, by promoting differentiation of bipolar OFF-type cells. In the brain, may promote maintenance and suppress differentiation of neural progenitor cells in the developing cortex.
Homodimer (via homeobox domain 1). Heterodimer with ZHX1 (via homeobox domain 1). Heterodimer with ZHX3 (via homeobox domain 1). Heterodimerization with ZHX1 is not necessary for repressor activity. Interacts (via homeobox domain) with NFYA (via N-terminus). Interacts with EFNB1 intracellular domain peptide; the interaction enhances ZHX2 transcriptional repression activity.
Activated by phosphorylation on Thr-215. Inhibited by phosphorylation at Ser-219.
Highly expressed in brain and spleen and at lower levels in kidney and skeletal muscle.
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.
Serine/threonine-protein kinase (By similarity). Involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU (By similarity). 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) (PubMed:14517247, PubMed:14741102, PubMed:9108484).
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) (By similarity).
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).
Catalyzes the last step of the oxidative degradation of choline to glycine. Converts sarcosine into glycine.
High levels in liver, lung, kidney, thymus and oviduct, and intermediate levels in the prostate, seminal vesicle, cardiac muscle and neuro-intermediate pituitary lobe. Also expressed in pancreas and adrenal gland.
Expressed in the brain, in the striatum, medial septum, descending arm of the band of Broca, the amygdaloid nucleus, the hippocampus and cortex (at protein level). High levels in the lateral striatum. In rostral brain regions, high expression levels in the dorsal lateral striatum, while in the caudal brain regions, high levels are observed in the ventral lateral striatum (PubMed:2165569, PubMed:10362691, PubMed:10891614, PubMed:16033894). Expressed in monocytes/macrophages (at protein level) (PubMed:23955712). Expressed in striated muscles and in vascular smooth muscles cells (at protein level) (PubMed:10362691, PubMed:26671069).
G-protein coupled receptor for cannabinoids, including endocannabinoids (eCBs), such as N-arachidonoylethanolamide (also called anandamide or AEA) and 2-arachidonoylglycerol (2-AG) (PubMed:2165569). 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. 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 (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. 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 (By similarity). Peripherally modulates energy metabolism. 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 (PubMed:26671069). In response to cannabinoid anandamide, elicits a pro-inflammatory response in macrophages, which involves NLRP3 inflammasome activation and IL1B and IL18 secretion. 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 (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:21895628).
Palmitoylation at Cys-416 is important for recruitment at both plasma membrane and lipid rafts and association with G protein alpha subunits.
Active in vitro against S.aureus, fungi, Gram-positive and Gram-negative bacteria and to a lesser extent against an enveloped virus.
Alleles A, B and C are highly divergent forms of Klrb1b. Alleles A and B differ in their susceptibility to evasion of innate immunity by the rat cytomegalovirus (CMV). In contrast to allele B, allele A shows very low binding of a viral protein mimicking the Klrb1b ligand CLEC2D as well as low susceptibility to this MHC class I-independent viral evasion mechanism.
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 leading to down-regulation of cell activation (By similarity).
Expressed in a subset of natural killer cells.
Homodimer; disulfide-linked. Interacts with tyrosine kinase LCK. Binds PTPN6/SHP-1 in a phosphorylation-dependent manner.
Receptor for CLEC2D/OCIL. Ligand-binding contributes to inhibition of cytotoxic natural killer (NK) cells. May mediate MHC class I-independent 'missing-self' recognition of allografts, tumor cells and virus-infected cells.
Belongs to the thioesterase PaaI family.
Belongs to the RNA polymerase beta' chain family.
Belongs to the tRNA pseudouridine synthase TruA family.
Monomer (By similarity). Forms a complex with RARG and the SRA1 RNA in the nucleus (By similarity).
Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs. Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA. Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3'. Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions. Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing. Involved in regulation of nuclear receptor activity through pseudouridylation of SRA1 mRNA.
Belongs to the universal ribosomal protein uS3 family.
Component of the 40S small ribosomal subunit. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with HNRPD. Interacts with PRMT1; the interaction methylates RPS3. Interacts with SUMO1; the interaction sumoylates RPS3. Interacts with UBC9. Interacts with CDK1; the interaction phosphorylates RPS3. Interacts with PRKCD; the interaction phosphorylates RPS3. Interacts with PKB/AKT; the interaction phosphorylates RPS3. 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. Interacts with the base excision repair proteins APEX1 and OGG1; interaction with OGG1 increases OGG1 N-glycosylase activity. Interacts with UNG; the interaction increases the uracil excision activity of UNG1. Interacts with HSP90; the interaction prevents the ubiquitination and proteasome-dependent degradation of RPS3 and is suppressed by increased ROS levels. Interacts with TOM70; the interaction promotes translocation of RPS3 to the mitochondrion. Interacts (via N-terminus) with RELA (via N-terminus); the interaction enhances the DNA-binding activity of the NF-kappa-B p65-p50 complex. Interacts with NFKBIA; the interaction is direct and may bridge the interaction between RPS3 and RELA. Interacts with IKKB; the interaction phosphorylates RPS3 and enhances its translocation to the nucleus. Interacts (via KH domain) with MDM2 and TP53. Interacts with TRADD. Interacts with CRY1.
Involved in translation as a component of the 40S small ribosomal subunit (By similarity). 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 (By similarity). Displays high binding affinity for 7,8-dihydro-8-oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species (ROS) (By similarity). Has also been shown to bind with similar affinity to intact and damaged DNA (By similarity). Stimulates the N-glycosylase activity of the base excision protein OGG1 (By similarity). Enhances the uracil excision activity of UNG1 (By similarity). Also stimulates the cleavage of the phosphodiester backbone by APEX1 (By similarity). When located in the mitochondrion, reduces cellular ROS levels and mitochondrial DNA damage. Has also been shown to negatively regulate DNA repair in cells exposed to hydrogen peroxide (By similarity). 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 (By similarity). Represses its own translation by binding to its cognate mRNA (By similarity). Binds to and protects TP53/p53 from MDM2-mediated ubiquitination (By similarity). Involved in spindle formation and chromosome movement during mitosis by regulating microtubule polymerization (By similarity). Involved in induction of apoptosis through its role in activation of CASP8 (By similarity). 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 (By similarity). Interacts with TRADD following exposure to UV radiation and induces apoptosis by caspase-dependent JNK activation (By similarity).
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. Phosphorylation by PRKCD occurs on a non-ribosomal-associated form which results in translocation of RPS3 to the nucleus and enhances its endonuclease activity. 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. Phosphorylation by MAPK is required for translocation to the nucleus following exposure of cells to DNA damaging agents such as hydrogen peroxide. Phosphorylation by PKB/AKT mediates RPS3 nuclear translocation, enhances RPS3 endonuclease activity and suppresses RPS3-induced neuronal apoptosis.
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. This is prevented by interaction with HSP90 which stabilizes the protein. 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.
Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
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. Reduces steroids and their derivatives and prostaglandins. Displays low enzymatic activity toward all-trans-retinal, 9-cis-retinal, and 13-cis-retinal. 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. 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).
Identified in the spliceosome C complex. 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 CTNNBL1 in the complex.
Involved in pre-mRNA splicing as component of the spliceosome. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing.
A short soluble form is also released from the membrane by proteolysis. 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. mIL11RA is cleaved by the proteases ADAM10, ELANE and PRTN3.
Belongs to the type I cytokine receptor family. Type 3 subfamily.
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. 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. 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.
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 ZNG1 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.
In vasectomized rats, autoantibodies against Txndc8 are present.
May be required for post-translational modifications of proteins required for acrosomal biogenesis. May act by reducing disulfide bonds within the sperm (By similarity).
Testis-specific. Expressed in spermatozoa, sperm tail, elongated and round spermatids.
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 (By similarity). 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).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5. LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer. 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. The Ragulator complex interacts with SLC38A9; the probable amino acid sensor. 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 LAMTOR2 and LAMTOR3; the interaction is direct (PubMed:19177150). Interacts with RRAGB and RRAGD; the interaction is direct indicating that it probably constitutes the main RAG-interacting subunit of the Ragulator complex. Interacts with MMP14. Interacts with CDKN1B; prevents the interaction of CDKN1B with RHOA leaving RHOA in a form accessible to activation by ARHGEF2 (By similarity). Interacts with PIP4P1 (By similarity).
Belongs to the zinc-containing alcohol dehydrogenase family. Class-IV subfamily.
Catalyzes the NAD-dependent oxidation of all-trans-retinol, alcohol, aldehyde and omega-hydroxy fatty acids and their derivatives. Oxidizes preferentially all trans-retinol, all-trans-4-hydroxyretinol, 9-cis-retinol, 2-hexenol, and long chain omega-hydroxy fatty acids such as juniperic acid. In vitro can also catalyzes the NADH-dependent reduction of all-trans-retinal and aldehydes and their derivatives. Reduces preferentially all trans-retinal, all-trans-4-oxoretinal and hexanal. Catalyzes in the oxidative direction with higher efficiency. Therefore may participate in retinoid metabolism, fatty acid omega-oxidation, and elimination of cytotoxic aldehydes produced by lipid peroxidation.
Retinol oxidation is inhibited by the detergent Tween 80. Ethanol inhibits both all-trans-retinol and 9-cis-retinol oxidation. 13-cis-retinol is an effective competitive inhibitor of the 9-cis-retinol oxidation. All-trans-retinoic acid is a powerful inhibitor of all-trans-retinol oxidation. 13-cis-retinoic acid is a powerful inhibitor of all-trans-retinol oxidation (By similarity). Cimetidine and ranitidine inhibited ethanol oxidation (PubMed:9600267).
Belongs to the Mrp/NBP35 ATP-binding proteins family.
T-box transcription factor that plays an essential role in the determination of the fate of axial stem cells: neural vs mesodermal. Acts in part by down-regulating, a specific enhancer (N1) of SOX2, to inhibit neural development. Seems to also play an essential role in left/right axis determination and acts through effects on Notch signaling around the node as well as through an effect on the morphology and motility of the nodal cilia (By similarity).
Multifunctional enzyme that catalyzes a series of post-translational modifications on Lys residues in procollagen. Plays a redundant role in catalyzing the formation of hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens (By similarity). Plays a redundant role in catalyzing the transfer of galactose onto hydroxylysine groups, giving rise to galactosyl 5-hydroxylysine (By similarity). Has an essential role by catalyzing the subsequent transfer of glucose moieties, giving rise to 1,2-glucosylgalactosyl-5-hydroxylysine residues. Catalyzes hydroxylation and glycosylation of Lys residues in the MBL1 collagen-like domain, giving rise to hydroxylysine and 1,2-glucosylgalactosyl-5-hydroxylysine residues. Catalyzes hydroxylation and glycosylation of Lys residues in the ADIPOQ collagen-like domain, giving rise to hydroxylysine and 1,2-glucosylgalactosyl-5-hydroxylysine residues. Essential for normal biosynthesis and secretion of type IV collagens. Essential for normal formation of basement membranes (By similarity).
The C-terminal domain that mediates lysyl hydroxylase activity is also important for homodimerization.
The N-terminal domain mediates glycosyltransferase activity.
Belongs to the complex I NDUFB2 subunit family.
Central and peripheral nervous systems, synthesized exclusively in neuronal and neuroendocrine cells. VGF and several of the derived peptides are present in the brain.
Interacts with HSPA8 on cell membrane (By similarity). Interacts with C3AR1 (By similarity). Interacts with C1QBP (PubMed:24106277).
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 (PubMed:24704271). Stimulates also feeding behavior in an orexin-dependent manner in the hypothalamus (PubMed:20551287). Functions as a positive regulator for the activation of orexin neurons resulting in elevated gastric acid secretion and gastric emptying (PubMed:28213131).
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 (PubMed:25917832).
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 (PubMed:28123945, PubMed:16983076). Activates the G-protein-coupled receptor C3AR1 via a folding-upon-binding mechanism leading to enhanced lipolysis in adipocytes (PubMed:23940034, PubMed:28123945). Interacts with C1QBP receptor in macrophages and microglia causing increased levels of intracellular calcium and hypersensitivity (PubMed:24106277, PubMed:19466987).
Secreted polyprotein that is packaged and proteolytically processed by prohormone convertases PCSK1 and PCSK2 in a cell-type-specific manner (PubMed:12065665, PubMed:7595538). VGF and peptides derived from its processing play many roles in neurogenesis and neuroplasticity associated with learning, memory, depression and chronic pain (By similarity).
Belongs to the archaeal Rpo12/eukaryotic RPC10 RNA polymerase subunit family.
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. 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. 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; BPTF; RBBP4 and RBBP7 (By similarity). Within the complex interacts with SMARCA1 (By similarity). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP. Interacts with CENPA. Interacts with BRCA1, HDAC7 and SUV39H1 (By similarity). 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 (By similarity).
Acetylated on lysine residues by CREBBP. Deacetylation by LOXL3 leads to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated.
Activated through tyrosine phosphorylation by BMX. Tyrosine phosphorylated in response to IL6, IL11, CNTF, LIF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha and OSM. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. 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. Tyrosine phosphorylated upon stimulation with EGF. Upon LPS challenge, phosphorylated within the nucleus by IRAK1. Phosphorylated on Ser-727 by RPS6KA5 (By similarity). Phosphorylation at Tyr-705 by FER, isoform M2 of PKM (PKM2) or PTK6 leads to an increase of its transcriptional activity. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates IL6/interleukin-6 signaling (By similarity).
Detected in lung, heart, oviduct, ovary, uterus and kidney (at protein level). Detected in ovary, oviduct, and at lower levels in uterus and lung.
Forms a homodimer or a heterodimer with a related family member (at least STAT1). Interacts with IL31RA, NCOA1, PELP1, SIPAR, SOCS7, STATIP1 and TMF1. Interacts with IL23R in presence of IL23. 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 (PubMed:19427337). Interacts with ARL2BP; interaction is enhanced with ARL2. Interacts with NEK6 (By similarity). Binds to CDK9 when activated and nuclear. Interacts with BMX. Interacts with ZIPK/DAPK3. Interacts with PIAS3; the interaction occurs on stimulation by IL6, CNTF or OSM and inhibits the DNA binding activity of STAT3. In prostate cancer cells, interacts with PRKCE and promotes DNA binding activity of STAT3 (By similarity). Interacts with STMN3, antagonizing its microtubule-destabilizing activity (By similarity). Interacts with the 'Lys-129' acetylated form of BIRC5/survivin. Interacts with FER. Interacts (via SH2 domain) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with FGFR4 (By similarity). Interacts with INPP5F; the interaction is independent of STAT3 Tyr-705 phosphorylation status (By similarity). Interacts with OCAD1 (By similarity). Interacts (unphosphorylated or phosphorylated at Ser-727) with PHB1 (By similarity). Interacts and may form heterodimers with NHLH1 (By similarity).
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. Once activated, recruits coactivators, such as NCOA1 or MED1, to the promoter region of the target gene. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4. 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. Activated by IL31 through IL31RA (By similarity). 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 (By similarity). Involved in cell cycle regulation by inducing the expression of key genes for the progression from G1 to S phase, such as CCND1 (By similarity). Mediates the effects of LEP on melanocortin production, body energy homeostasis and lactation. May play an apoptotic role by transctivating BIRC5 expression under LEP activation (By similarity). Cytoplasmic STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity (By similarity). Plays a crucial role in basal beta cell functions, such as regulation of insulin secretion. Plays an important role in host defense in methicillin-resistant S.aureus lung infection by regulating the expression of the antimicrobial lectin REG3G (By similarity).
Some lysine residues are oxidized to allysine by LOXL3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity. Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated.
May participate in suppression of cell proliferation and induces apoptotic cell death through activation of interleukin-1-beta converting enzyme (ICE)-like proteases.
The coiled coil domain is necessary for the homodimerization.
Belongs to the PIGG/PIGN/PIGO family. PIGO subfamily.
Component of the spliceosome B complex. Interacts with SMU1. Interacts with MAD1L1. May interact with DHX15.
Involved in pre-mRNA splicing as a component of the spliceosome. Auxiliary spliceosomal protein that regulates selection of alternative splice sites in a small set of target pre-mRNA species. Required for normal mitotic cell cycle progression. Recruits MAD1L1 and MAD2L1 to kinetochores, and is required to trigger the spindle assembly checkpoint. Required for normal accumulation of SMU1.
Lectin-like receptor for natural killer (NK) cells. Heterodimer formation with KLRE1 mediates NK cell cytolytic activity.
Transcription factor (PubMed:18539116). Recognizes and binds to the regulatory elements of target genes, such as visual system homeobox CHX10, negatively modulating transcription (By similarity). Plays a role in establishing motor neuron identity, in concert with LIM domain transcription factor LMO4 (By similarity). Involved in negatively modulating transcription of interneuron genes in motor neurons, acting, at least in part, by blocking regulatory sequence interactions of the ISL1-LHX3 complex (By similarity). Involved in pancreas development and function; may play a role in pancreatic cell fate specification (By similarity).
Transcriptional activator. Activates the gene for selenocysteine tRNA (tRNAsec). Binds to the SPH motif of small nuclear RNA (snRNA) gene promoters. Participates in efficient U6 RNA polymerase III transcription via its interaction with CHD8 (By similarity).
Belongs to the V-ATPase D subunit family.
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.
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 (By similarity). Associates with KCNE beta subunits that modulates current kinetics (By similarity) (PubMed:21911611). Induces a voltage-dependent by rapidly activating and slowly deactivating potassium-selective outward current (By similarity) (PubMed:11220365). Promotes also a delayed voltage activated potassium current showing outward rectification characteristic (PubMed:11220365). 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:11220365). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current (By similarity). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (By similarity). This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents (PubMed:21911611). 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 (By similarity). When associated with KCNE4, inhibits voltage-gated potassium channel activity (By similarity). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (By similarity). Also forms a heterotetramer with KCNQ5 that has a voltage-gated potassium channel activity (By similarity). Binds with phosphatidylinositol 4,5-bisphosphate (By similarity).
Tetramer. Heterotetramer with KCNE1; targets to the membrane raft. Interacts (via C-terminus) with CALM; forms a heterooctameric structure (with 4:4 KCNQ1:CALM stoichiometry) in a calcium-independent manner. 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. Interacts with KCNE2; form 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. Interacts with AP2M1; mediates estrogen-induced internalization via clathrin-coated vesicles. Interacts with NEDD4L; promotes internalization and decreases I(Ks) currents. Interacts with USP2; counteracts the NEDD4L-specific down-regulation of I(Ks) and restore plasma membrane localization. Heterotetramer with KCNQ5; has a voltage-gated potassium channel activity (By similarity). Interacts with KCNE3; produces a current with nearly instantaneous activation with a linear current-voltage relationship and alters membrane raft localization (By similarity) (PubMed:21911611). Interacts with KCNE4; impairs KCNQ1 localization in lipid rafts and inhibits voltage-gated potassium channel activity. Interacts with KCNE5; impairs KCNQ1 localization in lipid rafts and only conducts current upon strong and continued depolarization (By similarity).
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. 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.
Belongs to the cyclin family. Cyclin E subfamily.
By interleukin-18 and the induction is strongly mediated by an activator protein-1-dependent pathway.
Induces a strong chemotactic response. Induces calcium mobilization. Binds to CXCR6/Bonzo. Also 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).
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).
May play a role in mitochondrial aerobic respiration. May also regulate mitochondrial organization and fission (By similarity).
Plays a role in mitochondrial aerobic respiration. Regulates mitochondrial organization and fission.
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. 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. Responsible also for the proteolytic processing of CLTRN in pancreatic beta cells.
Brain, heart, lung, liver, spleen, testes and kidney; highest in the lung and lowest in the heart.
Forms high-affinity heterodimers with RNASE1, ANG and RNASE2.
Ribonuclease inhibitor which inhibits RNASE1, RNASE2 and ANG. May play a role in redox homeostasis.
The LRR domain forms a horseshoe-shaped structure that interacts tightly with target RNases via a large protein interaction surface on its interior side.
Belongs to the dynein heavy chain family.
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.
Widely expressed both in ciliated and unciliated tissues. Detected in brain and testis (at protein level).
Belongs to the potassium channel family. C (Shaw) (TC 1.A.1.2) subfamily. Kv3.2/KCNC2 sub-subfamily.
Expressed in neurons of the visual cortex during postnatal development (PubMed:18708127). Expressed in neurons of the globus pallidus at postnatal age day 7 (P7), onward (PubMed:10482766). Expressed in thalamic relay neurons. Expressed in neurons in layer IV and deeper cortical layers of the neocortex. Expressed in hippocampal interneurons (PubMed:7643197). Expressed in nonpyramidal interneurons in the basolateral amygdala (PubMed:16413129). Expressed in retinal ganglion cells (at protein level) (PubMed:22831914). Widely expressed in the brain (PubMed:1879548, PubMed:8120636). Expressed in numerous thalamic relay neurons throughout the dorsal thalamus. Expressed in interneurons of the deep layers V-VI of the cerebral cortex, the CA1 and CA3 pyramidal and dentate gyrus (DG) granule cells of the hippocampus, in neurons of the caudate-putamen, globus pallidus and subthalamic nucleus. Also expressed in the optic layer of interior colliculus, the inferior colliculus, the red nucleus, the medial geniculate, the ventral lateral lemiscus, the reticulotegmental nucleus and in the deep cerebellar nuclei (PubMed:1374908, PubMed:8120636, PubMed:7643197, PubMed:18708127). Expressed in globus pallidus (GP) neurons (PubMed:10414968).
Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNC1. Interacts with KCNC1 (PubMed:10482766, PubMed:14679187). Homotetramer or heterotetramer channel activity is regulated by association with modulating ancillary subunits such as KCNE1, KCNE2 and KCNE3, creating a functionally diverse range of channel complexes. Interacts with KCNE1, KCNE2 and KCNE3 (PubMed:14679187).
Inhibited by Stichodactyla helianthus peptide ShK (By similarity). Inhibited by millimolar levels of tetraethylammonium (TEA). Contrary to other channels, inhibited only by millimolar levels of 4-aminopyridine (4-AP) (PubMed:2367536, PubMed:1879548, PubMed:7643197, PubMed:10482766, PubMed:10414303).
Phosphorylated by PKA in cortical synaptosomes (PubMed:7643197). cAMP-dependent phosphorylation inhibits channel activity (PubMed:7643197). Histamine H2 receptor- and PKA-induced phosphorylation extends action potential spike duration, reduces action potential spike amplitude, sustains maximum firing frequency in hippocampal interneurons; also reduces the incidence of high-frequency oscillations in hippocampal CA3 pyramidal cell layers (By similarity).
Up-regulated in visual cortex during the second postnatal week from dark-reared animals (at protein level). Down-regulated in visual cortex by active visual experience until postnatal day P40 of dark-reared animals (PubMed:18708127). Down-regulated by chronic action potential activity deprivation in organotypic culture of the visual cortex (PubMed:18775767).
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Contributes to the regulation of the fast action potential repolarization and in sustained high-frequency firing in neurons of the central nervous system (PubMed:10482766, PubMed:10414968, PubMed:11506885, PubMed:22831914). Homotetramer channels mediate delayed-rectifier voltage-dependent potassium currents that activate rapidly at high-threshold voltages and inactivate slowly (PubMed:2367536, PubMed:1879548, PubMed:8120636, PubMed:7643197, PubMed:10414303). Forms tetrameric channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:2367536, PubMed:1879548, PubMed:8120636, PubMed:7643197). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC1, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:10482766, PubMed:14679187). Channel properties may be modulated either by the association with ancillary subunits, such as KCNE1, KCNE2 and KCNE3 or indirectly by nitric oxide (NO) through a cGMP- and PKG-mediated signaling cascade, slowing channel activation and deactivation of delayed rectifier potassium channels (PubMed:11281123, PubMed:14679187). Contributes to fire sustained trains of very brief action potentials at high frequency in retinal ganglion cells, thalamocortical and suprachiasmatic nucleus (SCN) neurons and in hippocampal and neocortical interneurons (PubMed:10482766, PubMed:10414968, PubMed:11506885, PubMed:22831914). Sustained maximal action potential firing frequency in inhibitory hippocampal interneurons is negatively modulated by histamine H2 receptor activation in a cAMP- and protein kinase (PKA) phosphorylation-dependent manner. Plays a role in maintaining the fidelity of synaptic transmission in neocortical GABAergic interneurons by generating action potential (AP) repolarization at nerve terminals, thus reducing spike-evoked calcium influx and GABA neurotransmitter release. Required for long-range synchronization of gamma oscillations over distance in the neocortex. Contributes to the modulation of the circadian rhythm of spontaneous action potential firing in suprachiasmatic nucleus (SCN) neurons in a light-dependent manner (By similarity).
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 (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.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression.
Phosphorylated by TGF-beta type II receptor.
Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes. Seems to be essential for the formation of spine apparatuses in spines of telencephalic neurons, which is involved in synaptic plasticity.
Depends on the long term potentiation (LTP) and the activation of NMDA receptor signaling.
Expressed at high levels in brain and at moderate, but still significant levels in the heart, skeletal muscle, lung and kidney. In brain, expressed in the cerebral cortex, hippocampus, olfactory bulb and striatum.
First expressed around day 15, increased thereafter, and reached the maximum level of expression in the adult brain. In vitro, in neurons, expression started at 12 dpc, increased thereafter in parallel with process of spine formation, and reached its maximum level after 25 days.
Interacts with BAIAP1. Interacts with actin. Interacts (via PPxY motifs) with WWC1 (via WW domains) (By similarity).
Belongs to the SCAMP family. SCAMP5 subfamily.
Interacts (via C-terminal part) with SYT1 and SYT2; interaction with synaptotagmins making a link with the SNARE molecules. Interacts with SLC9A7 (By similarity).
Required for the calcium-dependent exocytosis of signal sequence-containing cytokines such as CCL5. Probably acts in cooperation with the SNARE machinery (By similarity).
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 (By similarity).
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily.
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). 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. Interacts (phosphorylated on Tyr-766) with PLCG1 (via SH2 domains). Interacts with FRS2. Interacts (via C-terminus) with NEDD4 (via WW3 domain). Interacts with RPS6KA1 (PubMed:15117958). Interacts with KL (By similarity). Interacts with SHB (via SH2 domain) and GRB10. Interacts with ANOS1; this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2. Interacts with SOX2 and SOX3 (By similarity). Interacts with FLRT1, FLRT2 and FLRT3. Found in a ternary complex with FGF1 and ITGAV:ITGB3 (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 (By similarity).
Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by sequential autophosphorylation on tyrosine residues (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Belongs to the cytochrome c oxidase VIIb family.
Belongs to the ubiquitin-conjugating enzyme family. UFC1 subfamily.
E1-like enzyme which specifically catalyzes the second step in ufmylation. Accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms an intermediate with UFM1 via a thioester linkage. Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress.
Interacts with UBA5 (via C-terminus). Interacts with UFL1. Interacts with KIRREL3. Interacts with UFM1.
Belongs to the ClpA/ClpB family. Torsin subfamily.
It may play a role in renal development and may also be involved in the repair of the kidney after ischemia-reperfusion or folic acid administration.
Protein levels accumulate with age in postnatal renal development.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits.
Belongs to the major facilitator superfamily. Vesicular transporter family.
Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports a variety of catecholamines such as dopamine, adrenaline and noradrenaline, histamine, and indolamines such as serotonin (PubMed:1438304, PubMed:8125935, PubMed:8860238, PubMed:8606801, PubMed:25355561). Regulates the transvesicular monoaminergic gradient that determines the quantal size. Mediates somatodendritic dopamine release in hippocampal neurons, likely as part of a regulated secretory pathway that integrates retrograde synaptic signals (PubMed:16301178). Acts as a primary transporter for striatal dopamine loading ensuring impulse-dependent release of dopamine at the synaptic cleft (By similarity). Responsible for histamine and serotonin storage and subsequent corelease from mast cell granules (PubMed:8860238) (By similarity).
Expressed in the substantia nigra and the tuberomammillary nucleus of the posterior hypothalamus (PubMed:8860238). Expressed in stomach, in particular in varicose nerve fibers and enterochromaffin-like cells in the corpus region (at protein level) (PubMed:8860238).
Inhibited by reserpine, ketanserin and tetrabenazine. Not significantly inhibited by vesamicol.
Negative regulator of sphingolipid synthesis. May indirectly regulate endoplasmic reticulum-mediated Ca(+2) signaling (By similarity).
Negative regulator of sphingolipid synthesis. May indirectly regulate endoplasmic reticulum-mediated Ca(+2) signaling.
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 (By similarity).
Phosphorylated on tyrosine residues by ABL1 and ABL2. Phosphorylation at Ser-351 by PRKD1 induces interaction with 14-3-3 proteins (By similarity).
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 (By similarity).
Belongs to the immunoglobulin superfamily. BTN/MOG family.
AC 1 and AC 2 (clusters of acidic amino acids) contain sorting information. AC 1 directs TGN localization and interacts with the TGN sorting protein PACS-1.
Expressed in the intestine, brain, adrenal gland, anterior pituitary, thyroid, ovaries, testis and lung. Highest levels are found in the gut, duodenum, jejunum and ileum. Expression is higher in female than in male reproductive organs.
First detected at 9 dpc in highly restricted regions of the neural tube, in caudal myotomes, and at the materno-embryonic junction of the uterus. At 10 dpc, restricted expression is detected in the optic and otic vesicles, the roof of midbrain, and trunk myotomes. By mid-gestation (13 dpc to 16 dpc), expression in the developing nervous system has expanded to multiple regions including hippocampus, thalamus, hypothalamus, brain stem, and spinal cord. Expression is also detected in several peripheral organ systems, including gut, lung, adrenal and kydney primordia.
Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif. Likely functions in the constitutive and regulated secretory pathways. Plays an essential role in pregnancy establishment by proteolytic activation of a number of important factors such as BMP2, CALD1 and alpha-integrins. May be responsible for the maturation of gastrointestinal peptides. May be involved in the cellular proliferation of adrenal cortex via the activation of growth factors.
The propeptide domain acts as an intramolecular chaperone assisting the folding of the zymogen within the endoplasmic reticulum.
Belongs to the VPS10-related sortilin family. SORT1 subfamily.
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. 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 (By similarity). May also mediate transport from the endoplasmic reticulum to the Golgi (PubMed:12771154).
Highly expressed in fat, brain, and lung. Expressed in neuronal bodies and dendrites of the piriform cortex and hippocampus. Also expressed in the islands of Calleja, medial and lateral septal nuclei, amygdaloid nuclei, thalamic nuclei, the supraoptic nucleus, the substantia nigra, the Purkinje layer of the cerebellar cortex and the cranial motor nerve nuclei of the brainstem.
Interacts with LPL and SLC2A4 (By similarity). Interacts with the cytosolic adapter proteins GGA1 and GGA2. 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) (PubMed:15987945). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; may regulate their anterograde axonal transport and signaling. Interacts with CLN5. Interacts with PSAP. Interacts with GRN; this interaction mediates endocytosis and lysosome delivery of progranulin; interaction occurs at the neuronal cell surface in a stressed nervous system (By similarity). 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 (By similarity). Interacts with SMPD1; the interaction is required for SMPD1 targeting to lysosomes (By similarity).
Palmitoylated. 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.
Phosphorylation at Ser-819 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 (By similarity).
The extracellular domain may be shed following protease cleavage in some cell types.
Belongs to the TFIIF alpha subunit family.
Heterodimer of an alpha and a beta subunit. Interacts with GTF2F2, CTDP1, TAF6/TAFII80 and URI1 (By similarity). Interacts with GTF2B (via C-terminus and preferentially via acetylated form); this interaction prevents binding of GTF2B to GTF2F2 (By similarity).
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 (By similarity).
Expressed at a low level in normal kidney but are increased dramatically in postischemic kidney. Expressed in proliferating bromodeoxyuridine-positive and dedifferentiated vimentin-positive epithelial cells in regenerating proximal tubules.
Interacts with STAM. Interacts with SELPLG.
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. Controls thereby T-cell accumulation in the inflamed central nervous system (CNS) and the induction of autoimmune disease (By similarity). Regulates also expression of various anti-inflammatory cytokines and co-inhibitory ligands including IL10. Acts as regulator of T-cell proliferation (By similarity). May play a role in kidney injury and repair (By similarity).
Belongs to the glycerate kinase type-2 family.
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 (By similarity). 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 (By similarity).
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).
Belongs to the MsrB Met sulfoxide reductase family.
AKT2 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinases, 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.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.
Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PIK3CA) results in its targeting to the plasma membrane.
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 PH domain) with MTCP1, TCL1A and TCL1B. Interacts with TRAF6. Interacts (when phosphorylated) with CLIP3, the interaction promotes cell membrane localization (By similarity). Interacts with CLK2 (PubMed:20074525). Interacts with WDFY2 (via WD repeats 1-3) (By similarity).
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 so far 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. 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.
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 (By similarity).
Controls the reversible conversion of biologically active glucocorticoids such as 11-dehydrocorticosterone to corticosterone using NADP(H) (PubMed:12460758, PubMed:8613810, PubMed:14973125). Participates in the corticosteroid receptor-mediated anti-inflammatory response, as well as metabolic and homeostatic processes (By similarity). Bidirectional in vitro, predominantly functions as a reductase in vivo, thereby increasing the concentration of active glucocorticoids (PubMed:12460758). It has broad substrate specificity, besides glucocorticoids, it accepts other steroid and sterol substrates (PubMed:14973125). 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 (By similarity). Catalyzes the stereo-specific conversion of the major dietary oxysterol, 7-ketocholesterol (7-oxocholesterol), into the more polar 7-beta-hydroxycholesterol metabolite (PubMed:14973125). 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 (By similarity). 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 (By similarity). 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 (By similarity).
Expression of both isoforms is found in 1 week-old rats. Expression increases exponentially up to 4 weeks but after this time there is no further increase up to 16 weeks.
Liver, kidney, lung and testis (PubMed:2808402). Brain (PubMed:2387261). Expressed in liver (at protein level) (PubMed:21453287).
Belongs to the phosphatase and actin regulator family.
Binds actin and PPP1CA; thus inhibiting the protein phosphatase 1 (PP1) activity.
Diffusely expressed throughout the brain cortex, with highest levels in the cortex and the hippocampus and lower levels in the striatum and thalamus.
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 (By similarity).
Predominantly monomeric and to lesser extent homodimeric in endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and trans-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 (By similarity).
Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2 (By similarity). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs) (PubMed:17880894, PubMed:19234459). Interacts with GRIA1 (PubMed:17880894).
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), including GRIA1 and GRIA4. Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization (PubMed:17880894, PubMed:19234459).
Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.
Can homomultimerise (PubMed:27756895). Interacts with CACNG2 (PubMed:27756895). Interacts (via the SH3-Guanylate kinase-like sub-module) with DLG4/PSD95 and DLGAP1/GKAP (PubMed:27756895). Interacts (via the PDZ domain) with CADM1 (via C-terminus) (PubMed:27756895). Interacts with KCNN2/SK2 (via N-terminal domain) (By similarity). Interacts with SRC (By similarity).
Postsynaptic MAGUK scaffold protein that links CADM1 cell adhesion molecules to core components of the postsynaptic density (PubMed:27756895). 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 (By similarity).
Belongs to the cytochrome c oxidase IV 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)) (By similarity). Interacts with PHB2; the interaction decreases in absence of SPHK2 (By similarity). Interacts with AFG1L (By similarity). Interacts with ABCB7; this interaction allows the regulation of cellular iron homeostasis and cellular reactive oxygen species (ROS) levels in cardiomyocytes (PubMed:31511561).
Expressed in the pituitary, in brain, in particularly in supraoptic and paraventricular nuclei and the choroid plexus. Also found abundantly in the corpus luteum of the ovary and in kidney glomeruli. Expressed in the ductal epithelial cells of post-pubertal mammary glands. Expressed in the ductal and alveolar epithelial cells throughout the whole period of gestational evolution, lactation and involution.
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. May play a role in increasing vascular permeability during lactation, when increased transport of molecules from the blood is required for efficient milk protein synthesis. 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 (By similarity).
Homodimer; disulfide-linked (PubMed:7706320). Also found as heterodimer with PGF (PubMed:7706320). Interacts with NRP1 (By similarity). Interacts with isoform 2 of BSG (By similarity).
Increases during pregnancy (5.0-fold increase on day 12 with a subsequent decrease on day 18) and during lactation (18.5-fold increase on day 7). Levels appear to be minimally altered during involution.
Expression restricted to a few regions in the brain: thalamic, tectal and brainstem structures that include relay nuclei of the visual and auditory systems as well as other ascending systems conveying somatosensory information. Not expressed in kidney, heart, lung, tongue and adrenal gland.
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.
Neural expression in lateral and medial geniculate complex, superior and inferior colliculus, superficial gray layer of the superior colliculus, pontine reticular formation and inferior olive. Also expressed in non-neuronal structures around the oral cavity and in hip and shoulder regions.
Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
Heterotetramer of two alpha-3 chains and two beta chains (the beta chain is the multi-functional PDI).
N-glycosylation plays no role in the catalytic activity.
Acts as an adapter for the myotubularin-related phosphatases. Regulates phosphatase MTM1 protein stability and possibly its intracellular location. By stabilizing MTM1 protein levels, required for skeletal muscle maintenance but not for myogenesis.
Although it belongs to the non-receptor class myotubularin subfamily, lacks the conserved active site cysteine residue at position 392 in the dsPTPase catalytic loop and does not have phosphatase activity.
Heterodimer with lipid phosphatase MTM1 (By similarity). Heterodimer with lipid phosphatase MTMR2 (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA methyltransferase RlmE family.
Belongs to the BI1 family. LFG subfamily.
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 (By similarity).
Interacts via its C-terminal region with the CH1 domain of CREBBP and EP300. Interacts with all TFAP2/AP-2 isoforms (By similarity).
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).
Ubiquitous. Detected in aorta, brain, gut, heart, kidney, liver, spleen, uterus and skeletal muscle.
Regulatory subunit of L-type calcium channels that consist of a pore-forming alpha subunit and auxiliary beta, gamma and delta subunits (PubMed:21127204). 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 (By similarity). 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) (PubMed:21127204). Part of a L-type calcium channel complex that contains CACNA1D, CACNA2D1 and CACNB1. Part of a L-type calcium channel complex that contains CACNA1B, CACNA2D1 and CACNB1 (By similarity). Interacts with JSRP1. Interacts with RYR1 (By similarity). Interacts with CBARP (PubMed:24751537).
Regulatory subunit of L-type calcium channels. 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 (Probable). Required for functional expression L-type calcium channels that contain CACNA1D as pore-forming subunit. Regulates the activity of L-type calcium channels that contain CACNA1B as pore-forming subunit (By similarity).
Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. 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.
Detected both in virgin rats and after mammary gland involution. The level of STAT5A increases constantly during pregnancy, but decreases at the onset of lactation and remains lows throughout lactation.
Expressed in heart, lung, and weakly in muscle.
Forms a homodimer or a heterodimer with a related family member. Binds NR3C1. Interacts with NCOA1 and SOCS7. Interacts with ERBB4 (By similarity). Interacts with EBF4.
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 (By similarity). Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4 (PubMed:22673903). 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. Alternatively, can be phosphorylated by JAK2 at Tyr-694 (By similarity).
Inhibitor of PPP1CA. Has over 1000-fold higher inhibitory activity when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction (By similarity).
Belongs to the proteasome subunit S9 family.
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. 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). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; by mediating ubiquitination of WNK4. 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. 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. 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. 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. The BCR(KLHL25) ubiquitin ligase complex is involved in translational homeostasis by mediating ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1). The BCR(KLHL25) ubiquitin ligase complex is also involved in lipid synthesis by mediating ubiquitination and degradation of ACLY. 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. 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. 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. The BCR(KLHL24) E3 ubiquitin ligase complex mediates ubiquitination of KRT14, controls KRT14 levels during keratinocytes differentiation, and is essential for skin integrity. 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. 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. As part of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex functions mediates 'Lys-48' ubiquitination and proteasomal degradation of TIAM1. 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.
Forms neddylation-dependent homodimers (By similarity). 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 (By similarity). 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 (By similarity). Interacts with RBX1, RNF7, CYCE and TIP120A/CAND1 (By similarity). Part of the BCR(SPOP) containing SPOP, and of BCR containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL (By similarity). Part of the probable BCR(KLHL9-KLHL13) complex with BTB domain proteins KLHL9 and KLHL13 (By similarity). Part of the BCR(KLHL41) complex containing KLHL41 (By similarity). Component of the BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL12 and RBX1 (By similarity). Component of the BCR(KLHL3) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL3 and RBX1 (By similarity). Part of the BCR(ENC1) complex containing ENC1 (By similarity). Part of a complex consisting of BMI1/PCGF4, CUL3 and SPOP (By similarity). Part of a complex consisting of BRMS1, CUL3 and SPOP (By similarity). Component of the BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL21 and RBX1 (By similarity). Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1 (By similarity). Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL25 and RBX1 (By similarity). Part of a complex consisting of MACROH2A1, CUL3 and SPOP (By similarity). Component of the BCR(KLHL42) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL42 (By similarity). Component of the BCR(KBTBD8) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD8 and RBX1 (By similarity). Interacts with KLHL42 (via the BTB domain) (By similarity). Interacts with KATNA1; the interaction is enhanced by KLHL42 (By similarity). Interacts with KCTD5, KLHL9, KLHL11, KLHL13, GAN, ZBTB16, KLHL3, KLHL15, KLHL20, KLHL36, GMCL2, BTBD1 (By similarity). Part of a complex that contains CUL3, RBX1 and GAN (By similarity). Interacts (via BTB domain) with KLHL17; the interaction regulates surface GRIK2 expression (By similarity). Interacts with KCTD7 (By similarity). Part of the BCR(GAN) complex containing GAN (By similarity). Part of the BCR(KEAP1) complex containing KEAP1 (By similarity). vInteracts with KLHL10 (By similarity). Interacts with KAT5 and ATF2 (By similarity). Interacts with KCTD17 in the BCR(KCTD17) E3 ubiquitin ligase complex, at least composed of CUL3, KCTD17 and RBX1 (By similarity). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (By similarity). Interacts with COPS9 (By similarity). Interacts with PPP2R5B; this interaction is indirect and mediated through KLHL15-binding and leads to PPP2R5B proteasomal degradation (By similarity). Interacts with RBBP8/CtIP; this interaction is indirect and mediated through KLHL15-binding and leads to RBBP8 proteasomal degradation (By similarity). Interacts with KLHL24 in the BCR(KLHL24) E3 ubiquitin ligase complex, composed of CUL3, RBX1 and KLHL24 (By similarity). Interacts with RHOBTB2 (By similarity). Interacts (via BTB domain) with KLHL17; the interaction regulates surface GRIK2 expression (PubMed:17062563). Interacts with AURKA and KLHL18 (via BTB domain) (By similarity). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (By similarity). 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 (By similarity).
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.
Mainly expressed in several neuronal tissues and developing tissues.
Phosphorylated. Phosphorylation of Ser-34 and Ser-217 by MAPK14 enhances its transcriptional activity. Phosphorylation by CaMK2 increases its protein stability (By similarity).
Present at high levels in embryos on embryonic day 14 (14 dpc), in skeletal tissues on 18 dpc, and in adult brain. At lower levels in newborn rib cartilage, embryo soft tissues on 18 dpc, newborn skin and adult heart.
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 (By similarity).
Regulates osteoclastic bone resorption, probably via production of cyclic ADP-ribose and triggering of a cytosolic calcium ion signal through ryanodine receptor activation.
Spleen, liver, heart, thymus, thyroid gland, ileum, colon, cerebellum, salivary gland, adrenal gland, jejunum, islets of Langerhans and osteoclasts.
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.
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. 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 (By similarity).
N-glycosylated; required for activity and stability.
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.
Expressed at low levels in adult brain. Strongly expressed in parts of the neonatal brain, including the septum and the thalamus.
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 (By similarity).
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.
Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. 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. Interacts with HAX1. Interacts with BOK; translocates to the cytoplasm (By similarity). Interacts with HSP90AB1 (By similarity).
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. 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 (By similarity).
At 15.5 dpc, detected in axons extending from habenula nucleus explants (at protein level). Expressed in the habenula nucleus at 13.5 dpc and 15.5 dpc, and in the prosomere 2 adjacent to the fasciculus retroflexus at 15.5 dpc.
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). 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.
Dioxygenase that mediates demethylation of DNA and RNA containing 1-methyladenosine (m1A). Repairs alkylated DNA containing 1-methyladenosine (m1A) and 3-methylcytosine (m3C) by oxidative demethylation. Has a strong preference for single-stranded DNA. 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. Can repair exocyclic 3,N4-ethenocytosine adducs in single-stranded DNA. Also acts on RNA. 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. Requires molecular oxygen, alpha-ketoglutarate and iron.
Interacts with the ASCC complex composed of ASCC1, ASCC2 and ASCC3. Interacts directly with ASCC3, and is thereby recruited to the ASCC complex. Interacts with OTUD4; the interaction is direct. Interacts with USP7 and USP9X.
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.
Belongs to the small GTPase superfamily. SAR1 family.
Homodimer. Dimerization does not affect PPP2R5B-binding, but is required for its proteasomal degradation. Interacts with CUL3. Directly interacts with PPP2R5B; this interaction leads to PPP2R5B proteasomal degradation. Interacts with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal degradation. Interacts with PACMP micropeptide; interaction prevents ubiquitination and degradation of RBBP8/CtIP.
Substrate-specific adapter for CUL3 E3 ubiquitin-protein ligase complex. 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 and regulating PP2A holoenzyme composition. Acts as an adapter for CUL3 to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. 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).
Widely expressed at the mRNA level, with the highest levels in lung, muscle, and spleen.
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.
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.
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.
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.
Homodimer. Heterodimer with HTR1D (By similarity).
Ligands are bound in a hydrophobic pocket formed by the transmembrane helices.
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 (By similarity).
As a co-chaperone for HSPA5 it is required for proper folding, trafficking or degradation of proteins. 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. May help recruiting HSPA5 and other chaperones to the substrate. Stimulates HSPA5 ATPase activity. It is necessary for maturation and correct trafficking of PKD1.
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 (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. Binds to denatured substrates in an ATP-independent manner. Interacts via the J domain with HSPA5 in an ATP-dependent manner (By similarity).
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. Interacts with JUN, independently of JUN phosphorylation. Interacts (via C-terminus) with TRIM7.
The RING-CH-type zinc finger domain is required for E3 ligase activity.
Ubiquitinated; undergoes 'Lys-48'-linked autoubiquitination in the absence of growth factors and MAP3K1-induced 'Lys-63'-linked polyubiquitination. 'Lys-48'-autoubiquitination leads to degradation by the proteasome, while MAP3K1-induced 'Lys-63'-linked polyubiquitination results in the stabilization of the protein. 'Lys-48'- and 'Lys-63'-linked polyubiquitinations occur most probably on the same 3 C-terminal lysine residues (Lys-195, Lys-224 and Lys-225) and are thus mutually exclusive. Other sites of ubiquitination are not excluded. 'Lys-63'-linked polyubiquitination by TRIM7 in response to growth factor signaling via the MEK/ERK pathway enhances protein stability.
Abundant in all cerebral cortical layers, especially the piriform cortex, the pyramidal cells of the CA1-CA3 subfields of the hippocampus, as well as the granular layer of the dentate gyrus. Detected in the internal granular layer and the mitral cell layer of the olfactory bulb; in the medial habenular nucleus; and in amygdaloid, thalamic, hypothalamic, and pontine nuclei. In the cerebellum, found at high levels in the granular layer. Detected in the lateral ventricle. Expression overlaps with 5-HT2C receptor expression in all regions of the brain including the choroid plexus, where 5-HT2C receptors are highly enriched.
Interacts with F11R/JAM, CLDN1, NG2, CXADR, CRB1, MPP4 and PALS1, HTR2A, HTR2B, PLEKHA1/TAPP1 and PLEKHA2/TAPP2. Interacts with CXADR (By similarity). Interacts with HTR2C, CLDN5, DLG4, GRIN1, SYNGAP1, CAMK2A and CAMK2B. Interacts with FAT4 (via cytoplasmic domain) (By similarity). Interacts with DLL1 (By similarity).
Member of the NMDAR signaling complex that may play a role in control of AMPAR potentiation and synaptic plasticity in excitatory synapses (PubMed:15312654). Promotes clustering of HT2RC at the cell surface (PubMed:11150294).
Sequestered into cytoplasmic, detergent-resistant bodies upon Ad9 E4-ORF1 oncoprotein expression. Targeted to degradation upon HPV-18 E6 oncoprotein expression.
The PDZ domain 1 binds NG2. The PDZ domain 2 mainly binds CAMK2A and CAMK2B. The PDZ domain 9 binds F11R. The PDZ domain 10 binds the C-terminus of CLDN1 and KIT. The PDZ domains 10 and 13 bind PLEKHA1 and PLEKHA2. The PDZ domain 13 binds CXADR and SYNGAP1 (By similarity). The PDZ domains 7 and 10 bind the Ad9 E4-ORF1 oncoprotein. The PDZ domain 10 binds the C-terminal PDZ-binding motif of HTR2C.
Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as ARVCF (By similarity). Interacts (via the extreme C-terminus) with FRMPD2 (via the PDZ 2 domain). Interacts with CCDC85B (By similarity).
Contributes to the regulation of alternative splicing of pre-mRNAs.
Expressed in optic nerve sheath envelope (at protein level) (PubMed:29445566). Expressed in heart (at protein level) (PubMed:31384490).
Interacts with HOOK2. Interacts with ZFC3H1 in a RNase-sensitive manner.
Involved in poly(A) tail length control in neuronal cells. Binds the polyadenosine RNA oligonucleotides.
Particularly abundantly in adrenal glands.
May be involved in the negative regulation of skeletal muscle differentiation, independently of its glycerophosphocholine phosphodiesterase activity.
C2 domains are necessary for calcium-dependent cell membrane association. C2 domains are necessary for neuronal progenitor cell differentiation in a calcium-independent manner.
Calcium-dependent phospholipid-binding protein that plays a role in calcium-mediated intracellular processes. Involved in the TNF-alpha receptor signaling pathway in a calcium-dependent manner. Exhibits calcium-dependent phospholipid binding properties. Plays a role in neuronal progenitor cell differentiation; induces neurite outgrowth via a AKT-dependent signaling cascade and calcium-independent manner. May recruit target proteins to the cell membrane in a calcium-dependent manner. May function in membrane trafficking. Involved in TNF-alpha-induced NF-kappa-B transcriptional repression by inducing endoprotease processing of the transcription factor NF-kappa-B p65/RELA subunit. Also induces endoprotease processing of NF-kappa-B p50/NFKB1, p52/NFKB2, RELB and REL.
Expressed in liver, brain, heart, intestine, kidney and lung (at protein level) (PubMed:11123945).
Homodimer; homodimerizes via its C2 domains. Interacts with p65/RELA (via N-terminus); this interaction induces proteolytic cleavage of p65/RELA subunit and inhibition of NF-kappa-B transcriptional activity. Interacts (via VWFA domain) with ACTB, CCDC22, MYCBP2, PPP5C, RDX and UBE2O.
Binds to the Fc region of immunoglobulins epsilon. High affinity receptor. Responsible for initiating the allergic response. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators (such as histamine) responsible for the manifestations of allergy. The same receptor also induces the secretion of important lymphokines.
Exhibits night/day variations with a 15-fold increased expression at night in the pineal gland. Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway (at protein level).
Expressed in leukocytes and pinealocytes at night (at protein level).
Tetramer of an alpha chain, a beta chain, and two disulfide linked gamma chains.
Belongs to the AB hydrolase superfamily. ABHD14 family.
Possible role in granule neuron development.
Interacts (via cytoplasmic region) with ILK.
Belongs to the universal ribosomal protein uL18 family.
Component of the large ribosomal subunit (LSU). Part of a LSU subcomplex, the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11. Interacts with NVL in an ATP-dependent manner. Interacts with RRP1B (By similarity). Interacts with IPO5, IPO7 and KPNB1; these interactions may be involved in RPL5 nuclear import for the assembly of ribosomal subunits (By similarity).
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs. It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53. Interacts with RRP1B.
Interacts with GNAQ. Does not interact with GNAI1 and GNAI3. Interacts with EIF2B5. Interacts with PRKG1 (isoform alpha).
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 (By similarity). It is involved in the negative regulation of the angiotensin-activated signaling pathway (By similarity). 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 (By similarity).
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.
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.
Homomultimer and heteromultimer with other K-Cl cotransporters.
Intron retention. This sequence is incomplete at its 3'end and extensively differs from that shown in positions 214-251.
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (By similarity). 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).
Widely expressed with highest levels in kidney, liver and pancreas. Expressed in choroid plexus and suprachiasmatic nucleus.
Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.
Hydrolyzes extracellular Ap3A into AMP and ADP, and Ap4A into AMP and ATP. Ap3A and Ap4A are diadenosine polyphosphates thought to induce proliferation of vascular smooth muscle cells. Acts as a procoagulant, mediating platelet aggregation at the site of nascent thrombus via release of ADP from Ap3A and activation of ADP receptors.
Diabetes-prone biobreeding (DP-BB) rats have a frameshift mutation in Gimap5, which results in a truncated protein in which the C-terminal 215 amino acids, including the membrane anchor, are replaced by 19 other amino acids. These animals exhibit life-long T-cell lymphopenia, including lack of regulatory T cells, and spontaneously develop insulin-dependent diabetes resembling human type 1 diabetes.
Down-regulated during T lymphocyte activation.
Interacts with BAD, BAK1, BAX, BCL2, BCL2L1/Bcl-xL and BCL2L11/BimEL (By similarity). The interaction with BAX is increased, when cells initiate apoptosis upon IL2 withdrawal (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 (Probable).
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 (By similarity). 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). Promotes the survival of quiescent T-cells (PubMed:15307172). May regulate Ca(2+) homeostasis by modulating lysosomal Ca(2+) stores, preventing its accumulation in the absence of T cell activation (PubMed:28223986). May play a role in mitochondrial DNA segregation in hematopoietic tissues (By similarity). Is a regulator of liver endothelial cell homeostasis (By similarity).
Primarily expressed in spleen, heart, lung and intestine and, at lower levels, in kidney, stomach and muscle (PubMed:12031988). Expressed in thymus and lymph nodes (at protein level) (PubMed:12031988, PubMed:12930893, PubMed:21487483). In the spleen, expressed in periarteriolar lymphatic sheets (PubMed:12031988). Isoform 2: Expressed at higher levels in T lymphocytes compared to isoform 1 (PubMed:28223986).
Required for mitochondrial integrity and T-cell survival. May contribute to T-cell quiescence.
Expressed in the dorsal root ganglion neurons (at protein level).
Forms heterodimers with NEFL; which can further hetero-oligomerize (in vitro) (PubMed:9388258). Forms heterodimers with INA (in vitro) (PubMed:9388258).
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.
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, PSMB6 displays a peptidylglutamyl-hydrolyzing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.
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.
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.
Belongs to the acetyltransferase family. GNA1 subfamily.
Heterodimer with Kell; disulfide-linked. Interacts with VPS13A.
Recruits the lipid transfer protein VPS13A from lipid droplets to the endoplasmic reticulum (ER) membrane.
Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis. Modulates the secretion of AIMP1 and may be involved in generation of the inflammatory cytokine EMAP2 from AIMP1.
Interacts (via N-terminus) with AIMP1 (via N-terminus); this stimulates its catalytic activity. Interacts (via N-terminus) with LARS2 (via C-terminus). Monomer. 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. Interacts with QARS1. Part of a complex composed of RARS1, QARS1 and AIMP1.
The alpha-helical N-terminus (residues 1-72) mediates interaction with AIMP1 and thereby contributes to the assembly of the multisynthetase complex.
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. Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex.
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 (By similarity). Cleavage is blocked by ubiquitin aldehyde.
Expressed in mesangial cells of the kidney. Isoform 1 and isoform 2 are expressed in elongated spermatids; the shorter form appearing earlier than the longer form (at protein level). Isoform 1 and isoform 2 are expressed in early round spermatids of the testis. Isoform 1 is expressed in muscle and heart. Isoform 2 is expressed in muscle, lung, heart, brain, liver and ovary. During muscle differentiation, isoform 1 expression increases before the onset of membrane fusion and decreases as the myogenic processes proceeded; un counterpart, isoform 2 expression remains low until the burst of membrane fusion but increases thereafter.
Homooligomer. 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 (By similarity). Interacts with PER1. Interacts with KCNQ1; counteracts the NEDD4L-specific down-regulation of I(Ks) and restores plasma membrane localization of KCNQ1 (By similarity). Isoform 4: Interacts with PDZD3 and CLTC (By similarity).
Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1 (By similarity). Isoform 1 and isoform 2 possess both ubiquitin-specific peptidase and isopeptidase activities (PubMed:12107281). Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity (By similarity). Has no deubiquitinase activity against p53/TP53 (By similarity). Prevents MDM2-mediated degradation of MDM4 (By similarity). Plays a role in the G1/S cell-cycle progression in normal and cancer cells (By similarity). Regulates the circadian clock by modulating its intrinsic circadian rhythm and its capacity to respond to external cues (PubMed:23213472). Associates with clock proteins and deubiquitinates core clock component PER1 but does not affect its overall stability (PubMed:23213472). 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 (PubMed:12107281).
Inhibits both membrane fusion during myogenesis and accumulation of muscle-specific proteins.
Stimulates both membrane fusion during myogenesis and accumulation of muscle-specific proteins.
The different N-terminus extensions of isoform 1 and isoform 2 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 2 are not essential for their catalytic activity.
Up-regulated by IL-1. Isoform 1 is up-regulated with any signal for withdrawal from the cell cycle such as serum deprivation.
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.
Inhibits urokinase-type plasminogen activator.
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.
Expressed in brain and other neural tissues.
Inhibited by the sodium/calcium exchanger inhibitor CGP-37157. Strongly inhibited by zinc.
Mitochondrial sodium/calcium antiporter that mediates sodium-dependent calcium efflux from mitochondrion, by mediating the exchange of 3 sodium ions per 1 calcium ion. Plays a central role in mitochondrial calcium homeostasis by mediating mitochondrial calcium extrusion: calcium efflux is essential for mitochondrial function and cell survival, notably in cardiomyocytes (By similarity). Regulates rates of glucose-dependent insulin secretion in pancreatic beta-cells during the first phase of insulin secretion: acts by mediating efflux of calcium from mitochondrion, thereby affecting cytoplasmic calcium responses. Required for store-operated Ca(2+) entry (SOCE) and Ca(2+) release-activated Ca(2+) (CRAC) channel regulation: sodium transport by SLC8B1 leads to promote calcium-shuttling that modulates mitochondrial redox status, thereby regulating SOCE activity (By similarity). Involved in B-lymphocyte chemotaxis (By similarity). Able to transport Ca(2+) in exchange of either Li(+) or Na(+), explaining how Li(+) catalyzes Ca(2+) exchange. In contrast to other members of the family its function is independent of K(+) (By similarity).
Phosphorylation at Ser-258 by PKA prevents calcium overload.
Widely expressed. Present at higher level in pancreas, stomach, skeletal muscle and skin (at protein level). Ubiquitously expressed.
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.
Interacts with LMNA and binds to the farnesylated C-terminal domain.
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.
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.
Belongs to the peptidase M67A family. CSN6 subfamily.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes.
Homodimer; binds DNA as homodimer. Heterodimer; heterodimerizes with other members of ATF family and with JUN family members.
Stress-responsive chromatin regulator that plays a role in various biological processes including innate immunological memory, adipocyte differentiation or telomerase regulation. 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. 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. In response to TNF-alpha, which is induced by various stresses, phosphorylated ATF7 and telomerase are released from telomeres leading to telomere shortening.
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. Additionally, displays dehydratase activity, toward hydroperoxyeicosatetraenoates (HPETEs), especially toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE).
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 (By similarity).
Heterodimer with RAP1GAP (By similarity). Interacts with EPAC2 (By similarity). Interacts with SGSM1 (By similarity). Interacts with SGSM2 (By similarity). Interacts with SGSM3 (By similarity). Interacts with KRIT1 (By similarity). Interacts with RAP1GDS1 (By similarity).
Expressed in the central nervous system; especially in neurons.
Functions as a scaffold protein in neurons 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 (PubMed:10896157). Interacts (via C-terminus) with MAPK8/JNK1 and with 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 (PubMed:20098723).
Proteolytically cleaved by caspase-3 (PubMed:10896157). A minor C-terminal proteolytic fragment of 30 kDa is produced (PubMed:10896157). Proteolytic cleavage is required for JNK signaling activation (PubMed:17761173).
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.
Component of the conserved oligomeric Golgi complex which is composed of eight different subunits and is required for normal Golgi morphology and localization.
Belongs to the protein prenyltransferase subunit alpha 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. GRIK5 subfamily.
From embryonic day 14 through postnatal day 1, high expression in spinal cord, brain and some areas of the PNS. At 17 dpc and 19 dpc, high expression in spinal cord, mesencephalon and telencephalic structures as in olfactory neurons and in nasal epithelium. Strong expression also in the pituitary.
High expression in the cerebral cortex, pyriform cortex, caudate-putamen, hippocampal complex, medial habenulata and granule cell layer of the cerebellum. Weak expression in globus pallidus, thalamus, colliculi and the reticular thalamic nucleus.
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. This receptor binds kainate > quisqualate > glutamate >> AMPA.
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.
Belongs to the PPP phosphatase family. PP-2B subfamily.
Interacts with KNDC1 (via KIND2); the interaction enhances MAP2 phosphorylation and localizes KNDC1 to dendrites. Interacts with DPYSL5 (By similarity).
Isoform 3/MAP2c is expressed during embryonic brain development and until postanatal day 10. Isoform 2 is expressed throughout brain development.
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. Isoform 3/MAP2c is probably phosphorylated by PKA at Ser-319, Ser-350 and Ser-382 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.
Homodimer. Binds TNFRSF1A. Interacts with PIP4K2A; the interaction suppresses ubiquitination by the SPOP/CUL3 complex (By similarity). Probably interacts with PIP5K1A; the interaction inhibits PIP5K1A kinase activity (By similarity).
Participates in the biosynthesis of phosphatidylinositol 4,5-bisphosphate (PubMed:9685379). Preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation and its activity reflects changes in direct proportion to the physiological GTP concentration. Its GTP-sensing activity is critical for metabolic adaptation (By similarity). 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 (By similarity).
Ubiquitinated by the SPOP/CUL3 complex. Ubiquitination is stimulated by PtdIns5P levels.
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. In kidney podocytes, plays a role in podosomes and filopodia formation through CDC42 activation (PubMed:33523862).
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.
Mainly expressed in brain. Highly expressed in accessory olfactory bulb, caudate-putamen, cerebellum, cerebral cortex, dentate gyrus of the hippocampus, islands of Calleja, olfactory bulb and supraoptic nucleus. Expressed in kidney glomeruli podocytes (at protein level) (PubMed:33523862).
Belongs to the endothelin/sarafotoxin family.
Disulfide isomerase which catalyzes the formation, isomerization, and reduction or oxidation of disulfide bonds (By similarity). Associates with calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells (By similarity). Association with calcitriol does not affect its enzymatic activity (By similarity).
In caput epididymal spermatozoa, detected in the head, mid and principal pieces. In cauda epididymal spermatozoa detected only in the acrosome (at protein level).
Seems to be inhibited by acidic phospholipids.
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 (By similarity). Interacts with MZB1 in a calcium-dependent manner (By similarity). Interacts with SERPINA2 and with the S and Z variants of SERPINA1. Interacts with ATP2A2 (By similarity).
Was originally thought to be a phosphatidyl-inositol 4,5-bisphosphate phosphodiesterase type I (phospholipase C-alpha) then was thought (PubMed:1321829 and PubMed:1330685) to be a thiol protease.
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.
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.
Binds phosphatidylinositol 4,5-bisphosphate (PIP2). May play a role in the organization of nuclear PIP2, cell division and cell survival.
Monomer and homodimer. Interacts with SDCBP (PubMed:11152476). Interacts with TM4SF1.
The two PDZ domains mediate the interaction with phosphatidylinositol 4,5-bisphosphate (PIP2) and target SDCBP2 to the plasma membranes and nucleoli, PIP2-rich regions.
Phosphorylated. Phosphorylation is enhanced upon serum stimulation.
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 IFT57, IFT88 and DAW1. Interacts with ARL13B. Interacts with TTC26/IFT56 (By similarity). Interacts with TTC25 (By similarity). 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).
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).
Interacts with FMR1. Interacts with FRX2. Interacts with TDRD3. Interacts with HABP4. Interacts with CYFIP2 but not with CYFIP1.
RNA-binding protein required for embryonic and postnatal development of muscle tissue. May regulate intracellular transport and local translation of certain mRNAs (By similarity).
The tandem Agenet-like domains preferentially recognize trimethylated histone peptides.
This protein corresponds to isoform B in mouse and isoform 2 in human.
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 (By similarity).
Monomer; active form. Homodimer; inactive form. The homodimer is probably linked by 1 2Fe-2S cluster (By similarity).
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 (By similarity).
Down-regulated by theophylline (THP) and 1,3-dinitrobenzene (DNB), two reprotoxic agents thought to induce infertility.
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).
Belongs to the universal ribosomal protein uL24 family.
Detected in embryo, including embryonic brain. Detected at very low levels in adult testis, spleen, thymus and lung.
Highly expressed in embryo. Expressed at very low levels in adult.
Interacts with NTRK1 (By similarity). Isoform 1 and isoform 2 interact with NGFR. Interacts with SORT1.
Isoform 1 is N-glycosylated. Isoform 2 is not N-glycosylated.
Modulates NTRK1 signaling. Can activate several intracellular signaling pathways, leading to activation of JUN. Promotes translocation of SORT1 to the cell membrane, and thereby hinders lysosomal degradation of SOTR1 and promotes its interaction with NGFR (By similarity). Both isoform 1 and isoform 2 promote apoptosis.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family.
Catalyzes the decomposition of L-selenocysteine to L-alanine and elemental selenium.
May be involved as a regulatory molecule in GPR24/MCH-R1 signaling.
Belongs to the glycosyl hydrolase 79 family.
Homodimer. May also form higher oligomers. Interacts with FLII (By similarity). Interacts with MYD88 (By similarity). Competes with FLII for MyD88-binding, even in the absence of LPS (By similarity).
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 (By similarity).
Up-regulated after artery wall injury (at protein level).
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 specifically elongates C24:0 and C26:0 acyl-CoAs. 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. May play a critical role in early brain and skin development.
Belongs to the DPH1/DPH2 family. DPH1 subfamily.
Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction with PCDH15.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing.
antiparallel heterodimer with PCDH15 (By similarity). Interacts with USH1C and USH1G (By similarity).
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. 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.
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. NUDT21/CPSF5 activates indirectly the mRNA 3'-processing machinery by recruiting CPSF6 and/or CPSF7. Binds to 5'-UGUA-3' elements localized upstream of pA signals that act as enhancers of pre-mRNA 3'-end processing. The homodimer mediates simultaneous sequence-specific recognition of two 5'-UGUA-3' elements within the pre-mRNA. Plays a role in somatic cell fate transitions and pluripotency by regulating widespread changes in gene expression through an APA-dependent function. Binds to chromatin. Binds to, but does not hydrolyze mono- and di-adenosine nucleotides.
Homodimer (via N- and C-terminus); binds RNA as homodimer. 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. The cleavage factor Im (CFIm) complex associates with the CPSF and CSTF complexes to promote the assembly of the core mRNA 3'-processing machinery. Interacts with CPSF6 (via the RRM domain); this interaction is direct and enhances binding to RNA. Interacts with CPSF7. Interacts with FIP1L1; this interaction occurs in a RNA sequence-specific manner. Interacts with PABPN1. Interacts (via N-terminus) with PAPOLA (via C-terminus); this interaction is direct and diminished by acetylation. Interacts with SNRNP70. Interacts with VIRMA.
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 is not expected to have hydrolase activity.
Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8 (By similarity).
Monomer; in the absence of TGF-beta activation (By similarity). Heterotrimer; on TGF-beta activation (By similarity). Heterotrimer composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex (By similarity). Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Found in a complex with SMAD1 and YY1. Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity).Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with USP9X. Interacts with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Interacts with CITED1 and CITED2. Interacts with PDPK1 (via PH domain). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive (By similarity). Interacts (via MH2 domain) with ZNF451 (via N-terminal zinc-finger domains) (By similarity). Interacts with ZC3H3 (By similarity). Interacts weakly with ZNF8 (By similarity). Interacts with NUP93 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (By similarity). Interacts with CREB3L1, the interaction takes place upon TGFB1 induction and SMAD4 acts as CREB3L1 coactivator to induce the expression of genes involved in the assembly of collagen extracellular matrix (By similarity). Interacts with DLX1 (By similarity). Interacts with ZBTB7A; the interaction is direct and stimulated by TGFB1 (By similarity). Interacts with CREBBP; the recruitment of this transcriptional coactivator is negatively regulated by ZBTB7A (By similarity). Interacts with EP300; the interaction with this transcriptional coactivator is negatively regulated by ZBTB7A (By similarity). Interacts with HDAC1 (By similarity). 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 (By similarity).
Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling (By similarity).
The MH1 domain is required for DNA binding.
The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. TrmB family.
Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA.
Phosphorylation at Ser-21 inactivates its catalytic activity but does not affect the interaction with WDR4.
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. CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility and proliferation of epithelial cells. Has a potent invasive suppressor role. It is a ligand for integrin alpha-E/beta-7.
During apoptosis or with calcium influx, cleaved by a membrane-bound metalloproteinase (ADAM10), PS1/gamma-secretase and caspase-3 (By similarity). Processing by the metalloproteinase, induced by calcium influx, causes disruption of cell-cell adhesion and the subsequent release of beta-catenin into the cytoplasm (By similarity). The residual membrane-tethered cleavage product is rapidly degraded via an intracellular proteolytic pathway (By similarity). Cleavage by caspase-3 releases the cytoplasmic tail resulting in disintegration of the actin microfilament system (By similarity). The gamma-secretase-mediated cleavage promotes disassembly of adherens junctions (By similarity). 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 (By similarity).
Homodimer; disulfide-linked (By similarity). 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 (By similarity). Interacts with the TRPV4 and CTNNB1 complex (By similarity). Interacts with CTNND1 (By similarity). The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex (By similarity). Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1 (By similarity). Interaction with PSEN1, cleaves CDH1 resulting in the disassociation of cadherin-based adherens junctions (CAJs) (By similarity). Interacts with AJAP1 and DLGAP5 (By similarity). Interacts with TBC1D2 (By similarity). Interacts with LIMA1 (By similarity). Interacts with CAV1 (By similarity). Interacts with PIP5K1C (By similarity). Interacts with DDR1; this stabilizes CDH1 at the cell surface and inhibits its internalization (By similarity). Interacts with RAPGEF2 (By similarity). Interacts with RAB8B (PubMed:12639940). Interacts with KLRG1 (By similarity). 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 (By similarity). Interacts with CTNNB1 and PKP2 (By similarity).
N-glycosylation at Asn-641 is essential for expression, folding and trafficking. Addition of bisecting N-acetylglucosamine by MGAT3 modulates its cell membrane location (By similarity).
O-glycosylated. O-manosylated by TMTC1, TMTC2, TMTC3 or TMTC4. Ser-289 and Thr-513 are O-manosylated by TMTC2 or TMTC4 but not TMTC1 or TMTC3.
Ubiquitinated by a SCF complex containing SKP2, which requires prior phosphorylation by CK1/CSNK1A1. Ubiquitinated by CBLL1/HAKAI, requires prior phosphorylation at Tyr-758 (By similarity).
Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as splicing regulator ARVCF. Interacts with TXNL4/DIM1.
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) (By similarity).
ATPase that regulates mitochondrial ABC transporters ABCB7, ABCB8/MITOSUR and ABCB10. Regulates mitochondrial ferric concentration and heme biosynthesis and plays a role in the maintenance of mitochondrial homeostasis and cell survival.
Homodimer. Interacts with ABCB7, ABCB8/MITOSUR and ABCB10.
Interacts with SREK1IP1 (By similarity). Homodimer. Binds SFRS1, SFRS2, SFRS3 and SFRS6. Interacts with the spliceosome.
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.
Ubiquitous. Detected in liver, brain, lung, spleen, testis and pancreas.
Belongs to the copper/topaquinone oxidase family.
Topaquinone (TPQ) is generated by copper-dependent autoxidation of a specific tyrosyl residue.
Expressed in liver, pancreas and pituitary (at protein level).
N-glycosylated; N-glycans are of the complex type and modified by sialic acid residues.
O-glycosylated; modified by sialic acid residues.
Phosphorylated by c-AMP-dependent kinases most probably 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.
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. May also be involved in the biogenesis of lysosome-related organelles such as melanosomes.
Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN. Associates with the BLOC-1 complex. Interacts with BLOC1S1. Interacts with DTNBP1/BLOC1S7 (via coiled-coil domain).
Abundantly expressed in 14.5-day fetal liver. Expression decreases during late liver development and stays at low levels until birth. Expression increases 24 hours after birth and reaches highest levels in adult liver.
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with VCP, CHEK1 and CUL1 (By similarity).
Substrate-recognition component of some SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complexes. Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Able to recognize and bind denatured glycoproteins, which are modified with not only high-mannose but also complex-type oligosaccharides. Also recognizes sulfated glycans. Also involved in DNA damage response by specifically recognizing activated CHEK1 (phosphorylated on 'Ser-345'), promoting its ubiquitination and degradation. Ubiquitination of CHEK1 is required to insure that activated CHEK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication (By similarity).
May be involved in signal transduction as a component of a multimeric receptor complex.
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. 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.
Belongs to the glycosyl hydrolase 47 family.
Regulates negatively FAS-induced apoptosis and NGFR-mediated pro-apoptotic signaling.
Down-regulated by parathyroid hormone (PTH).
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.
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.
Belongs to the Mediator complex subunit 31 family.
Belongs to the universal ribosomal protein uL15 family.
Belongs to the gluconokinase GntK/GntV family.
Associates with the cytoplasmic CCR4-NOT deadenylase and RNA exosome complexes to trigger ARE-containing mRNA deadenylation and decay processes. Interacts with CNOT1. Interacts (via N-terminus) with CNOT6. Interacts with CNOT7; this interaction is inhibited in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts (via N-terminus) with EXOSC2. Interacts with XRN1. Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner. Interacts (via phosphorylated form) with YWHAZ; this interaction occurs in a p38 MAPK- and AKT-signaling pathways.
Phosphorylated. 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. 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. AKT1-mediated phosphorylation at Ser-92 does not impair ARE-containing RNA-binding. 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. MAPKAPK2-mediated phosphorylations at Ser-54, Ser-92 and Ser-203 do not impair ARE-containing RNA-binding (By similarity). 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). Phosphorylated by protein kinase AKT1 at Ser-92 (PubMed:15538381).
Ubiquitinated. Ubiquitination leads to proteasomal degradation, a process inhibited by phosphorylations at Ser-90, Ser-92 and Ser-203.
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:10751406, PubMed:12748283). Acts as a 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:12748283). 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:12748283). Induces also the degradation of ARE-containing mRNAs even in absence of poly(A) tail (PubMed:11279239). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:10751406). Positively regulates early adipogenesis by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Promotes ARE-mediated mRNA decay of mineralocorticoid receptor NR3C2 mRNA in response to hypertonic stress. Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Positively regulates monocyte/macrophage cell differentiation by promoting ARE-mediated mRNA decay of the cyclin-dependent kinase CDK6 mRNA. 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. May play a role in mediating pro-apoptotic effects in malignant B-cells by promoting ARE-mediated mRNA decay of BCL2 mRNA. 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. 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. Participates in the delivery of target ARE-mRNAs to processing bodies (PBs). 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. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in vasculogenesis and endocardial development. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role in myoblast cell differentiation (By similarity).
Brain-specific (PubMed:7679676). Expressed in oligodendrocytes and small subsets of neurons (mainly interneurons and motoneurons) of the cerebellum, hippocampus and olfactory bulb (PubMed:7679676). Expressed in dorsal root ganglia (PubMed:28270793).
Contains N-linked oligosaccharides, O-linked sialylated structures (By similarity). Contains O-linked chondroitin sulfate glycosaminoglycans. Contains N-linked oligosaccharides with a sulfated carbohydrate structure type GalNAc-4-SO4 or HNK-1 (SO4-3-GlcUABeta1,3GalBeta1,4GlcNAc). The levels of HNK-1 rise and fall in parallel to those of TNR during postnatal development of the cerebellum. In contrast, levels of GalNAc-4-SO4 are regulated independently from those of TNR, rising late in cerebellar development and continuing into adulthood. Early in postnatal development, GalNAc-4-SO4 is found predominantly on isoform 1, whereas in the adult it is predominantly on isoform 2.
Expression in oligodendrocytes is highest between the second and third postnatal week and low in the adult. In contrast the expression in neurons increases from birth to third postnatal week and is continuous from late development to adulthood. Isoform 1 is the dominant form early in development. Isoform 2 is more prominent later in development and in adulthood.
Forms oligomers. Interacts with TNC and FN1 (By similarity). Interacts with BCAN and ACAN in a calcium -dependent manner. Interacts with CNTN1, SCN2B, PTPRZ1, and CSPG3.
Neural extracellular matrix (ECM) protein involved in interactions with different cells and matrix components. Theses interactions can influence cellular behavior by either evoking a stable adhesion and differentiation, or repulsion and inhibition of neurite growth. Binding to cell surface gangliosides inhibits RGD-dependent integrin-mediated cell adhesion and results in an inhibition of PTK2/FAK1 (FAK) phosphorylation and cell detachment. Binding to membrane surface sulfatides results in a oligodendrocyte adhesion and differentiation. Interaction with CNTN1 induces a repulsion of neurons and an inhibition of neurite outgrowth. Interacts with SCN2B may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier. TNR-linked chondroitin sulfate glycosaminoglycans are involved in the interaction with FN1 and mediates inhibition of cell adhesion and neurite outgrowth. The highly regulated addition of sulfated carbohydrate structure may modulate the adhesive properties of TNR over the course of development and during synapse maintenance (By similarity).
The EGF-like domains mediate interaction with CNTN1. The fibronectin type-III domains 3-5 mediate interaction with BCAN. The fibronectin type-III domains 1-2 and 7-9 mediate interaction with SCN2B.
Transiently increased in dorsal root ganglia 1 day post-dorsal rhizotomy, returning to comparable levels 3 days post-injury (PubMed:28270793). Increased in dorsal root ganglia in response to both sciatic nerve crush and transection injury (PubMed:28270793).
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.
High levels seen in the brain and testis, while a lower level expression is seen in the liver, spleen, kidney, lung, skeletal muscle and heart.
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. Isoform 1, isoform 2 and isoform 3 interact with DYNC1H1. Isoform 1, isoform 2 and isoform 3 interact with DYNLT3. Isoform 1, isoform 2 and isoform 3 interact with DYNLT1. Interacts with DCTN1.
Contaminating sequence. Sequence of unknown origin in the C-terminal part.
Functions as a sequence-specific transcriptional repressor.
Interacts with TRIM28; enhances the transcriptional repressor activity.
Ubiquitously expressed with higher expression in lung, kidney and testis.
Up-regulated by EGF; delayed early response target for EGF (at protein level).
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.
Belongs to the protein arginine deiminase family.
Catalyzes the deimination of arginine residues of proteins.
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 (By similarity).
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 (By similarity).
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.
Belongs to the fructosamine kinase family.
Expressed by connecting tubule cells and intercalated cells of the collecting duct in kidney (at protein level).
Functions as an electroneutral and bidirectional ammonium transporter. May regulate transepithelial ammonia secretion (By similarity).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily.
Catalyzes the hydrolysis of ATP coupled with the transport of calcium.
Down-regulated in all tissues except pancreas in a rat hypertension model.
Found in most tissues. Most abundant in large and small intestine, spleen and lung. Also detected in PC12 cells.
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 (By similarity). Interacts with TUNAR; the interaction occurs at low levels in low glucose conditions and is increased by high glucose levels (By similarity).
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.
This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of the calcium. Transports calcium ions from the cytosol into the sarcoplasmic/endoplasmic reticulum lumen. Contributes to calcium sequestration involved in muscular excitation/contraction.
Belongs to the copper type II ascorbate-dependent monooxygenase family.
Chromaffin granules of the adrenal medulla and synaptic vesicles of the sympathetic nervous system.
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.
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.
The small GTPases Rab are key regulators in vesicle trafficking.
Ethanolamine-phosphate cytidylyltransferase that catalyzes the second step in the synthesis of phosphatidylethanolamine (PE) from ethanolamine via the CDP-ethanolamine pathway. 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.
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). Forms a heterodimer with BMAL1 (By similarity). 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 (By similarity). Interacts with ESR1 and estrogen stimulates this interaction (By similarity). Interacts with the complex p35/CDK5 (By similarity). Interacts with RELA/p65 (By similarity). Interacts with KAT2B, CREBBP and EP300 (By similarity). Interacts with ID1 and ID3 (By similarity). Interacts with ID2 (By similarity). 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 PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (By similarity). Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation (By similarity). Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By similarity). Interacts with KDM5A (By similarity). Interacts with KMT2A; in a circadian manner (By similarity). 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. Interacts with ASS1 and IMPDH2; in a circadian manner. Interacts with NDUFA9 (By similarity). Interacts with PIWIL2 (via PIWI domain) (By similarity). Interacts with HNF4A (By similarity).
Expressed in the suprachiasmatic nucleus (SCN), and in the piriform cortex (PC).
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.
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. CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3'. The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. 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. 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 (By similarity). Drives the circadian rhythm of blood pressure through transcriptional activation of ATP1B1 (By similarity).
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.
Without light exposure, high levels at ZT6 and low levels at ZT18 and ZT22. Light exposure increases levels in the SCN in phase dependent manner. Levels increased significantly during the subjective night (ZT10-20). In the piriform cortex, levels increased by light at ZT14.
Component of an histone acetyltransferase complex.
Component of an histone acetyltransferase complex. Interacts with H3K4me3 and to a lesser extent with H3K4me2.
The PHD-type zinc finger mediates the binding to H3K4me3.
Belongs to the glycosyl hydrolase 33 family.
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. 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. Desialylates EGFR and activates downstream signaling in proliferating cells. Contributes to clathrin-mediated endocytosis by regulating sorting of endocytosed receptors to early and recycling endosomes.
Expressed in brain, cardiac muscle and weakly in liver.
Interacts with CAV1; this interaction enhances NEU3 sialidase activity within caveola. Interacts with EGFR; this interaction mediates desialylation of EGFR enhancing downstream signaling.
Palmitoylated; may regulate intracellular trafficking and anchorage to plasma membrane and endomembranes.
Belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.
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 only in erythroid tissues, reticulocytes and liver.
Associates with the BLOC-1 complex. Interacts with BLOC1S6 (By similarity). Interacts with NAPA and SNAP23 (PubMed:9507000). Identified in a complex containing STX6, STX12, VAMP4 and VTI1A (PubMed:17159904). Interacts with GRIPAP1 (PubMed:20098723). 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 (PubMed:16037816). Interacts with NSG1 (PubMed:12070131). Interacts with TPC1 (By similarity). Interacts (via N-terminus) with VPS13B (PubMed:30962439).
SNARE promoting fusion of transport vesicles with target membranes (PubMed:17159904, PubMed:30962439). Together with SNARE STX6, promotes movement of vesicles from endosomes to the cell membrane, and may therefore function in the endocytic recycling pathway (PubMed:30962439). 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 (PubMed:16037816).
Contains hydroxylated asparagine residues.
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. LTBP1 does not bind directly to TGF-beta-1, the active chain of TGFB1. Interacts (via C-terminal domain) with FBN1 (via N-terminal domain). Interacts with FBN2. Interacts with ADAMTSL2. Interacts with EFEMP2 (By similarity).
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:7593177). 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 (By similarity). Outcompeted by LRRC32/GARP for binding to LAP regulatory chain of TGF-beta (By similarity).
O-glycosylated on serine residues by POGLUT2 and POGLUT3.
The 8-Cys3 region in the third TB domain mediates the interchain disulfide bond interaction with the Latency-associated peptide chain (LAP) regulatory chain of TGFB1.
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.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
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).
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 PRDM1.
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/TP53LOG.
Belongs to the glycosyltransferase 14 family. XylT subfamily.
Interacts with SIRT1. Interacts weakly with TLE2. Interacts with HES6 (By similarity). Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family. Interacts (via WPRW motif) with TLE1. Interacts with an FA complex, composed of FANCA, FANCF, FANCG and FANCL, but not of FANCC, nor FANCE (By similarity).
Present in all tissues examined but highest in epithelial cells and in mesoderm-derived tissues such as embryonal muscle cells.
The bHLH, as well as cooperation between the central Orange domain and the C-terminal WRPW motif, is required for transcriptional repressor activity.
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. 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 (By similarity).
Belongs to the RecA family. RAD51 subfamily.
Plays an important role in homologous strand exchange, a key step in DNA repair through homologous recombination (HR). Binds to single-stranded DNA in an ATP-dependent manner to form nucleoprotein filaments which are essential for the homology search and strand exchange. 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. Recruited to resolve stalled replication forks during replication stress. Also involved in interstrand cross-link repair.
Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR2 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 cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development (By similarity).
Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2798 and Ser-2804 increases the open probability of the calcium channel. Phosphorylation is increased in failing heart, leading to calcium leaks and increased cytoplasmic Ca(2+) levels (By similarity).
Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). The calcium release is activated by increased cytoplasmic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity).
Detected in heart muscle myocytes (at protein level). Widely expressed. Detected in heart muscle and cerebral artery smooth muscle. Detected in pancreatic islet cells.
Homotetramer. Can also form heterotetramers with RYR3. Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1. Interacts directly with FKBP1B, PKA, PP1 and PP2A (By similarity). Interacts with FKBP1A and FKBP1B; these interactions may stabilize the channel in its closed state and prevent Ca(2+) leaks. Interacts with CALM and S100A1; these interactions regulate channel activity. Interacts with SELENON (By similarity). In cardiac muscles, identified in a complex composed of FSD2, CMYA5 and RYR2 (By similarity).
Phosphorylation at Ser-2021 by PKA enhances the response to lumenal calcium.
The calcium release channel activity resides in the C-terminal region while the remaining part of the protein resides in the cytoplasm.
Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. Seems to be coupled to the G(i)/G(o) and G(q) families of heteromeric G proteins (By similarity).
Antiparallel homodimer; disulfide-linked. Also found as heterodimer with VEGFA/VEGF.
Growth factor active in angiogenesis and endothelial cell growth, stimulating their proliferation and migration. It binds to the receptor FLT1/VEGFR-1. Also promotes cell tumor growth (By similarity).
Can bind at least three actin monomers and thereby provides a nucleus for actin filament formation. Interacts (via N-terminus) with tropomyosin alpha (TPM1) (via N-terminus). May also interact with TPM2 (via N-terminus).
Mediates nucleation of actin filaments and thereby promotes actin polymerization (PubMed:18403713). Plays a role in the regulation of actin filament length (By similarity). Required for normal sarcomere organization in the heart, and for normal heart function (PubMed:18403713).
PubMed:8334153 incorrectly assigned their sequence fragment as a fatty acid-binding protein.
Belongs to the thiolase-like superfamily. Beta-ketoacyl-ACP synthases family.
May play a role in the biosynthesis of lipoic acid as well as longer chain fatty acids required for optimal mitochondrial function.
Belongs to the peptidase S1 family. Elastase subfamily.
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.
Expressed after birth, reaching a maximum at postnatal day 14 in the cerebrum and postnatal day 3 in the cerebellum. Then, it decreases abruptly thereafter (at protein level).
Specifically expressed in the nervous system. Expressed in cerebrum and cerebellum but at low level in spinal chord. In brain, it is expressed in highly restricted regions at postnatal day 7, such as the auditory pathway, including the cochlear nucleus, superior olive, inferior colliculus, medial geniculate nucleus and auditory cortex. Expressed in the accessory olfactory bulb, glomerular and mitral cell layers in the olfactory bulb, anterior thalamic nuclei, layers II-IV of the cerebral cortex, dentate gyrus of the hippocampus and external granule cells and Purkinje cells of the cerebellum. Also expressed in the piriform cortex, inferior olive and facial nucleus. Weakly or not expressed in other parts of the brain.
Activated by GTP. Inhibited by CDP-diacylglycerol and by phosphatidylglycerol 4,5-bisphosphate (PPI2).
Brain, retina and testis. Found in cerebellar Purkinje cells, pineal body, inner segment of photoreceptor cells and postmitotic spermatocytes and spermatids.
Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PubMed:9083091, PubMed:9345289, PubMed:29253589, PubMed:30862571). Exhibits almost no acyl chain preference for PA, showing no discrimination for the sn-1/sn-2 acyl chain composition of PAs (By similarity). Plays an important role in regulatinng the growth of lipid droplets which are storage organelles at the center of lipid and energy homeostasis (By similarity). Positively regulates the differentiation and development of adipocytes (By similarity).
Homodimer (PubMed:29253589). Interacts with FOS; this interaction may enhance catalytic activity (By similarity).
Adapter protein that plays a key role in innate immune response against fungi by forming signaling complexes downstream of C-type lectin receptors (By similarity). CARD9-mediated signals are essential for antifungal immunity against a subset of fungi from the phylum Ascomycota (By similarity). 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 (PubMed:17936701). 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:17936701). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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).
Maintained in an autoinhibited state via homodimerization in which the CARD domain forms an extensive interaction with the adjacent linker and coiled-coil regions (By similarity). 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 (By similarity). Zinc-binding inhibits activation by stabilizing the CARD ground-state conformation and restricting its capacity to form BCL10-nucleating filaments (By similarity).
Monomer. 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. Homomultimer; polymerizes following activation, forming a nucleating helical template that seeds BCL10-filament formation via a CARD-CARD interaction (By similarity). 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. Component of a CBM complex (CARD9-BCL10, MALT1), composed of CARD9, BCL10 and MALT1. Interacts with RASGRF1. Interacts with NOD2 (via NACHT domain); interaction is direct. Interacts with RIPK2 (By similarity). Interacts with VHL; without leading to protein degradation (PubMed:17936701).
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 (PubMed:17936701).
The linker region, also named autoinhibitory interface, is required to prevent constitutive activation and maintain CARD9 in an autoinhibitory state. Disruption of this region triggers polymerization and activation, leading to formation of BCL10-nucleating filaments.
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. Deubiquitinated at Lys-125 by USP15, inhibiting CARD9.
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 (By similarity). May play a role in synaptic transmission by modulating calcium and proton dynamics at the synaptic vesicles.
Isoform B is ubiquitously expressed. Isoforms A and E have only been found in brain cortex. Isoform C is found in brain cortex, skeletal muscle and heart muscle. Isoform D has only been found in fetal skeletal muscle. Isoform K has been found in small intestine and liver. Isoform B is expressed in hair cells of inner ear (PubMed:16803870).
Isoforms A, C, D and E contain and additional calmodulin-binding subdomain B which is different in the different splice variants and shows pH dependent calmodulin binding properties.
Monomer. Dimer. Oligomer. Calmodulin binding. Interacts with PDZD11. Interacts with SLC35G1 and STIM1. 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 (By similarity). Interacts with NPTN; this interaction stabilizes ATP2B1 and increases ATPase activity; this interaction controls T cell calcium homeostasis following T cell activation. Interacts with EPB41; regulates small intestinal calcium absorption through regulation of membrane expression of ATP2B1 (By similarity).
Activated by forskolin. Activated by GNAS. Activity is further increased by interaction with the G protein beta and gamma subunit complex formed by GNB1 and GNG2 (By similarity). 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 (By similarity).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:1409703). Mediates signaling downstream of ADRB1. 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.
Interacts with GNAS, GNB1 and GNG2 (By similarity). Part of a complex containing AKAP5, ADCY6, PDE4C and PKD2 (By similarity). Interacts with RAF1 (By similarity).
Functions as an adapter recruiting ubiquitin-protein ligases to their specific substrates. Plays a role in endocytosis of activated G protein-coupled receptors (GPCRs) Through an ubiquitination-dependent mechanism also plays a role in the incorporation of SLC11A2 into extracellular vesicles. May play a role in glucose uptake.
Interacts with ADRB2. Interacts (via PPxY motifs) with ITCH, NEDD4L and WWP2. Interacts with AVPR2. Identified in a complex containing at least ARRDC4, AVPR2 and HGS. Interacts with SLC11A2; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism.
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 (PubMed:1379236, PubMed:3422231, PubMed:8483907, PubMed:9890952). Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis (PubMed:1379236, PubMed:3422231). 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 (By similarity).
Monomer. Interacts with heparan sulfate co-polymerase subunits EXT1 and EXT2.
The deacetylase activity is specifically inhibited by N-Ethylmaleimide (PubMed:8483907). The sulfotransferase activity is specifically inhibited by 3',5'-ADP (PubMed:8483907).
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.
Catalyzes the final step in the metabolic pathway of hydroxyproline.
Belongs to the WD repeat CDC20/Fizzy family.
Deubiquitinating enzyme which may play an important role during spermatogenesis.
It is uncertain whether Met-1 or Met-50 is the initiator.
May be an activator of G protein signaling.
Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells. Actin exists in both monomeric (G-actin) and polymeric (F-actin) forms, both forms playing key functions, such as cell motility and contraction. In addition to their role in the cytoplasmic cytoskeleton, G- and F-actin also localize in the nucleus, and regulate gene transcription and motility and repair of damaged DNA.
Expressed in the epididymis (at protein level).
Methylated at His-73 by SETD3 (PubMed:30526847). Methylation at His-73 is required for smooth muscle contraction of the laboring uterus during delivery (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. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Component of the BAF complex, which includes at least actin (ACTB), ARID1A, ARID1B/BAF250, SMARCA2, SMARCA4/BRG1, ACTL6A/BAF53, ACTL6B/BAF53B, SMARCE1/BAF57 SMARCC1/BAF155, SMARCC2/BAF170, SMARCB1/SNF5/INI1, and one or more of SMARCD1/BAF60A, SMARCD2/BAF60B, or SMARCD3/BAF60C. In muscle cells, the BAF complex also contains DPF3. Found in a complex with XPO6, Ran, ACTB and PFN1. Interacts with XPO6 and EMD. Interacts with ERBB2. Interacts with GCSAM (By similarity). Interacts with TBC1D21. Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain) (By similarity). Interacts with DHX9 (via C-terminus); this interaction is direct and mediates the attachment to nuclear ribonucleoprotein complexes. Interacts with FAM107A (By similarity).
Expressed in bone. Main expression is present in mesenchymal osteochondroprogenitors with fibroblast-like morphology abundant in the regions of active bone modeling and remodeling.
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 (PubMed:14962803).
N-terminally cleaved to produce a form of around 663 residues.
Binds SREK1/SFRS12 (By similarity). Interacts with DYRK1A.
Detected in liver and brain (at protein level).
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 (By similarity).
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 (By similarity).
Belongs to the phosphatidylethanolamine-binding protein family. Mitochondrion-specific ribosomal protein mL38 subfamily.
In the suprachiasmatic nucleus, it increases during subjective night with a peak at midnight under constant dark conditions. Expressed at a constant level in neurons throughout the brain (at protein level) (PubMed:10570941). Isoform 2 expression increases over development and maturation in the hippocampus. Isoform 1 expression is low in embryonic stages, increases during postnatal development and is falling back to low embryonic levels in adulthood (PubMed:20819118).
Inhibited by insulin in a PI3K-dependent manner.
Insensitive to okadaic acid. Deubiquitination by WDR48-USP12 complex positively regulates PHLPP1 stability.
Interacts with the nucleotide free form of K-Ras (KRAS) via its LRR repeats (PubMed:12594205). Interacts with AKT2, AKT3 and PRKCB isoform beta-II. Interacts with WDR48 and USP12 (By similarity).
Mainly present in brain (at protein level) (PubMed:10570941). Isoform 2 is more abundant in adult brain neurons than isoform 1 in (PubMed:20819118). Isoforms 1 and 2 are expressed in the retina but not found in rod outer segments (PubMed:20089132).
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:20819118). Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons while isoform 1 may promote Akt and PKC activation and inhibit ERK signaling (PubMed:20819118). 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. Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (By similarity). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (By similarity). Inhibits cancer cell proliferation and may act as a tumor suppressor (By similarity). Dephosphorylates RAF1 inhibiting its kinase activity (By similarity). May act as a negative regulator of K-Ras signaling in membrane rafts (PubMed:12594205). 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.
Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP. 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. Interacts directly with GEMIN6 and GEMIN7. Associates with the SMN complex in the cytoplasm but not in the nucleus. Also interacts with CSDE1/UNR and MAWBP. Interacts with PDPK1. Interacts with TRIM48.
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. STRAP plays a role in the cellular distribution of the SMN complex. Negatively regulates TGF-beta signaling but positively regulates the PDPK1 kinase activity by enhancing its autophosphorylation and by significantly reducing the association of PDPK1 with 14-3-3 protein (By similarity).
Dihydrolipoamide succinyltransferase (E2) component of the 2-oxoglutarate dehydrogenase complex (By similarity). The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) (By similarity). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion. 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 (By similarity).
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.
Serves as a reserve supply of oxygen and facilitates the movement of oxygen within muscles.
Belongs to the prefoldin subunit beta family.
PPIases accelerate the folding of proteins during protein synthesis.
Belongs to the MINDY deubiquitinase family. FAM188 subfamily.
Hydrolase that can remove 'Lys-48'-linked conjugated ubiquitin from proteins.
Belongs to the class IV-like SAM-binding methyltransferase superfamily. TRM10 family.
S-adenosyl-L-methionine-dependent guanine N(1)-methyltransferase that catalyzes the formation of N(1)-methylguanine at position 9 (m1G9) in tRNAs. Probably not able to catalyze formation of N(1)-methyladenine at position 9 (m1A9) in tRNAs.
Ubiquitously expressed. Is more abundant in brain and pancreatic islets compared to other tissues (at protein level).
Has a helix-hairpin-helix (HhH) structural motif conserved among proteins that bind non-specifically to DNA.
Homodimer (By similarity). Heterodimerizes with BANF2 (By similarity). Interacts with ANKLE2/LEM4, leading to decreased phosphorylation by VRK1 and promoting dephosphorylation by protein phosphatase 2A (PP2A) (By similarity). Binds non-specifically to double-stranded DNA, and is found as a hexamer or dodecamer upon DNA binding (By similarity). Binds to LEM domain-containing nuclear proteins such as LEMD3/MAN1, TMPO/LAP2 and EMD (emerin) (PubMed:10393804). Interacts with ANKLE1 (via LEM domain); the interaction may favor BANF1 dimerization (By similarity). Interacts with CRX and LMNA (lamin-A) (By similarity). Binds linker histone H1.1 and core histones H3 (By similarity). Interacts with LEMD2 (via LEM domain) (By similarity). Interacts with PARP1; interaction takes place in response to oxidative DNA damage (By similarity).
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. Contains two non-specific double-stranded DNA (dsDNA)-binding sites which promote DNA cross-bridging. 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. 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. Also acts as a negative regulator of innate immune activation by restricting CGAS activity toward self-DNA upon acute loss of nuclear membrane integrity. Outcompetes CGAS for DNA-binding, thereby preventing CGAS activation and subsequent damaging autoinflammatory responses. Also involved in DNA damage response: interacts with PARP1 in response to oxidative stress, thereby inhibiting the ADP-ribosyltransferase activity of PARP1. 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.
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.
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 (By similarity).
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'.
A sequential activation is proposed: autophosphorylation at consensus sites is leading to dimerization of the catalytic domain 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. Inhibited by pyridone 6 (K00225), a potent, ATP-competitive inhibitor. Phosphorylation at Thr-180, Thr-225 and Thr-265 is essential for activity (By similarity).
A species-specific loss of a key phosphorylation site in murine DAPK3 seems to direct it mainly to the nucleus which is proposed to be compensated by the interaction with PAWR to maintain at least the cytoplasmic basic membrane blebbing function in the apoptosis pathway.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily.
Homooligomer in its kinase-active form (homotrimers and homodimers are reported); monomeric in its kinase-inactive form. Homodimerization is required for activation segment autophosphorylation (By similarity). Interacts with DAXX, ATF4, NLK, TCF7L2, UBE2D1, UBE2D2, UBE2D3 and CDC5L. Interacts with PAWR; also demonstrated in aorta smooth muscle cells indicative for the cytoskeletal targeting function of PAWR. Interacts with AR; enhanced by AATF.
Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation and actin cytoskeleton reorganization. Regulates both type I (caspase-dependent) apoptotic and type II (caspase-independent) autophagic cell deaths signal, depending on the cellular setting. Involved in formation of promyelocytic leukemia protein nuclear body (PML-NB). Involved in apoptosis involving PAWR which mediates cytoplasmic relocation; in vitro phosphorylates PAWR. Phosphorylates MYL12B in non-muscle cells leading to reorganization of actin cytoskeleton such as in regulation of cell polarity and cell migration. Positively regulates canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2; disrupts the NLK-TCF7L2 complex thereby influencing the phosphorylation of TCF7L2 by NLK. 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 (By similarity). Phosphorylates STAT3 and enhances its transcriptional activity (By similarity). Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Phosphorylates histone H3 on 'Thr-11' at centromeres during mitosis.
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 and 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.
Ubiquitinated. Ubiquitination mediated by the UBE2D3 E3 ligase does not lead to proteasomal degradation, but influences promyelocytic leukemia protein nuclear bodies (PML-NBs) formation in the nucleus (By similarity).
Ubiquitously expressed in all tissue types examined. High levels in brain, heart, lung and spleen, lower expression in kidney, liver, skeletal muscle and testis. Isoform 2 is expressed in the smooth muscle.
Has also a significant activity in oxidation of tazarotenic acid and may therefore metabolize that xenobiotic in vivo.
Involved in the metabolism of retinoic acid (RA), rendering this classical morphogen inactive through oxidation. Involved in the specific inactivation of all-trans-retinoic acid (all-trans-RA), with a preference for the following substrates: all-trans-RA > 9-cis-RA > 13-cis-RA. Generates several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA, and 18-OH-RA. Essential for postnatal survival. Plays a central role in germ cell development: acts by degrading RA in the developing testis, preventing STRA8 expression, thereby leading to delay of meiosis. Required for the maintenance of the undifferentiated state of male germ cells during embryonic development in Sertoli cells, inducing arrest in G0 phase of the cell cycle and preventing meiotic entry. Plays a role in skeletal development, both at the level of patterning and in the ossification of bone and the establishment of some synovial joints (By similarity).
Belongs to the eukaryotic ribosomal protein eL37 family.
Heterodimer of an alpha and a beta subunit (By similarity). Beta-3 (ITGB3) associates with either alpha-IIB (ITGA2B) or alpha-V (ITGAV). Interacts with FLNB and COMP (By similarity). Interacts with PDIA6 following platelet stimulation (By similarity). Interacts with SYK; upon activation by ITGB3 promotes platelet adhesion (By similarity). Interacts with MYO10 (By similarity). Interacts with DAB2. Interacts with FERMT2. Integrin ITGAV:ITGB3 interacts with FBLN5 (via N-terminus) (By similarity). Interacts with EMP2; regulates the levels of the heterodimer ITGA5:ITGB3 integrin expression on the plasma membrane (By similarity). ITGAV:ITGB3 interacts with CCN3 (By similarity). ITGAV:ITGB3 interacts with AGRA2 (By similarity). ITGAV:ITGB3 is found in a ternary complex with CX3CR1 and CX3CL1. ITGAV:ITGB3 is found in a ternary complex with NRG1 and ERBB3. ITGAV:ITGB3 is found in a ternary complex with FGF1 and FGFR1. ITGAV:ITGB3 interacts with FGF2; it is likely that FGF2 can simultaneously bind ITGAV:ITGB3 and FGF receptors (By similarity). ITGAV:ITGB3 binds to IL1B (By similarity). ITGAV:ITGB3 is found in a ternary complex with IGF1 and IGF1R (By similarity). ITGAV:ITGB3 interacts with IGF2 (By similarity). ITGAV:ITGB3 interacts with FBN1 (By similarity). ITGAV:ITGB3 interacts with CD9, CD81 and CD151 (via second extracellular domain) (By similarity). Interacts (via the allosteric site (site 2)) with CXCL12 in a CXCR4-independent manner (By similarity). Interacts with MXRA8/DICAM; the interaction inhibits ITGAV:ITGB3 heterodimer formation (By similarity). ITGAV:ITGB3 interacts with PTN. Forms a complex with PTPRZ1 and PTN that stimulates endothelial cell migration through ITGB3 Tyr-772 phosphorylation (By similarity). 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 surfaces. 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. ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling. ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling. ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling (By similarity). ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling (By similarity). ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling (By similarity). ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling (By similarity). 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 (By similarity). ITGAV:ITGB3 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (By similarity). 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 (By similarity). Controls excitatory synaptic strength by regulating GRIA2-containing AMPAR endocytosis, which affects AMPAR abundance and composition (PubMed:18549786). ITGAV:ITGB3 acts as a receptor for CD40LG (By similarity).
Phosphorylated on tyrosine residues in response to thrombin-induced platelet aggregation. Probably involved in outside-in signaling.
Catalyzes phosphatidylcholine biosynthesis from CDP-choline. It thereby plays a central role in the formation and maintenance of vesicular membranes.
Administration of an antisense oligonucleotide specific for GPR17 significantly reduced brain damage following ischemia.
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, and heart. Highest level in brain.
Belongs to the HAD-like hydrolase superfamily. PHOSPHO family.
Protects cells and enzymes from oxidative damage, by catalyzing the reduction of hydrogen peroxide, lipid peroxides and organic hydroperoxide, by glutathione. May constitute a glutathione peroxidase-like protective system against peroxide damage in sperm membrane lipids.
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 (By similarity).
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 (By similarity).
The SH3 domain mediates interaction with NOXO1 and NCF1 and has autoregulatory function.
The TPR repeats mediate interaction with RAC1.
Widely expressed. Detected in gastrum, spleen, uterus, small intestine, colon, inner ear, and brain.
Has antimicrobial activity against E.coli (PubMed:11230693). Plays a role in the defense response in the male reproductive tract, contributing to sperm maturation, storage and protection (PubMed:11230693).
Its expression starts at 30 days of age, reaches a maximum during the sexually mature period, and then decreased in old rats.
Only expressed in epididymis (middle part of the caput).
Belongs to the EGR C2H2-type zinc-finger protein family.
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.
Belongs to the immunoglobulin superfamily. CEA family.
Cell adhesion protein that mediates homophilic cell adhesion in a calcium-independent manner (PubMed:8454589, PubMed:2373740). Plays a role as coinhibitory receptor in immune response, insulin action and functions also as an activator during angiogenesis (PubMed:11850617). Its coinhibitory receptor function is phosphorylation- and PTPN6 -dependent, which in turn, suppress signal transduction of associated receptors by dephosphorylation of their downstream effectors (By similarity). Plays a role in immune response, of T-cells, natural killer (NK) and neutrophils (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Down-regulates neutrophil production by acting as a coinhibitory receptor for CSF3R by downregulating 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 (PubMed:11850617). Upon INS stimulation, undergoes phosphorylation by INSR leading to INS clearance by increasing receptor-mediated insulin endocytosis (PubMed:7592607, PubMed:9712832). 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 (PubMed:7592607, PubMed:16054098). 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 (PubMed:11694516). 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 (By similarity). 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 (PubMed:15467833). 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 (By similarity). Mediates bile acid transport activity in a phosphorylation dependent manner (PubMed:7518458). Negatively regulates osteoclastogenesis (By similarity).
Cell adhesion proteins that mediates homophilic cell adhesion in a calcium-independent manner (PubMed:8536699, PubMed:7774714). Promotes populations of T-cells regulating IgA production and secretion associated with control of the commensal microbiota and resistance to enteropathogens (By similarity).
Dubious isoform. Probable cloning artifact lacking polyadenylation evidence.
Expressed in epithelia, vessel endothelia, leukocytes and platelets. Isoform 1 and isoform 2 are highly expressed in liver and intestine, moderately in lung, and weakly in muscle, kidney, and spleen (PubMed:8454589). Expressed in granulocytes, lymphocytes, granulocytes, B cells, and T-cells (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.
Monomer (PubMed:9003371, PubMed:19948503). Oligomer. Heterodimer. Homodimer (PubMed:19948503). 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 (PubMed:19948503, PubMed:2373740, PubMed:8831574, PubMed:9003371). Interacts (via cytoplasmic domain) with calmodulin in a calcium dependent manner; reduces homophilic cell adhesion through dissociation of dimer (PubMed:8576129). 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 2 cis-heterodimers and is dependent on the monomer/dimer equilibrium; this interaction is phosphorylation-dependent (PubMed:19948503). 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:19948503). Isoform 1 interacts (via cytoplasmic domain) with LCK; mediates phosphorylation at Tyr-488 and Tyr-513 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 (By similarity). Isoform 1 interacts (via cytoplasmic domain) with SHC1 (via SH2 domain); SHC1 mediates interaction with INSR or EGFR in a Ser-503 phosphorylation-dependent manner (PubMed:11694516). 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. 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. Isoform 1 interacts with KLRK1; recruits PTPN6 that dephosphorylates VAV1. Isoform 1 interacts with CEACAM8 (By similarity). Isoform 1 interacts with FASN; this interaction is insulin and phosphorylation-dependent; reduces fatty-acid synthase activity (PubMed:16054098). 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. Isoform 2 interacts (via the cytoplasmic domain) with ANXA2; this interaction is regulated by phosphorylation and appears in the AIIt complex. 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 (By similarity).
Phosphorylated on serine and tyrosine (PubMed:8420979). 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:7626603, PubMed:9712832, PubMed:16054098). Phosphorylated at Ser-503; mediates activity. Phosphorylated at Tyr-488; regulates activity (PubMed:7518458). Phosphorylated at Tyr-488 by EGFR and INSR upon stimulation; this phosphorylation is Ser-503-phosphorylation-dependent; mediates cellular internalization; increases interaction with FASN (PubMed:16054098, PubMed:15467833, PubMed:7626603, PubMed:9712832). Phosphorylated at Tyr-488 and Tyr-513 by LCK; mediates PTPN6 association and is regulated by homophilic ligation of CEACAM1 in the absence of T-cell activation (By similarity). Phosphorylated at Tyr-513; mediates interaction with PTPN11 (By similarity).
There are two different allelic variants of CEACAM1, named a and b. The allelic variants differ in 16 amino acids in the Ig-like V-type domain. The sequence shown here, corresponds to allele A.
Belongs to the sulfotransferase 1 family.
Highly expressed in kidney and at lower levels in stomach and liver. More specifically found in the epithelia of proximal tubules of the kidney, of the bile duct, of the gastric mucosa, and in hepatocytes.
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.
Belongs to the lariat debranching enzyme family.
Defects in Arsb are the cause of mucopolysaccharidosis type VI (MPS-VI) (PubMed:8575749).
Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation (PubMed:24311516). In the central nervous system, is a regulator of neurite outgrowth and neuronal plasticity, acting through the control of sulfate glycosaminoglycans and neurocan levels (PubMed:24311516). Involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium (By similarity).
Belongs to the 'GDSL' lipolytic enzyme family. Phospholipase B1 subfamily.
Calcium-independent membrane-associated phospholipase that catalyzes complete diacylation of phospholipids by hydrolyzing both sn-1 and sn-2 fatty acyl chains attached to the glycerol backbone (phospholipase B activity) (By similarity). Has dual phospholipase and lysophospholipase activities toward diacylphospholipids (PubMed:9442065, PubMed:9442064, PubMed:11401559). Preferentially cleaves sn-2 ester bonds over sn-1 bonds (PubMed:9442064). Acts as a lipase toward glycerolipid substrates (PubMed:9442065, PubMed:9442064, PubMed:11401559). Hydrolyzes fatty acyl chains of diacylglycerols with preference for the sn-2 position and of triacylglycerols with not positional selectivity (PubMed:9442065, PubMed:9442064, PubMed:11401559). May also hydrolyze long chain retinyl esters such as retinyl palmitate (By similarity). May contribute to digestion of dietary phospholipids, glycerolipids and retinoids, facilitating lipid absorption at the brush border (Probable).
Expressed in the ileum mucosa, Paneth cells spermatocytes, spermatids and sperm (at protein level). Expressed in the ileum, jejunum, esophagus and testis.
Undergoes proteolytic cleavage in the ileum.
Up-regulated by bile acids such as deoxycholate (PubMed:9442065, PubMed:9442064). Inhibited by diisopropyl fluorophosphate (PubMed:9442065, PubMed:9442064).
First expressed at low levels at P15 in the epididymis. Expression increases from P30 onward. Reaches its highest level at P120 and remains at a stable level in mature animals.
May be a serine protease inhibitor (By similarity). Essential for sperm maturation and fertility. Inhibits sperm acrosome reaction, protecting sperm from premature reaction.
Restricted to the epididymis, with highest levels in the initial segment, including epithelial cells, lumen, and sperm (at protein level). Localizes to the sperm heads, where it is restricted to the acrosomal region in epididymal spermatozoa, but not in testicular spermatozoa (at protein level).
By 2D-PAGE, the determined pI of this protein (spot P2) is: 8.9, its MW is: 25 kDa.
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 (By similarity). Also involved in the sympathetic neuronal development (By similarity). Mediates, with CAPN3, the proteasome-independent degradation of p53/TP53 (By similarity).
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.
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 (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 (By similarity). 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 (By similarity).
Highly expressed in hypothalamus, in the dentate gyrus of hippocampus, cerebral cortex, cerebellum, liver and lung.
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 (By similarity). 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).
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. Interacts with RBPMS2.
Diphthamide is 2-[3-carboxyamido-3-(trimethyl-ammonio)propyl]histidine.
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.
Belongs to the bacterial ribosomal protein bL19 family.
Brain-specific. Expressed in neurons and rather enriched at synaptic junctions.
Interacts with DLG4 and DLGAP1 and forms a ternary complex.
May sustain the structure of the postsynaptic density (PSD).
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 (By similarity). 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.
G proteins are composed of 3 units, alpha, beta and gamma. Interacts with beta-1 and beta-3, but not with beta-2 (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).
Belongs to the opioid growth factor receptor family.
Detected in heart, brain, spleen, liver, skeletal muscle, kidney and testis.
Interacts with TBP (PubMed:8954946). 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 (By similarity). Interacts with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions are bridged by cullins and strongly inhibits the neddylation of cullins (By similarity).
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 (By similarity). May indirectly enhance transcription from various types of promoters.
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.
Transcription factor involved in unfolded protein response (UPR). Binds the DNA consensus sequence 5'-GTGXGCXGC-3' (By similarity). 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 (By similarity).
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.
Belongs to the 1-acyl-sn-glycerol-3-phosphate acyltransferase family.
May act as a transporter of organic cations based on a proton efflux antiport mechanism. May play a role in the transport of chloroquine and quinidine-related compounds in kidney (By similarity).
Autophosphorylated at Tyr-420 (By similarity). Phosphorylation on the C-terminal tail at Tyr-531 by CSK maintains the enzyme in an inactive state. PTPRC/CD45 dephosphorylates Tyr-531 leading to activation. Dephosphorylation at Tyr-420 by PTPN2 negatively regulates T-cell receptor signaling (By similarity). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).
Detected in spinal cord oligodendrocytes (at protein level).
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) (PubMed:15715669). 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 (By similarity). 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 (By similarity).
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.
Up-regulated during oligodendrocyte differentiation.
Orphan receptor. May regulate nociceptor function and/or development, including the sensation or modulation of pain.
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.
Oligomeric complex of 4 set of homotrimers.
S-nitrosylation at Cys-34 and Cys-39 alters the quaternary structure which results in a pro-inflammatory chemoattractive signaling activity with macrophages.
Probable regulator of exocrine pancreas development.
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 (By similarity). Interacts with USP20 and USP33 (By similarity). 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. Interacts with ARRDC3. Interacts with NEDD4 (By similarity). Interacts with MARCHF2.
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. Interacts with SERPINB2. Interacts with RFPL4A.
Up-regulated in prefrontal cortex (PFC) after nicotine exposure. Down-regulated by theophylline (THP) and 1,3-dinitrobenzene (DNB), two reprotoxic agents thought to induce infertility.
Detected in smooth muscle, in stomach and uterus, blood vessel wall, and in slow fibers in extraocular muscle, urinary bladder and sternothyroid muscle (at protein level).
Required for proper contractility of visceral smooth muscle cells (By similarity). Mediates nucleation of actin filaments (By similarity).
Belongs to the ubiquitin-activating E1 family.
Interacts with C3b. Interacts with C4b. Interacts with moesin/MSN.
May be involved in the fusion of the spermatozoa with the oocyte during fertilization.
Not expressed in embryonic and immature rats. Expressed in parallel with synthesis of spermatids.
Specifically expressed in testis. Within testis, present only in elongated spermatids and spermatozoa (at protein level).
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC5 subfamily.
Cation channel that gives rise to very low constitutive currents in the absence of activation. The activated channel exhibits selectivity for sodium and lithium, and is inhibited by amiloride.
Detected in brain, liver, duodenum, jejunum, ileum and testis.
Homotrimer or heterotrimer with other ASIC proteins.
Component of heteromultimeric potassium channels (PubMed:15356203, PubMed:14980206). Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Part of a heterooctamer composed of the tetrameric channel and four KCNIP1 chains (By similarity). Interacts with KCND3 and the N-terminal domain of KCND2. Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2 (PubMed:14980206). Self-associates to form homodimers and homotetramers. Interacts with KCNIP2 isoform 3 in a calcium-dependent manner.
Detected in hippocampus and in the molecular layer of the dentate gyrus (at protein level) (PubMed:15356203). Isoform 1 and isoform 2 are predominantly expressed at equal levels in brain. Colocalizes with KCND3 in inhibitory interneurons in cortex and hippocampus and in striatal interneurons.
Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels (PubMed:14980206). Regulates channel density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner (PubMed:14980206). Modulates KCND2/Kv4.2 currents (PubMed:14980206). In vitro, modulates KCND1/Kv4.1 currents (By similarity). Increases the presence of KCND2 at the cell surface (PubMed:14980206).
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.
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:7623849). Interacts with DNM1L; mediates its mitotic kinase cyclin B-CDK1-mediated phosphorylation during mitosis to promote mitochondrial fission. Interacts with the mitotic kinase cyclin B-CDK1 during mitosis. Interacts with the GTP-bound form of RALB (via effector domain) (By similarity). Interacts with REPS1; the interaction is direct and does not affect RALA-binding nor GTPase activator activity of RALBP1 (PubMed:9395447). 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. Interacts with AP2M1; as part of the AP2 complex. Interacts with CDC42. Interacts with RAC1 (By similarity).
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. As a GTPase-activating protein/GAP can inactivate CDC42 and RAC1 by stimulating their GTPase activity (PubMed:7623849, PubMed:9422736). As part of the Ral signaling pathway, may also regulate ligand-dependent EGF and insulin receptors-mediated endocytosis (PubMed:10393179). 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. During mitosis, also controls mitochondrial fission as an effector of RALA. Recruited to mitochondrion by RALA, acts as a scaffold to foster the mitotic kinase cyclin B-CDK1-mediated phosphorylation and activation of DNM1L (By similarity).
The Rho-GAP domain mediates the GTPase activator activity toward CDC42.
Tyrosine-phosphorylated upon stimulation of cells with EGF.
Belongs to the class-IV pyridoxal-phosphate-dependent aminotransferase family.
Brain, low expression in ovary and placenta, but not found in liver, kidney, and skeletal muscle.
Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine.
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 (By similarity).
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 (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 glycogen phosphorylase, glycogen synthase and phosphorylase kinase.
Ubiquitinated by NHLRC1/malin in a EPM2A/laforin-dependent manner.
Belongs to the complex I NDUFA7 subunit family.
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. The short isoform efficiently converts progelatinase A to the intermediate form but not to the mature one. 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.
Interacts with CSPG4 through CSPG4 chondroitin sulfate glycosaminoglycan.
Strongly expressed in the lung, brain and smooth muscle cells. Weakly detectable in the spleen and liver and indetectable in the heart, skeletal muscle and kidney.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9. In the complex, it probably interacts directly with COPS2, COPS3, COPS4 and COPS5. Interacts directly with inositol kinase ITPK1. Interacts with CAPN8.
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 (By similarity).
The N-terminal part (1-196), 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).
Widely expressed. Highly expressed in testis.
Detected in liver and kidney (at protein level).
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides.
Belongs to the sarcoglycan beta/delta/gamma/zeta family.
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 a putative PH domain present in its tail domain.
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 (By similarity). Interacts (via its IQ motifs) with CALM; this precludes interaction with YWHAB (By similarity). Interacts with YWHAB; this precludes interaction with CALM (By similarity). Interacts with RPS6 (By similarity). Interacts with actin (By similarity). Interacts with LLPH (By similarity). Interacts with GLUT4 (PubMed:22918957). Interacts (via its IQ motifs) with SH3BGRL3; the interaction is dependent on calcium and takes place at membrane ruffles (By similarity).
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 (By similarity).
Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P) (By similarity). 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 (By similarity). Regulates lysosomal positioning by recruiting JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules (By similarity). Contributes to assembly of the V-ATPase complex in lipid rafts of the lysosomal membrane and to subsequent amino acid-dependent activation of mTORC1 (By similarity). May play a role in the regulation of cellular cholesterol metabolism (By similarity).
Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P).
Interacts (via transmembrane domain) with ATP6V0D1 (By similarity). Interacts with LAMTOR1, RRAGA and RRAGC (By similarity).
Expressed in testis. Exclusively expressed in haploid spermatids and very weakly in spermatogonia, spermatocytes, and Sertoli cells as well as in interstitial cell.
Involved in the differentiation of haploid spermatids.
This protein hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans (GPI-anchor) thus releasing these proteins from the membrane.
Expressed in all tissues examined including brain, eye, lung, heart, liver, kidney, pancreas, placenta and testis. Highest levels of expression in eye, lung, liver, placenta and kidney. Expressed throughout the suprachiasmatic nucleus (SCN).
Homodimer or homomultimer (By similarity). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSKN1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with PER2; the interaction with PER2 is via its second PAS domain (PubMed:11112428). Interacts directly with PER1 and PER3 (By similarity). Interacts with CRY2, CHEK1, ATR and ATRIP (By similarity). Interacts with CRY1 (By similarity). Interacts with CLSPN; the interaction is required for leading-strand replication. Interacts with TIPIN. Associates with the MCM2-7 complex. Interacts with DNA polymerases alpha, delta and epsilon. Interacts with DDX11; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea. Interacts with PARP1; interaction is direct and independent of poly-ADP-ribose (By similarity).
In both brain and pancreas, no circadian oscillation was detected.
Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication, DNA repair and in the regulation of the circadian clock (By similarity). Required to stabilize replication forks during DNA replication by forming a complex with TIPIN: this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. During DNA replication, inhibits the CMG complex ATPase activity and activates DNA polymerases catalytic activities, coupling DNA unwinding and DNA synthesis (By similarity). TIMELESS promotes TIPIN nuclear localization (By similarity). Involved in cell survival after DNA damage or replication stress by promoting DNA repair (By similarity). In response to double-strand breaks (DSBs), accumulates at DNA damage sites and promotes homologous recombination repair via its interaction with PARP1 (By similarity). May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light (By similarity). Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock (By similarity). Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus (By similarity). May also play an important role in epithelial cell morphogenesis and formation of branching tubules (PubMed:10963667).
Component of the large ribosomal subunit (By similarity). Interacts with CRY1 (By similarity). Interacts with DICER1, AGO2, TARBP2, MOV10 and EIF6; they form a large RNA-induced silencing complex (RISC) (By similarity).
Plays a role during the calcification of cartilage and the transition of cartilage to bone.
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).
A serine-rich region promotes activation of the serum response element (SRE).
Contains a central domain (substrate domain) containing multiple potential SH2-binding sites and a C-terminal domain containing a divergent helix-loop-helix (HLH) motif. The SH2-binding sites putatively bind CRK, NCK and ABL SH2 domains. The HLH motif is absolutely required for the induction of pseudohyphal growth in yeast and mediates heterodimerization with NEDD9.
Docking protein which plays a central coordinating role for tyrosine-kinase-based signaling related to cell adhesion (By similarity). Implicated in induction of cell migration and cell branching (By similarity). Involved in the BCAR3-mediated inhibition of TGFB signaling (By similarity).
Forms complexes in vivo with PTK2/FAK1, adapter protein CRKL and LYN kinase. Can heterodimerize with NEDD9. Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (By similarity). Within the complex, interacts with SH2D3C (via C-terminus), and CRK (By similarity). Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on intergrin mediated-tyrosine phosphorylation of PTPRA (By similarity). Interacts with BCAR3 (via Ras-GEF domain); the interaction regulates adhesion-dependent serine phosphorylation (By similarity). Interacts with SMAD2 and SMAD3 (By similarity). Interacts with NPHP1 (By similarity). Interacts with PTK2B/PYK2 (By similarity). Interacts (via C-terminus) with SH2D3C/CHAT isoform 2 (via C-terminus) (By similarity). Interacts with activated CSPG4. Interacts with BMX, INPPL1/SHIP2 and PEAK1 (By similarity). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas (By similarity). Interacts with TNK2 via SH3 domains. Interacts with PTK2B/PYK2 (By similarity). Interacts (when tyrosine-phosphorylated) with tensin TNS1; the interaction is increased by phosphorylation of TNS1 (By similarity).
PTK2/FAK1 activation mediates phosphorylation at the YDYVHL motif; phosphorylation is most likely catalyzed by SRC family members. SRC-family kinases are recruited to the phosphorylated sites and can phosphorylate other tyrosine residues. Tyrosine phosphorylation is triggered by integrin mediated adhesion of cells to the extracellular matrix.
Phosphorylated by SRC kinase in a EDN1- and PTK2B-mediated manner; phosphorylation strengthens its interaction with BCAR3 as part of the PTK2B/BCAR1/BCAR3/RAP1 signaling pathway.
The SH3 domain is necessary for the localization of the protein to focal adhesions and interacts with one proline-rich region of PTK2/FAK1.
Widely expressed. Higher expression in lung, intestine and testis.
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.
Mainly expressed in the Purkinje cell of cerebellum.
Monomer. May interact with SFRS7 and SFRS9/SRP30C.
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.
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 (By similarity).
Manganese or magnesium. Binds 1 divalent metal ion per monomer in the absence of substrate. May bind a second metal ion after substrate binding.
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. 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. Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A5/ANT2 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity). Proton transporter activity requires free fatty acids as cofactor, but does not transport it. Probably mediates mitochondrial uncoupling in tissues that do not express UCP1. 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. It is however unclear if SLC25A5/ANT2 constitutes a pore-forming component of mPTP or regulates it (By similarity). Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity). As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation (By similarity).
Monomer (By similarity). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5/ANT2. Interacts with AK4 (By similarity). Interacts with TIMM44; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
Present in kidney, brain, heart, liver and skeletal muscle.
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.
In liver, lung, intestines, thymus and brain (mostly in the cerebral cortex and hippocampus).
Not expressed in the fetal lung, but is expressed at high levels 2 weeks after birth.
This is a receptor for VIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Belongs to the immunoglobulin superfamily. AMIGO family.
May mediate heterophilic cell-cell interaction. May contribute to signal transduction through its intracellular domain.
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, Muc1b, rMuc-2 or mG-Muc substrates.
Interacts with EXT2. Does not interact with EXT1, EXTL1 or EXTL3 (By similarity).
Predominantly expressed in sublingual gland. Expressed at lower level in stomach and small intestine. Weakly or not expressed in submandibular gland, parotid gland, kidney, liver, heart, brain, spleen, lung, skeletal muscle, testis, ovary, cervix and uterus.
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 (By similarity). Interacts with DLG4, PDLIM5, PDLIM7 and LZTS3. Interacts with the actin cytoskeleton.
Phosphorylated at Ser-1367 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.
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.
Ubiquitinated and degraded by the SCF(BTRC) following phosphorylation by PLK2.
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.
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.
The C-terminal coiled-coil domain mediates homotrimerization of CNGA subunits.
Abundant in the brain. Expressed at low levels in the aorta, uterus and intestine.
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton (symport system).
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. After binding to its receptor IL1R1 together with its accessory protein IL1RAP, forms the high affinity interleukin-1 receptor complex. Signaling involves the recruitment of adapter molecules such as MYD88, IRAK1 or IRAK4. In turn, mediates the activation of NF-kappa-B and the three MAPK pathways p38, p42/p44 and JNK pathways. 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. 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.
Monomer. Interacts with TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion. Interacts with IL1R1. 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.
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.
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 (By similarity). 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 (By similarity). Contributes to the synthesis of O-linked glycans on mucins and proteoglycans of the central nervous system (By similarity). Can glycosylate both unmodified peptides and glycopeptides that already contain an O-linked GalNAc sugar. Transfers GalNAc to Thr-/Ser-rich tandem repeats GTTPSPVPTTSTTSAP of MUC5AC. Transfers GalNAc to three consecutive serine/threonine residues on SDC3 forming a triplet-Tn epitope expressed in Purkinje cells of the developing brain (By similarity). May promote neurogenesis through glycosylation and stabilization of PDPN (By similarity).
Interacts with C1QBP; the association may represent a cell surface C1q receptor.
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.
Widely expressed. Highly expressed in lung and heart. Expressed at lower level in brain, thymus, liver, spleen, intestine, kidney, adrenal gland, muscle and testis. Expressed on endothelial cells, platelets, undifferentiated monocytes and circulating natural killer cells.
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 (By similarity).
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.
Primarily expressed in spleen, thymus, heart, lung and intestine and, at lower levels, in liver, kidney, stomach and muscle (PubMed:12031988). In the spleen, expressed in periarteriolar lymphatic sheets (PubMed:12031988). In the thymus, detected in the medulla (PubMed:12031988).
(Microbial infection) Interacts with NS1 from parvovirus H-1 (PubMed:9557704).
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. Functions in tail-anchored/type II transmembrane proteins membrane insertion constituting with ASNA1 and the BAG6 complex a targeting module. Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins. 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. Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins associated with the BAG6 complex (By similarity). Binds directly to HSC70 and HSP70 and regulates their ATPase activity (PubMed:12878599).
Homodimer (By similarity). Homooligomer (PubMed:12878599). Interacts with DNAJC5 and DNAJC5B (By similarity). Interacts (via TPR repeats) with HSP90AA1 (PubMed:15708368). Interacts (via Gln-rich region) with SLC2A1 (By similarity). Interacts with HSP90AB1 (By similarity). Interacts (via TPR repeats) with HSPA8/Hsc70; the interaction is direct (PubMed:15708368). Interacts with BAG6 (via ubiquitin-like domain); interaction prevents interaction between BAG6 and RNF126 (By similarity). Forms a multiprotein complex, at least composed of DNAJB12, DNAJB14, HSPA8/Hsc70 and SGTA; interaction with DNAJB14 and HSPA8/Hsc70 is direct (By similarity).
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).
Interacts with GRID2 and may also interact with GRID1 (PubMed:11829466). Interacts with EML3 (By similarity). Binds unpolymerized tubulins via its WD repeat region (By similarity).
Tubulin binding protein that inhibits microtubule nucleation and growth, resulting in shorter microtubules.
Widely expressed in both brain and peripheral tissues, including brainstem and enrichment in the postsynaptic density, PSD.
Belongs to the ALG10 glucosyltransferase family.
Highly expressed in brain, skeletal muscle, uterus, small intestine and liver. Moderately expressed in lung and kidney. Weakly expressed in heart and stomach.
Putative alpha-1,2-glucosyltransferase, which adds the third glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Glc(2)Man(9)GlcNAc(2)-PP-Dol (By similarity). When coupled to KCNH2 may reduce KCNH2 sensitivity to classic proarrhythmic drug blockade, possibly by mediating glycosylation of KCNH2 (PubMed:9722534, PubMed:14525949). Has a role in maintenance of cochlear outer hair cell function (By similarity).
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 (By similarity).
Alpha- and beta-B subunits are the predominant forms found in rat testis. Also expressed in ovary.
Homodimer or heterodimer; disulfide-linked. 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 (By similarity).
Increased expression in methimazole-induced goiter.
A cysteine residue is required for ubiquitin-thioester formation.
Activated by NDFIP1- and NDFIP2-binding.
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 (By similarity). Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Is 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 (PubMed:20159449). Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (By similarity). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (By similarity). Ubiquitinates DAZAP2, leading to its proteasomal degradation (By similarity). Ubiquitinates POLR2A (By similarity).
Interacts with UBE2D2. 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, NDFIP1, and PRRG2 (By similarity). Interacts (via C2 domain) with GRB10 (via SH2 domain) (By similarity). Binds SCNN1A, SCNN1B and SCNN1G (PubMed:8665844, PubMed:11323714). Interacts with ERBB4. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interacts with TNIK; the interaction is direct, allows the TNIK-dependent recruitment of RAP2A and its ubiquitination by NEDD4 (PubMed:20159449). Interacts (via WW3 domain) with TNK2; EGF promotes this interaction. Interacts (via WW3 domain) with FGFR1 (via C-terminus). Interacts with OTUD7B (By similarity). Interacts with ISG15 (By similarity). 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) (By similarity). Interacts with LAPTM4B; may play a role in the lysosomal sorting of LAPTM4B (By similarity). Interacts with ZBTB7B (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (By similarity). Interacts directly with LDLRAD3; this interaction promotes NEDD4 auto-ubiquitination (By similarity). Interacts with ADRB2 (By similarity). Interacts (via WW domains) with DAZAP2 (via PPAY motif) (By similarity).
The WW domains mediate interaction with PPxY motif-containing proteins (By similarity). The WW domains mediate interaction with LITAF, RNF11, WBP1, WBP2, PMEPAI, NDFIP1 and PRRG2 (By similarity).
Ubiquitously expressed. Expression is highest in lung, kidney and brain.
Plays role in pre-mRNA splicing as core component of the SMN-Sm complex that mediates spliceosomal snRNP assembly and as component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes. Is also a component of the minor U12 spliceosome. As part of the U7 snRNP it is involved in histone 3'-end processing.
Belongs to the eukaryotic ribosomal protein eS6 family.
Component of the 40S small ribosomal subunit (By similarity). Plays an important role in controlling cell growth and proliferation through the selective translation of particular classes of mRNA (By similarity).
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.
Chromatin reader component of some histone acetyltransferase (HAT) SAGA-type complexes like the TFTC-HAT, ATAC or STAGA complexes (By similarity). SGF29 specifically recognizes and binds methylated 'Lys-4' of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3) (By similarity). In the SAGA-type complexes, SGF29 is required to recruit complexes to H3K4me (By similarity). Involved in the response to endoplasmic reticulum (ER) stress by recruiting the SAGA complex to H3K4me, thereby promoting histone H3 acetylation and cell survival (By similarity). Also binds non-histone proteins that are methylated on Lys residues: specifically recognizes and binds CGAS monomethylated on 'Lys-491' (By similarity). May be involved in MYC-mediated oncogenic transformation (PubMed:17334388).
Interacts with dimethylated and trimethylated 'Lys-4' of histone H3 (H3K4me2 and H3K4me3), with a preference for the trimethylated form (H3K4me3) (By similarity). Component of some SAGA-type complexes. Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (By similarity). Interacts with (methylated) CGAS (By similarity). Interacts with TADA3L, GCN5L2, SUPT3H and MYC (PubMed:17334388).
The SGF29 C-terminal (also named tudor-like) domain mediates binding to methylated 'Lys-4' of histone H3 (H3K4me).
Widely expressed with highest levels in testis. Highly expressed in hepatoma and other tumor cell lines.
Binds 1 heme b (iron(II)-protoporphyrin IX) group covalently per monomer.
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.
Binds AP2A2. Interacts with AP2B1; clathrin competes with SNAP91.
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. The form with phosphorylated O-linked N-acetylglucosamine is predominant in brain synaptosomes. There is no evidence for direct Thr-310 phosphorylation (PubMed:21500857).
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 (By similarity).
Belongs to the WD repeat G protein beta family. Ribosomal protein RACK1 subfamily.
Monomer; also forms homodimers and homooligomers (By similarity). Interacts with CPNE3 (By similarity). May interact with ABCB4 (By similarity) Component of the small (40S) ribosomal subunit (PubMed:15340087). Interacts with LARP4. Interacts with LARP4B. Interacts with PKD2L1 (By similarity). Binds SLC9A3R1. Forms a ternary complex with TRIM63 and PRKCE. Interacts with HABP4, KRT1 and OTUB1. Interacts with SRC (via SH2 domain); the interaction is enhanced by tyrosine phosphorylation of RACK1. Recruited in a circadian manner into a nuclear complex which also includes BMAL1 and PRKCA. Interacts with AR. Interacts with IGF1R but not with INSR. Interacts with ADAM12. Interacts with CLEC1B (via N-terminal region) and with HIF1A; the interaction promotes their degradation. Interacts with RHOA; this enhances RHOA activation and promotes cell migration. Interacts with CHRM2; the interaction regulates CHRM2 internalization. Interacts with TRPM6 (via kinase domain). Interacts with PTK2/FAK1; required for PTK2/FAK1 phosphorylation and dephosphorylation. Interacts with FLT1. Interacts with HRAS.
Phosphorylated on Tyr-228 and/or Tyr-246 by SRC. This is required for binding to SRC (By similarity).
Scaffolding protein involved in the recruitment, assembly and/or regulation of a variety of signaling molecules. Interacts with a wide variety of proteins and plays a role in many cellular processes. Component of the 40S ribosomal subunit involved in translational repression (PubMed:15340087). Involved in the initiation of the ribosome quality control (RQC), a pathway that takes place when a ribosome has stalled during translation, by promoting ubiquitination of a subset of 40S ribosomal subunits (By similarity). Binds to and stabilizes activated protein kinase C (PKC), increasing PKC-mediated phosphorylation. May recruit activated PKC to the ribosome, leading to phosphorylation of EIF6. Inhibits the activity of SRC kinases including SRC, LCK and YES1. Inhibits cell growth by prolonging the G0/G1 phase of the cell cycle. Enhances phosphorylation of BMAL1 by PRKCA and inhibits transcriptional activity of the BMAL1-CLOCK heterodimer. Facilitates ligand-independent nuclear translocation of AR following PKC activation, represses AR transactivation activity and is required for phosphorylation of AR by SRC. Modulates IGF1R-dependent integrin signaling and promotes cell spreading and contact with the extracellular matrix. Involved in PKC-dependent translocation of ADAM12 to the cell membrane. Promotes the ubiquitination and proteasome-mediated degradation of proteins such as CLEC1B and HIF1A. Required for VANGL2 membrane localization, inhibits Wnt signaling, and regulates cellular polarization and oriented cell division during gastrulation. Required for PTK2/FAK1 phosphorylation and dephosphorylation. Regulates internalization of the muscarinic receptor CHRM2. Promotes apoptosis by increasing oligomerization of BAX and disrupting the interaction of BAX with the anti-apoptotic factor BCL2L. Inhibits TRPM6 channel activity. Regulates cell surface expression of some GPCRs such as TBXA2R. Plays a role in regulation of FLT1-mediated cell migration. Involved in the transport of ABCB4 from the Golgi to the apical bile canalicular membrane.
The 7 WD repeats mediate protein-protein interactions with binding partners.
Expressed in the ovary, essentially in granulosa cells in a follicle-stage specific manner. Highest levels found in large luteinizing granulosa cells.
Homotrimer (By similarity). Interacts with TGFB1; the interaction inhibits TGFB-mediated signaling. Interacts with BMP4; the interaction inhibits BMP4-mediated signaling. Interacts with TGFB2, GDF5 and MYH9 (By similarity).
In the developing ovary, high expression, especially of the longer isoform, at 12 days of age after birth. Expression restricted to the interstitial cells surrounding the follicles. Levels are further increased during ovarian maturation.
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 (By similarity).
Belongs to the Antp homeobox family. Labial subfamily.
Highly expressed in neocortex, hippocampus, striatum and spinal cord by astrocytes (at protein level) (PubMed:15390093). Expressed in brain, lung, stomach, kidney, spleen and testis (PubMed:11698233). Expressed in the cerebral cortex between the second and third postnatal week, where expressed exclusively in glial cells from postnatal day 14 to adulthood (at protein level) (PubMed:24333324). Expressed in the cerebellum at post natal day 12 (P12) (PubMed:24333324). Expressed in liver (PubMed:15218073, PubMed:11698233). Expressed inside the cell body of the astrocytes (PubMed:22821889).
Nakanishi et al (PubMed:11698233) shows that the transport process is electrogenic, contrary to the conclusions of Hamdani et al (PubMed:22821889) who finds that the transport is electroneutral with a Na(+):L-glutamine stoichiometry of 1:1 (PubMed:22821889, PubMed:11698233). Hamdani et al. shows that this electrogenic transport describes by Nakanishi et al. would correspond to large uncoupled fluxes of protons (PubMed:22821889, PubMed:11698233).
Not inhibited by lithium (By similarity). Partial allosteric regulation on ions sodium binding (PubMed:16629640).
Symporter that cotransports neutral amino acids and sodium ions, coupled to an H(+) antiporter activity (PubMed:11698233, PubMed:16629640, PubMed:15218073, PubMed:22821889, PubMed:16249471). Releases L-glutamine and glycine from astroglial cells and may participate in the glutamate/GABA-glutamine cycle and the NMDA receptors activation (PubMed:22821889). In addition contributes significantly to L-glutamine uptake in retina, namely in ganglion and Mueller cells and, therefore participates in the retinal glutamate-glutamine cycle (PubMed:16249471). The transport activity is pH sensitive (PubMed:22821889, PubMed:15218073 and PubMed:11698233), Li(+) tolerant (PubMed:22821889, PubMed:15218073 and PubMed:11698233), bidirectional (PubMed:22821889 and PubMed:15218073) and associated with large uncoupled fluxes of protons (PubMed:22821889, PubMed:15218073, PubMed:11698233). The transport is electroneutral coupled to the cotransport of 1 Na(+) and the antiport of 1 H(+) (PubMed:22821889). May have particular importance for modulation of net hepatic glutamine flux (PubMed:15218073).
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. Required for normal skeletal muscle strength. Plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats.
Detected in skeletal muscle (at protein level). Detected in skeletal muscle.
Homooligomer of variable subunit number; disulfide-linked. Interacts with CASQ1 in skeletal muscle. Interacts with CASQ2 (By similarity). Interacts with RYR1 in skeletal muscle.
Homooligomer (By similarity). Interacts (via SAM domain) with ANKS6 (via SAM domain) (PubMed:25671767). 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 (By similarity).
Hydroxylated at Asn-96, most probably by HIF1AN.
May be involved in vasopressin signaling in the kidney.
Phosphorylations at Ser-5, Ser-225, Thr-318, Ser-319, Ser-366 and Ser-369 occur in a NEK7-dependent manner.
The SAM domain mediates homooligomerization.
Component of the gamma-secretase complex.
Potential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors.
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 (By similarity).
Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors. Plays an essential role in phototransduction, by mediating cGMP replenishment. May also participate in the trafficking of membrane-asociated proteins to the photoreceptor outer segment membrane.
Expressed in retina and enriched in photoreceptor outer segments.
Homodimer; requires homodimerization for guanylyl cyclase activity (PubMed:9153227). Interacts (via C-terminus) with RD3 (via C-terminus); promotes the exit of GUCY2E from the endoplasmic reticulum and its trafficking to the photoreceptor outer segments (By similarity). Interaction with RD3 negatively regulates GUCY2E guanylate cyclase activity (By similarity).
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.
Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I.
Component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP). Required for the early cleavages during pre-18S ribosomal RNA processing.
Transport protein involved in the redistribution of lysosomes to the peri-Golgi region (By similarity). Plays a role in the maturation of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays a role in the fusion of phagosomes with lysosomes (By similarity). Acts also as a positive regulator of hedgehog signaling and regulates ciliary function (By similarity).
Binds to and inhibits kallikreins. Inhibits trypsin but not chymotrypsin or elastase.
By growth hormone, thyroid hormone and sex hormones. Its expression is reduced by inflammation. In male rats, its level is several fold higher than in female rats. Reduced during acute inflammation.
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 serpin reactive site and the protease. The resulting inactive serpin-protease complex is highly stable (By similarity). Variability within the reactive center loop (RCL) sequences of Serpina3 paralogs may determine target protease specificity.
The single human alpha1-antichymotrypsin gene (SERPINA3) is represented by a cluster of 6 individual rat paralogs.
Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM5/TYW2 family.
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 (By similarity).
Involved in tRNA methylation. Facilitates the recognition and targeting of tRNA(Arg)(CCU) and tRNA(Arg)(UCU) substrates for N(3)-methylcytidine modification by METTL2.
Part of a complex containing tRNA(Arg) and METTL2. Interacts with tRNA(Arg)(CCU) and tRNA(Arg)(UCU). Interacts with METTL2.
Brain-specific. Predominantly cerebellar granule cells.
Interacts with PKD1; this prevents rapid proteasomal degradation. Interacts with GNB5. Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with GNB5. Interacts (phosphorylated form) with 14-3-3 protein YWHAQ. Interacts with SNAPIN. Interacts with GNAI1 (By similarity). Interacts with GNAO1, GNAI3 and GNAZ (PubMed:10092682).
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. The RGS7/GNB5 dimer enhances GNAO1 GTPase activity. May play a role in synaptic vesicle exocytosis. Modulates the activity of potassium channels that are activated by GNAO1 in response to muscarinic acetylcholine receptor M2/CHRM2 signaling (PubMed:10092682).
Ubiquitinated, leading to rapid proteasomal degradation.
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.
Interacts with RARB. 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.
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.
Widely expressed. Highest levels in heart, liver, skeletal muscle and kidney.
Homodimer. Interacts with MUC1 and promotes cell aggregation in epithelial cells. Interacts with ARHGEF26/SGEF. Interacts (on T cell side) with CD81, CD247 and CD9 at immunological synapses between antigen-presenting cells and T cells.
ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). During leukocyte trans-endothelial migration, ICAM1 engagement promotes the assembly of endothelial apical cups through ARHGEF26/SGEF and RHOG activation (By similarity).
Monoubiquitinated, which is promoted by MARCH9 and leads to endocytosis.
Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.
Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. Probably involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.
With succinic semialdehyde or 4-nitrobenzaldehyde as substrate, it exhibits a substantially greater specific activity with NADPH than with NADH Conversely, it has a 3-fold higher activity towards 2-carboxybenzaldehyde with NADH than with NADPH.
Homodimer; disulfide-linked. Interacts with TXN/thioredoxin through its redox-active site. Interacts with transcriptional repressors ZBTB16, ZBTB32 and HDAC1 (By similarity). Interacts (via C-terminus) with ITCH (via WW domains). Interacts with DDIT4 (By similarity).
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. Inhibits the proteasomal degradation of DDIT4, and thereby contributes to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1) (By similarity). 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 (By similarity).
Ubiquitinated; undergoes polyubiquitination catalyzed by ITCH resulting in proteasomal degradation.
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 at high levels in brain, mainly in neurons in different regions, including brain stem, hippocampus, cortex and cerebellum. Also expressed in cerebral vasculature. Not detected in kidney, nor liver.
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 (By similarity).
Widely expressed with high levels in brain, heart, placenta, skeletal muscle, testis, thymus and spleen.
Catalyzes the oxidation of uric acid to 5-hydroxyisourate, which is further processed to form (S)-allantoin.
Expressed in liver. Not detected in other tissues tested.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A4 subfamily.
Expressed in the intestinal crypt epithelial cells and myenteric neurons of the small intestine (at protein level) (PubMed:8601815). Expressed in the brain (PubMed:1944572).
Monomer or homooligomer (PubMed:10716733). Interacts with TGFB1I1. 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 (By similarity). Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly (PubMed:16870614). Interacts with filamentous actin and STX1A (PubMed:11709063). Interacts with ITGAV:ITGB3 (By similarity).
Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.
Reported to be glycosylated with sialylated N-glycans and in its sialylated form to interact with MYH9 (PubMed:12944413). However, this publication was retracted due to image duplication in the figures.
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.
This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
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.
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.
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 (By similarity).
Detected in cartilage, cardiac valves and valvular interstitial cells (at protein level). Expressed in eye.
Expression first detected in heart at 9.5 dpc and persisted in the adult.
Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2. Interacts with PIGQ. Interacts with the heterodimer PIGA:PIGH.
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.
Calcium-selective channel required to prevent calcium stores from overfilling, thereby playing a key role in calcium homeostasis. 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. Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis. 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.
Homodimer and homotetramer. Homodimer under resting conditions; forms homotetramers following and ER calcium overload. 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.
May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.
Nine of the thirteen 22-amino acid tandem repeats (each 22-mer is actually a tandem array of two, A and B, related 11-mers) occurring in this sequence are predicted to be highly alpha-helical, and many of these helices are amphipathic. They may therefore serve as lipid-binding domains with lecithin:cholesterol acyltransferase (LCAT) activating abilities.
Myristoylated in vitro; myristoylation is not essential for protein targeting to Golgi compartment.
Necessary for correct organization of Golgi apparatus. Involved in bone development.
Belongs to the HAD-like hydrolase superfamily. EYA family.
Cilium- and flagellum-specific protein that plays a role in axonemal structure organization and motility. May play a role in outer and inner dynein arm assembly.
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 (By similarity). 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 (By similarity). 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 (By similarity).
Acts as a guanine nucleotide exchange factor (GEF) for ARF1.
Expressed at 18 dpc in hippocampal neurons.
Expressed in brain. Localized to dendrites, as well as somas of neuronal cells.
Interacts with DLG1 and DLG4 (PubMed:15189337). Interacts with GPHN (By similarity).
Belongs to the PIEZO (TC 1.A.75) family.
Myosin is a hexamer of 2 heavy chains and 4 light chains.
Myosin regulatory subunit that plays an essential to maintain muscle integrity during early development (By similarity). Plays a role in muscle contraction (By similarity).
Becomes detectable in testis between postnatal days 15 and 21 and expression levels remain high in the adult. Not detected in fetal testis.
Expressed in testis, predominantly in elongated spermatids (at protein level) (PubMed:14585816, PubMed:16643851). Detected in spermatocytes only at the mRNA, but not at the protein level (PubMed:14585816).
Plays a role in spermatogenesis (By similarity). When overexpressed, prevents nuclear localization of HIF1A (By similarity).
Processed into N-terminal 27-kDa and C-terminal 55-kDa fragments.
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.
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.
Interacts with RALA through the TIG domain.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (PubMed:9405631, PubMed:26582389). Interacts with EXOC3L1 (By similarity). Interacts with GNEFR/DELGEF; this interaction occurs only in the presence of magnesium or manganese and is stimulated by dCTP or GTP (By similarity). Interacts with RALA and RALB (PubMed:11744922, PubMed:12839989). Interacts with ARL13B; regulates ARL13B localization to the cilium membrane.
Seems to promote the survival of visceral and proprioceptive sensory neurons.
Belongs to the glycosyl hydrolase 30 family.
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 (via the N-terminal Ubl domain) with PRKN. Interacts (via N-terminal region) with PINK1. Interacts with PSMF1 (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. 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 (By similarity).
The proline-rich region is important for protein-protein interactions.
The ubiquitin-like region mediates interaction with PRKN.
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. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with 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. OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits. OST can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes. The association of TUSC3 or MAGT1 with the STT3B-containing complex seems to be mutually exclusvice.
May be involved in Mg(2+) transport in epithelial cells.
Potential multifunctional C-type lectin receptor that may play roles in endocytosis and phagocytosis as well as in cell adhesion and migration.
Homodimer (By similarity). Directly interacts with KIF14 depending on the activation state (stronger interaction with the kinase-dead form) (By similarity). Interacts with TTC3 (By similarity).
Plays a role in cytokinesis (By similarity). Required for KIF14 localization to the central spindle and midbody (By similarity). Putative RHO/RAC effector that binds to the GTP-bound forms of RHO and RAC1 (By similarity). It probably binds p21 with a tighter specificity in vivo (By similarity). Displays serine/threonine protein kinase activity (By similarity). Plays an important role in the regulation of cytokinesis and the development of the central nervous system (PubMed:24695496). Phosphorylates MYL9/MLC2 (By similarity).
Plays a role in cytokinesis. Displays serine/threonine protein kinase activity.
Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism. Beta-D-galactose is metabolized in the liver into glucose 1-phosphate, the primary metabolic fuel, by the action of four enzymes that constitute the Leloir pathway: GALM, GALK1 (galactokinase), GALT (galactose-1-phosphate uridylyltransferase) and GALE (UDP-galactose-4'-epimerase). Involved in the maintenance of the equilibrium between the beta- and alpha-anomers of galactose, therefore ensuring a sufficient supply of the alpha-anomer for GALK1. Also active on D-glucose although shows a preference for galactose over glucose.
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.
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes retinyl esters (PubMed:12230550). Hydrolyzes p-nitrophenyl butyrate (PNPB), triacylglycerol and monoacylglycerol. Shows higher activity against PNPB, a short-chain fatty acid ester, than against triolein, a long-chain fatty acid ester. Shows no detectable activity against diacylglycerol, cholesterol ester or phospholipids. May play a role in adipocyte lipolysis (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. C5-methyltransferase family.
Receptor for Dickkopf proteins. Cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt receptors LRP5 and LRP6.
Highly expressed during development in ventricular zone, intermediate zone, cortical plate, striatum, hippocampus, and brain stem.
Homodimer. Interacts with AP2M1; required for clathrin-mediated endocytosis (By similarity).
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 (By similarity).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-10/CHRNA10 sub-subfamily.
Expressed in the outer hair cells of the cochlea and the neurons of dorsal root ganglia.
Expression in the inner hair cells of the ear is lost at the onset of hearing, around P12. This correlates with a loss of sensitivity of these cells to cholinergic stimuli.
Forms heterooligomeric channels in conjunction with CHRNA9. The native outer hair cell receptor may be composed of CHRNA9-CHRNA10 heterooligomers. Interacts with the conotoxin GeXXA (PubMed:26395518). Interacts with the alpha-conotoxin RgIA (PubMed:25740413).
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this leads to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma.
The heterooligomeric receptor composed of CHRNA9 and CHRNA10 has an atypical pharmacological profile, binding several non-nicotinic ligands including strychnine (a glycine receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist).
Belongs to the bZIP family. Fos subfamily.
Constitutively sumoylated with SUMO1, SUMO2 and SUMO3. Desumoylated by SENP2. Sumoylation requires heterodimerization with JUN and is enhanced by mitogen stimulation. Sumoylation inhibits the AP-1 transcriptional activity and is, itself, inhibited by Ras-activated phosphorylation on Thr-232 (By similarity).
Heterodimer; with JUN (By similarity). Component of the SMAD3/SMAD4/JUN/FOS complex required for synergistic TGF-beta-mediated transcription at the AP1-binding site (By similarity). Interacts with SMAD3; the interaction is weak even on TGF-beta activation (By similarity). Interacts with MAFB (PubMed:9571165). Interacts with DSIPI; this interaction inhibits the binding of active AP1 to its target DNA (By similarity). Interacts with CDS1 and PI4K2A (By similarity). Interacts (via bZIP domain and leucine-zipper region) with the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF) subunits SMARCB1, SMARCC2 and SMARCD1 (By similarity). Interacts (via bZIP domain and leucine-zipper region) with ARID1A (By similarity).
In quiescent cells, the small amount of FOS present is phosphorylated at Tyr-10 and Tyr-30 by SRC. This Tyr-phosphorylated form is cytosolic. In growing cells, dephosphorylated by PTPN2. Dephosphorylation leads to the association with endoplasmic reticulum membranes and activation of phospholipid synthesis (By similarity).
Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex, at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling (By similarity). Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum (By similarity).
Phosphorylated in the C-terminal upon stimulation by nerve growth factor (NGF) and epidermal growth factor (EGF) (By similarity). Phosphorylated, in vitro, by MAPK and RSK1. Phosphorylation on both Ser-362 and Ser-374 by MAPK1/2 and RSK1/2 leads to protein stabilization with phosphorylation on Ser-374 being the major site for protein stabilization on NGF stimulation. Phosphorylation on Ser-362 and Ser-374 primes further phosphorylations on Thr-325 and Thr-331 through promoting docking of MAPK to the DEF domain. Phosphorylation on Thr-232, induced by HA-RAS, activates the transcriptional activity and antagonizes sumoylation. Phosphorylation on Ser-362 by RSK2 in osteoblasts contributes to osteoblast transformation.
This protein is a cell adhesion molecule involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, etc.
Belongs to the small GTPase superfamily. Rheb family.
Binds GTP and exhibits intrinsic GTPase activity. May activate NF-kappa-B-mediated gene transcription. Promotes signal transduction through MTOR, activates RPS6KB1, and is a downstream target of the small GTPase-activating proteins TSC1 and TSC2 (By similarity).
Both isoform 1 and isoform 2 appear to be restricted to the brain. Isoform 2 is strongly expressed in the neurons of the subventricular zone and granule cells of the olfactory bulb, Islands of Calleja, hippocampal dentate gyrus and cerebellum.
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 (By similarity). 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. Isoform 2 may play a role in neuronal transcriptional regulation.
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. Also functions as a guanyl-nucleotide exchange factor/GEF for the MFN1 and MFN2 mitofusins thereby regulating mitochondrial fusion. By regulating both mitochondrial dynamics and bioenergetic function, it contributes to cell survival following oxidative stress.
Belongs to the tRNA(His) guanylyltransferase family.
Homotetramer. Interacts with MFN1 and MFN2; functions as a guanyl-nucleotide exchange factor/GEF for MFN2 and also probably MFN1.
Detected in pachytene spermatocytes and round spermatids.
Belongs to the palmitoyl-protein thioesterase family.
Highest amounts in brain, testis, lung, and spleen. Lowest amounts in liver and skeletal muscle.
Interacts with CLN5, ATP5F1A and ATP5F1B.
Removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. Prefers acyl chain lengths of 14 to 18 carbons.
Adds the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation.
Belongs to the heparin-binding growth factors family.
Interacts (phosphorylated and unphosphorylated form) with SMC3. Interacts with SYCP3. Interacts (phosphorylated and unphosphorylated form) with SMC1B. Does not interact with SMC1A (By similarity). Interacts with RAD51. 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).
Binds 2 divalent metal cations per subunit (By similarity). Site 2 has a preference for magnesium and/or manganese ions (By similarity).
Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP), which is a key regulator of many important physiological processes.
Interacts with LYN (via SH3 domain). Interacts with ARRB2.
Phosphorylated by MAPKAPK2 at Ser-147; it counteracts PKA-induced activation of PDE4A and modulates intracellular cAMP levels. Likely involved in cellular desensitization to cAMP signaling.
Associated with actin, delta-catenin and alpha and beta tubulins (PubMed:12639940). Interacts with OTOF (By similarity). Interacts with PEX5R (PubMed:11278749). Interacts with RAB3IP (By similarity). Interacts with VIM (PubMed:12639940). Interacts with CDH1 (PubMed:12639940). Interacts with MICALL2 (By similarity). Interacts with GDI1, GDI2 and CHM; phosphorylation at Thr-72 disrupts these interactions (By similarity).
Hight levels of expression in the spleen, heart, kidney, testis and brain. Expression increases in Sertoli and germ cells during their maturation.
Localizes in the basal compartment associating with spermatocytes in all stages of the spermatogenic cycle. Detected at the site of elongate spermatids in stages XII-XIV in addition to being found in the basal compartment in these stages.
Phosphorylation of Thr-72 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM and RAB GDP dissociation inhibitors GDI1 and GDI2.
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab may be involved in polarized vesicular trafficking and neurotransmitter release. May participate in cell junction dynamics in Sertoli cells.
Belongs to the glycosyltransferase group 1 family. Glycosyltransferase 4 subfamily.
Required for N-linked oligosaccharide assembly.
Acetylated. Acetylation at Lys-256 and Lys-268 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death. Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-250. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation. Acetylated at Lys-417, promoting its localization to the nucleus and transcription factor activity. Deacetylation at Lys-417 by SIRT6, promotes its translocation into the cytoplasm, preventing its transcription factor activity. 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.
Acetylation at Lys-256 and Lys-268 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death. Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-250. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation (By similarity).
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-250 leading to its nuclear import. 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 (acetylated form) with PPARG. Interacts with XBP1; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (By similarity). 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 (By similarity). 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-250 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-250 and Ser-313 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-250 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-313, permitting phosphorylation of Ser-316 and Ser-319, 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-323 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-250 by PP2A in beta-cells under oxidative stress leading to nuclear retention. Phosphorylation of Ser-243 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-206, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export (By similarity). PPIA/CYPA promotes its dephosphorylation on Ser-250 (By similarity).
Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (By similarity). 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'. Activity suppressed by insulin (By similarity). 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 (By similarity). Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (By similarity). Promotes neural cell death (By similarity). 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 (By similarity). Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (PubMed:26436652). 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 (By similarity).
Ubiquitinated by SKP2. Ubiquitination leads to proteasomal degradation (By similarity).
Catalyzes the covalent attachment of ubiquitin to other proteins. 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 autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by RIGI in response to viral infection Plays a role in early maturation of the testis.
Testis-specific. Mainly expressed in the round spermatids (at protein level).
Dual specificity protein phosphatase; active with phosphotyrosine, phosphoserine and phosphothreonine residues. The highest relative activity is toward ERK1.
Activated by autophosphorylation on Ser-215. Kinase activity is inhibited by SPRED1.
Autophosphorylated on serine and tyrosine residues.
Dual specificity protein kinase activity catalyzing autophosphorylation and phosphorylation of exogenous substrates on both serine/threonine and tyrosine residues (PubMed:10207045). Regulates the cellular cytoskeleton by enhancing actin stress fiber formation via phosphorylation of cofilin and by preventing microtubule breakdown via inhibition of TAOK1/MARKK kinase activity (PubMed:18216281, PubMed:11555644). Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1 (By similarity). Positively regulates integrin-mediated cell spreading, via phosphorylation of cofilin (By similarity). Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, suppression of ciliary vesicle directional trafficking to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (By similarity). Probably plays a central role at and after the meiotic phase of spermatogenesis (PubMed:8537404).
Induced by fibronectin-mediated cell adhesion of Schwann cells (PubMed:22302232). Induced by sciatic nerve crush injury, expression peaks 2 weeks post-injury and returns to normal at 4 weeks post-injury in the macrophages of promyelinating Schwann tubules (PubMed:22302232).
Interacts (via both C- and N-termini) with SPRY4 (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:17974561). Interacts with TAOK1; the interaction inhibits TAOK1 kinase activity (PubMed:18216281). Interacts (via C-terminus) with SPRED1 (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:17974561, PubMed:18216281). Interacts (via C-terminus) with PARVA/PARVIN (via C-terminus); the interaction inhibits TESK1 kinase activity (PubMed:15817463). Interacts with YWHAB/14-3-3 beta; the interaction is dependent on the phosphorylation of TESK1 Ser-439 and inhibits TESK1 kinase activity (PubMed:11555644). Interacts with SPRY1, SPRY3 and SPRED2 (PubMed:17974561). Interacts (via C-terminus) with SPRY2 (via C-terminus); the interaction disrupts SPRY2 interaction with PPP2CA/PP2A-C, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Therefore dephosphorylation of SPRY2 by the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme is lost, inhibiting its interaction with GRB2 (PubMed:17974561).
The extracatalytic C-terminal part is highly rich in proline residues.
Weakly expressed in sciatic nerves (at protein level) (PubMed:22302232). Highly expressed in testicular germ cells (PubMed:8537404, PubMed:10207045). Expressed at low levels in brain, lung, heart, liver and kidney (PubMed:10207045).
Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities (By similarity). Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4) (PubMed:1544505). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides. 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). 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 (By similarity).
Inhibited by bestatin (By similarity). Inhibited by captopril (PubMed:1544505). The epoxide hydrolase activity is restrained by suicide inactivation that involves binding of LTA4 to Tyr-379. 4-(4-benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits the epoxide hydrolase activity (By similarity).
Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase activity.
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).
Involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues. Mediates Ca(2+)-regulation of exocytosis acrosomal reaction in sperm. May mediate Ca(2+)-regulation of exocytosis in insulin secreted cells (By similarity).
The second C2 domain/C2B is responsible for SYNCRIP and inositol 1,3,4,5-tetrakisphosphate (IP4)-binding.
Ubiquitous. Strongly expressed in heart, kidney, cerebral cortex, pancreas, and many insulin-secreting cells; lower expression in spleen. Broadly distributed in kidney.
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 (By similarity).
Dual specificity protein phosphatase (By similarity). Shows high activity towards MAPK1/ERK2 (By similarity). Also has lower activity towards MAPK14 and MAPK8 (By similarity). In arrested oocytes, plays a role in meiotic resumption. 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. May also inactivate PRKCA and/or PRKCG. 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.
Interacts with MAPK1/ERK2; the interaction enhances DUSP7 phosphatase activity.
Strongly inhibited by sodium orthovanadate.
Orphan receptor. Seems to act through a G(q/11)-mediated pathway.
Expressed mainly in the cerebellum, spleen, and testis.
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.
Found in a nuclear export complex with XPO5, EEF1A1, Ran and aminoacylated tRNA. Interacts with PARP1 and TXK. Interacts with KARS1. May interact with ERGIC2. Interacts with IFIT1 (via TPR repeats 4-7) (By similarity). 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 (By similarity). Interacts with PPP1R16B (By similarity). Interacts with SPHK1 and SPHK2; both interactions increase SPHK1 and SPHK2 kinase activity (By similarity).
Phosphorylated by TXK. Phosphorylation by PASK increases translation efficiency. Phosphorylated by ROCK2.
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.
Trimethylated at Lys-79 by EEF1AKMT1. 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. Trimethylated at Lys-318 by EEF1AKMT2. 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. Trimethylated at Gly-2 by METTL13. Mono- and dimethylated at Lys-55 by METTL13; dimethylated form is predominant.
As part of a SNARE complex may be involved in endoplasmic reticulum membranes fusion and be required for the maintenance of endoplasmic reticulum organization. Also plays a role in apoptosis. It is for instance required for endoplasmic reticulum stress-induced apoptosis. As a substrate of RNF185 interacting with SQSTM1, might also be involved in mitochondrial autophagy.
Component of a SNARE complex consisting of STX18, USE1L, BNIP1/SEC20L and SEC22B. Interacts directly with STX18, RINT1/TIP20L and NAPA. Interacts with ZW10 through RINT1. Interacts with BCL2. Interacts with RNF186. Interacts with RNF185. Interacts with SQSTM1; increased by 'Lys-63'-linked polyubiquitination of BNIP1.
Polyubiquitinated. 'Lys-63'-linked polyubiquitination by RNF185 increases the interaction with the autophagy receptor SQSTM1. Undergoes 'Lys-29'- and 'Lys-63'-linked polyubiquitination by RNF186 that may regulate BNIP1 localization to the mitochondrion.
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 (By similarity).
Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio (By similarity). Interacts with PFN2 (By similarity).
Detected in brain, lung, spleen and skeletal muscle. Expressed in small renal tumors but not in normal kidney.
Regulates phosphorylation of a number of proteins involved in translation regulation including EIF2A, EIF4EBP1 and RPS6KB1. May be involved in the endoplasmic reticulum stress response (By similarity).
Belongs to the inorganic phosphate transporter (PiT) (TC 2.A.20) family.
By 1,25-dihydroxyvitamin D3 and phosphate deprivation.
Sodium-phosphate symporter which plays a fundamental housekeeping role in phosphate transport, such as absorbing phosphate from interstitial fluid for normal cellular functions such as cellular metabolism, signal transduction, and nucleic acid and lipid synthesis. May play a role in extracellular matrix and cartilage calcification as well as in vascular calcification.
Belongs to the tigger transposable element derived protein family.
Mediator of sterol homeostasis involved in sterol uptake, trafficking and distribution into membranes.
Belongs to the FPP/GGPP synthase family.
Homodimer. Interacts with RSAD2 (By similarity).
Inactivated by interferon-induced RSAD2. This inactivation may result of disruption of lipid rafts at the plasma membrane, and thus have an antiviral effect since many enveloped viruses need lipid rafts to bud efficiently out of the cell (By similarity).
Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids, and ubiquinones. FPP also serves as substrate for protein farnesylation and geranylgeranylation. Catalyzes the sequential condensation of isopentenyl pyrophosphate with the allylic pyrophosphates, dimethylallyl pyrophosphate, and then with the resultant geranylpyrophosphate to the ultimate product farnesyl pyrophosphate (By similarity).
Testis, liver, kidney, brain and adrenal gland.
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.
Belongs to the glycosyltransferase 39 family.
Transfers mannose from Dol-P-mannose to Ser or Thr residues on proteins.
Belongs to the mitochondrion-specific ribosomal protein mS29 family.
Expressed in many tissues, with highest levels in fat, heart and skeletal muscle. Also detected in kidney, liver and lung.
GTPase-activating protein for the ADP ribosylation factor family (Potential). Binds phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4). Binding of phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 3,4-bisphosphate occurs at a much lower affinity. Possesses a stoichiometry of two binding sites for InsP4 with identical affinity (By similarity).
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.
Belongs to the nonaspanin (TM9SF) (TC 9.A.2) family.
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).
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. As intracellular fragment AlcICD, suppresses APBB1-dependent transactivation stimulated by APP C-terminal intracellular fragment (AICD), most probably by competing with AICD for APBB1-binding. May modulate calcium-mediated postsynaptic signals (By similarity).
Preferentially expressed in the retina and brain.
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). Beta-Alc-alpha secretion is largely dependent upon PSEN1 and PSEN2. This processing is strongly suppressed in the tripartite complex formed with APBA2 and APP, which seems to prevent the association with PSEN1 (By similarity).
The cytoplasmic domain is involved in interaction with APBA2, as well as the binding of synaptic Ca(2+).
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 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 (By similarity).
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 (By similarity).
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) (By similarity).
Belongs to the potassium channel KCNE family.
Expressed in the heart (PubMed:2183220, PubMed:19219384). Expressed in kidney (PubMed:2344412). Expressed in estrogen-induced uterus (PubMed:2344412).
Interacts with KCNB1 (PubMed:19219384). Interacts with KCNC2 (PubMed:14679187). Associates with KCNH2/HERG (By similarity). Interacts with KCNQ1; targets the complex KCNQ1-KCNE1 to the membrane raft (By similarity).
Mutagenesis experiments were carried out by expressing in Xenopus oocytes the mutant Asn-77 either individually (homomultimers) or in combination with wild-type KCNE1 (heteromultimers) in a 1:1 ratio (PubMed:7605639).
N-glycosylation at Asn-26 occurs post-translationally, and requires prior cotranslational glycosylation at Asn-5.
Phosphorylation inhibits the potassium current.
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. Acts also as a positive regulator of hedgehog signaling and regulates ciliary function.
Interacts with the CCT chaperonin complex (By similarity). Forms a complex with the beta and gamma subunits of the GTP-binding protein, transducin.
Binds to various extracellular matrix proteins.
Down-regulated by oncogenes (isoform 1). Isoform 2 is down-regulated by beta estradiol in mammary gland (at mRNA level). Isoform 2 is up-regulated by beta estradiol in mammary glands (at protein level). Up-regulated in lactating mammary glands and mammary tumors (at protein level).
Isoform 2 is expressed in uterus, liver, lung, spleen, kidney, heart, bladder, skeletal muscle and brain (at protein level). Isoform 2 is expressed very low in mammary gland and intestine (at protein level). Isoform 2 is expressed in lactating mammary glands and mammary tumors (at protein level). Ubiquitous (isoform 1). Isoform 2 is expressed in ovary, uterus, mammary glands, liver, lung, spleen, kidney, heart, bladder, intestine, skeletal muscle and brain.
Promotes cell adhesion and matrix assembly.
Activated by forskolin (PubMed:2255909, PubMed:1633161, PubMed:24363043). After forskolin treatment, activity is further increased by calcium/calmodulin (PubMed:1633161). In the absence of forskolin, calcium/calmodulin has little effect on enzyme activity (PubMed:1633161).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:2255909, PubMed:1633161, PubMed:24363043). Participates in signaling cascades triggered by odorant receptors via its function in cAMP biosynthesis (PubMed:2255909). 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 (By similarity).
Detected on cilia on the olfactory epithelium (at protein level) (PubMed:2255909, PubMed:25908845). Detected on cilia on the olfactory epithelium.
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.
Belongs to the amino acid-polyamine-organocation (APC) superfamily.
Mediates the transport L-aspartate and L-glutamate in a sodium-independent manner.
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. Interacts with ZP3.
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. ZP2 may act as a secondary sperm receptor.
O-glycosylated; contains sulfate-substituted glycans.
Proteolytically cleaved before the transmembrane segment to yield the secreted ectodomain incorporated in the zona pellucida.
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.
The ZP domain is involved in the polymerization of the ZP proteins to form the zona pellucida.
Expressed in brain (at protein level) (PubMed:12151521, PubMed:27307232, PubMed:20962234). Detected in juxtaparanodal zones in the central nervous system and at nerve terminal plexuses of basket cells in the cerebellum (PubMed:20089912). Expressed in cerebrum (PubMed:27307232). Expressed in hippocampal neurons (at protein level) (PubMed:11502259, PubMed:12151521, PubMed:27307232, PubMed:27756895). Isoform 1 and isoform 2: highly expressed in cerebellum, cortex, hippocampus, and corpus striatum (PubMed:12151521, PubMed:20962234).
Expression gradually increases from late embryonic (E18) stage until adulthood.
Interacts through its PDZ domains with ANO2 and NETO1 (By similarity). Interacts with KCNJ4 (PubMed:11997254). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C and GRIN2D (PubMed:7569905). Interacts with ERBB4 (By similarity). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (By similarity). Interacts with LRRC4 and LRRC4B (By similarity). Interacts with SYNGAP1 (PubMed:9581761). Interacts with ASIC3 (PubMed:15317815). Interacts with SEMA4C (PubMed:11134026). Interacts with CXADR (PubMed:15304526). Interacts with KCND2 (PubMed:11923279). Interacts (via first PDZ domain) with CRIPT (PubMed:9581762). Interacts through its first PDZ domain with GRIK2 and KCNA4 (By similarity). Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON (PubMed:23300088). Interacts through its third PDZ domain with NLGN1 and CRIPT, and probably with NLGN2 and NLGN3 (By similarity). Interacts through its guanylate kinase-like domain with DLGAP1/GKAP, DLGAP2, DLGAP3, DLGAP4, MAP1A, BEGAIN and SIPA1L1 (PubMed:9115257, PubMed:9756850, PubMed:11502259, PubMed:9786987). Interacts through its guanylate kinase-like domain with KIF13B (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (By similarity). Interacts with ANKS1B (PubMed:17334360). Interacts with ADR1B (By similarity). May interact with HTR2A (By similarity). Interacts with ADAM22, KLHL17 and LGI1 (PubMed:16054660, PubMed:16990550, PubMed:20089912). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1 and LRFN2 (PubMed:16495444, PubMed:16630835). Interacts with LRFN4 (By similarity). 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 (PubMed:23300088). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N-terminal domain) (PubMed:23300088). Interacts with SHANK3 (By similarity). Interacts with GPR85 (By similarity). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (PubMed:27756895). Interacts with ADGRB1 (By similarity). Found in a complex with PRR7 and GRIN1 (PubMed:27458189). Interacts (via PDZ3 domain and to lesser degree via PDZ2 domain) with PRR7 (PubMed:27458189, PubMed:15629447). 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 (via PDZ domain 2) with SEMA4F (via PDZ-binding motif); this interaction may promote translocation of DLG4/SAP90 to the membrane (PubMed:11483650). Interacts with RPH3A and GRIN2A; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (PubMed:26679993). 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 (By similarity). Interacts with PTEN (via PDZ domain-binding motif); the interaction is induced by NMDA and is required for PTEN location at postsynaptic density (PubMed:20628354).
Palmitoylated (PubMed:10629226, PubMed:27307232). Palmitoylation is required for targeting to postsynaptic density, plasma membrane and synapses (PubMed:10629226, PubMed:27307232). Palmitoylation by ZDHHC2 occurs when the synaptic activity decreases and induces DLG4 synaptic clustering (PubMed:19596852). Palmitoylation by ZDHHC15 regulates trafficking to the postsynaptic density and function in synaptogenesis (PubMed:15603741, PubMed:31189538). Palmitoylation may play a role in glutamate receptor GRIA1 synapse clustering (PubMed:27307232). Depalmitoylated by ABHD17A and ABHD17B and to a lesser extent by ABHD17C, ABHD12, ABHD13, LYPLA1 and LYPLA2 (PubMed:27307232). Undergoes rapid synaptic palmitoylation/depalmitoylation cycle during neuronal development which slows down in mature neurons (PubMed:27307232).
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 (PubMed:15317815, PubMed:15358863, PubMed:19596852, PubMed:23300088, PubMed:26679993, PubMed:20628354). 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 (By similarity). 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 (PubMed:19596852).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 (By similarity).
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.
Belongs to the activator 1 large subunit family.
Plays a role in spermiogenesis. Involved in the elongation of flagella and the formation of sperm heads.
Testis-specic protein that plays an important role in fusion of proacrosomal vesicles and perinuclear theca formation.
Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3. Interacts with RAB11FIP2 (By similarity). Interacts with RAB11A and RAB8A (By similarity). Found in a complex with CFTR and RAB11A (By similarity). Interacts with NPC1L1 (By similarity). Interacts with LIMA1 (By similarity).
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.
Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70. Plays an indispensable role in the organization of KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone for neuronal proteins including huntingtin. Suppresses aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins. Also reduces cellular toxicity and caspase-3 activity.
Highest levels of expression found in brain and retina, and lower levels in heart, kidney, liver and placenta.
Homooligomer. Interacts with BAG3, HSPB8 and STUB1 (By similarity). Interacts with ALKBH1 (By similarity). Interacts with HSP70, KRT18 and PTTG (By similarity).
Low levels detected in testes at day 7 postnatally, with 10-fold increased levels detected by day 28, remaining into adulthood.
Belongs to the GTP-binding SRP family. SRP54 subfamily.
Component of a signal recognition particle (SRP) complex that consists of a 7SL RNA molecule of 300 nucleotides and six protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9 (By similarity). Interacts with RNPS1 (By similarity). Interacts with the SRP receptor subunit SRPRA (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). As part of the SRP complex, associates with the SRP receptor (SR) component SRPRA to target secretory proteins to the endoplasmic reticulum membrane (By similarity). Binds to the signal sequence of presecretory proteins when they emerge from the ribosomes (By similarity). Displays basal GTPase activity, and stimulates reciprocal GTPase activation of the SR subunit SRPRA (By similarity). Forms a guanosine 5'-triphosphate (GTP)-dependent complex with the SR subunit SRPRA (By similarity). SR compaction and GTPase mediated rearrangement of SR drive SRP-mediated cotranslational protein translocation into the ER (By similarity). Requires the presence of SRP9/SRP14 and/or SRP19 to stably interact with RNA (By similarity). Plays a role in proliferation and differentiation of granulocytic cells, neutrophils migration capacity and exocrine pancreas development (By similarity).
The M domain binds the 7SL RNA in presence of SRP19 and binds the signal sequence of presecretory proteins.
The NG domain, also named G domain, is a special guanosine triphosphatase (GTPase) domain, which binds GTP and forms a guanosine 5'-triphosphate (GTP)-dependent complex with a homologous NG domain in the SRP receptor subunit SRPRA (By similarity). The two NG domains undergo cooperative rearrangements upon their assembly, which culminate in the reciprocal activation of the GTPase activity of one another (By similarity). SRP receptor compaction upon binding with cargo-loaded SRP and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER (By similarity).
Expressed in germ cells of the testis (at protein level).
May play a role in sperm development or sperm function. However, does not appear to have an essential role in spermatogenesis or male fertility.
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.
In the brain, expressed in all types of glial cells. In the kidney, expressed in the mesangial cells of the glomerulus, smooth muscle cells of the renal arterioles, and in transitional cell epithelium of renal pelvis.
Interacts with RPGRIP1L. Interacts with RACK1; the interaction regulates TBXA2R cell surface expression (By similarity).
Receptor for thromboxane A2 (TXA2), a potent stimulator of platelet aggregation. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. In the kidney, the binding of TXA2 to glomerular TP receptors causes intense vasoconstriction. Activates phospholipase C and adenylyl cyclase.
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.
Most abundant in kidney. Also found in liver and testis.
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 (By similarity).
Belongs to the DEAD box helicase family. eIF4A subfamily.
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions. It is composed of at least EIF4A, EIF4E and EIF4G1/EIFFG3 (By similarity). Interacts with EIF4E. May interact with NOM1 (By similarity).
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
Interacts with TNNI3, ACTC, ACTA1, MYBPC3, AIP, FABP3 and HADHB.
Belongs to the eukaryotic ribosomal protein P1/P2 family.
Heterodimer with RPLP2 at the lateral ribosomal stalk of the large ribosomal subunit.
Plays an important role in the elongation step of protein synthesis.
Has an actin-binding and actin-bundling activity. Can induce the formation of F-actin networks. 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 (By similarity). 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 (PubMed:23434281). Involved in regulation of cell migration. May be a tumor suppressor (By similarity).
May self-associate in muscle cells under oxidative stress. Binds F-actin. Interacts with ACTN2; ACTN2 is proposed to anchor SYOP2 at Z lines in mature myocytes. 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. Interacts with IPO13; may be implicated in SYNOP2 nuclear import. Interacts with ZYX, FLNC, ILK (By similarity). Interacts with BAG3 (via WW 1 domain) (By similarity). May associate with the CASA complex consisting of HSPA8, HSPB8 and BAG3 (PubMed:23434281). Interacts with VPS18 (By similarity).
Phosphorylated by PKA, and by CaMK2 at multiple sites. Dephosphorylated by calcineurin at Ser-558 and Thr-605; abrogating interaction with YWHAB and impairing nuclear import.
The PPPY motif interacts with the WW domain 1 of BAG3.
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) (By similarity). 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 (By similarity). Interacts with isoform beta of PRKG1 (By similarity).
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 (By similarity). Required for the formation of functional ARID3A DNA-binding complexes and for activation of immunoglobulin heavy-chain transcription upon B-lymphocyte activation (By similarity).
Transiently phosphorylated on tyrosine residues by BTK in response to B-cell receptor stimulation. Phosphorylation on Tyr-248 and Tyr-379, and perhaps, on Tyr-484 contributes to BTK-mediated transcriptional activation (By similarity).
Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha subunit contains the guanine nucleotide binding site (PubMed:2159473). 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). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI3 (By similarity). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif) and NUCB2 (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:21653697). Interacts (inactive GDP-bound form) with PLCD4 (via GBA motif); the interaction leads to activation of GNAI3 (By similarity). Interacts with INSR; the interaction is probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with GPSM1 (PubMed:11121039). Interacts (GDP-bound form) with GPSM2 (via GoLoco domains). Does not interact with RGS2. Interacts with RGS8 and RGS10; this strongly enhances the intrinsic GTPase activity (By similarity). Interacts with RGS12 (PubMed:11387333). Interacts with RGS16; this strongly enhances the intrinsic GTPase activity (By similarity). Interacts (via active GTP- or inactive GDP-bound form) with RGS14 (PubMed:11387333, PubMed:16870394).
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 (PubMed:2159473). Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins. Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels. Stimulates the activity of receptor-regulated K(+) channels. 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.
Alpha-latrotoxin competes with alpha-dystroglycan for binding.
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 (By similarity). Both alpha-type and beta-type isoforms may play a role in the formation or maintenance of synaptic junctions via their interactions (via the extracellular domains) with neuroligin family members, CBLN1 or CBLN2. In vitro, triggers the de novo formation of presynaptic structures. May be involved in specification of excitatory synapses. Alpha-type isoforms were first identified as receptors for alpha-latrotoxin from spider venom.
Interacts (via laminin G-like domain 2 and/or laminin G-like domain 6) with NLGN1 forming a heterotetramer, where one NLGN1 dimer interacts with one NRXN1 dimer (By similarity). Interacts (via cytoplasmic C-terminal region) with CASK (via the PDZ, SH3 and guanylate kinase-like domains) (PubMed:8786425, PubMed:12040031). Interacts (via cytoplasmic C-terminus) with CASKIN1 and APBA1 (PubMed:12040031). Interacts with SYT13 and SYTL1 (By similarity). Interacts (via laminin G-like domain 2 and/or laminin G-like domain 6) with NLGN1, NLGN2 and NLGN3; these interactions are calcium-dependent. Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity). Interacts (via laminin G-like domain 2 and/or laminin G-like domain 6) with NLGN4. Interacts (via laminin G-like domain 2) with NXPH1 and NXPH3. Alpha-type isoforms (neurexin-1-alpha) interact (via laminin G-like domain 2 and/or laminin G-like domain 6) with DAG1 (via alpha-dystroglycan chain). Alpha-type isoforms interact with alpha-latrotoxin from spider venom. Isoform 9a and isoform 13a bind to DAG1 (via alpha-dystroglycan chain). Isoform 13a binds to alpha-latrotoxin. Interacts with LRRTM1, LRRTM2, LRRTM3 and LRRTM4.
Cytosolic dehydrogenase that catalyzes the irreversible oxidation of a wide range of aldehydes to their corresponding carboxylic acid (PubMed:7832787, PubMed:15623782). Functions downstream of retinol dehydrogenases and catalyzes the oxidation of retinaldehyde into retinoic acid, the second step in the oxidation of retinol/vitamin A into retinoic acid. This pathway is crucial to control the levels of retinol and retinoic acid, two important molecules which excess can be teratogenic and cytotoxic (PubMed:7832787). Also oxidizes aldehydes resulting from lipid peroxidation like (E)-4-hydroxynon-2-enal/HNE, malonaldehyde and hexanal that form protein adducts and are highly cytotoxic. By participating for instance to the clearance of (E)-4-hydroxynon-2-enal/HNE in the lens epithelium prevents the formation of HNE-protein adducts and lens opacification (PubMed:15623782). Functions also downstream of fructosamine-3-kinase in the fructosamine degradation pathway by catalyzing the oxidation of 3-deoxyglucosone, the carbohydrate product of fructosamine 3-phosphate decomposition, which is itself a potent glycating agent that may react with lysine and arginine side-chains of proteins (By similarity). Has also an aminobutyraldehyde dehydrogenase activity and is probably part of an alternative pathway for the biosynthesis of GABA/4-aminobutanoate in midbrain, thereby playing a role in GABAergic synaptic transmission (By similarity).
Homotetramer (By similarity). Interacts with PRMT3; the interaction is direct, inhibits ALDH1A1 aldehyde dehydrogenase activity and is independent of the methyltransferase activity of PRMT3 (By similarity).
Strongly expressed in kidney, lung, testis, intestine, stomach, and trachea, but weakly in the liver.
The N-terminus is blocked most probably by acetylation.
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.
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. Cleaves aggrecan at the '392-Glu-|-Ala-393' site.
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).
The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix.
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 (By similarity).
Inhibited by monoubiquitin and diubiquitin.
Preferentially binds diubiquitin; the interaction does not hydrolyze diubiquitin but, in vitro, inhibits the hydrolyzing activity on other substrates.
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-402 and allows the kinase domain to adopt an active structure. Following caspase cleavage, autophosphorylated PAK-2p34 is constitutively active (By similarity).
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. 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 (By similarity).
Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with SH3MD4. Interacts with SCRIB. Interacts with ARHGEF7 and GIT1. PAK-2p34 interacts with ARHGAP10. Interacts with RAC1 (By similarity).
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. 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. Full-length PAK2 stimulates cell survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Phosphorylates JUN and plays an important role in EGF-induced cell proliferation. Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP. Phosphorylates CASP7, thereby preventing its activity. Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. 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. Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation (By similarity).
Belongs to the alkaline ceramidase family.
Hydrolyzes the sphingolipid ceramide into sphingosine and free fatty acid.
Belongs to the SIX/Sine oculis homeobox family.
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. Has fatty acyl-CoA thioesterase and ATPase activities (By similarity). 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:10207018).
Homodimers (PubMed:11883951). Can form heterodimers with ABCD1 and ABCD2. Dimerization is necessary to form an active transporter. Interacts with PEX19; mediates the targeting of ABCD3 to peroxisomes (By similarity).
Ubiquitinated by PEX2 during pexophagy in response to starvation, leading to its degradation.
Belongs to the class I-like SAM-binding methyltransferase superfamily. rRNA adenine N(6)-methyltransferase family.
Belongs to the class I-like SAM-binding methyltransferase superfamily. rRNA adenine N(6)-methyltransferase family. KsgA subfamily.
Homodimer. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT. 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. Interacts with mitochondrial RNA polymerase POLRMT. Interacts with TFAM.
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. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA. 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. Stimulates transcription independently of the methyltransferase activity.
Interacts with PLXNA4 (By similarity). Interacts with RAB1B (By similarity). Interacts with MAPK1/ERK2 (By similarity). Interacts with RAB35, RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms); binding to RAB35 is of low affinity compared to other Rab proteins; at least in case of RAB8A may bind 2 molecules of RAB8A simultaneously through a high and a low affinity binding site, respectively (By similarity). May interact with MAPK1/ERK2 (By similarity).
Methionine monooxygenase that promotes depolymerization of F-actin by mediating oxidation of residues 'Met-44' and 'Met-47' on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization (By similarity). Regulates the disassembly of branched actin networks also by oxidizing ARP3B-containing ARP2/3 complexes leading to ARP3B dissociation from the network. Acts as a key regulator of the SRF signaling pathway elicited by nerve growth factor and serum: mediates oxidation and subsequent depolymerization of nuclear actin, leading to increase MKL1/MRTF-A presence in the nucleus and promote SRF:MKL1/MRTF-A-dependent gene transcription. Does not activate SRF:MKL1/MRTF-A through RhoA (By similarity).
The C-terminal RAB-binding domain (RBD) (1796-1945), also described as bivalent Mical/EHBP Rab binding (bMERB) domain, mediates binding to predominantly RAB8A, RAB10, RAB13 and RAB15 (in their GTP-bound forms).
Involved in the regulation of homocysteine metabolism.
Involved in the regulation of homocysteine metabolism. Converts betaine and homocysteine to dimethylglycine and methionine, respectively. This reaction is also required for the irreversible oxidation of choline (By similarity).
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.
By interleukin-1, dexamethasone, lipolysaccharide and indinavir. Up-regulated upon muscle denervation, immobilization and unweighting and more generally upon muscle atrophy. Up-regulated upon sepsis. Down-regulated upon aging.
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.
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. Interacts with CKM (By similarity).
Muscle specific. Selectively expressed in heart and skeletal muscle.
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 (when phosphorylated at Ser-67) with PPP2R2D. Interacts with ABCC8. Interacts with SNCA; interaction is disrupted when phosphorylated at Ser-109 (By similarity).
Phosphorylation at Ser-67 by GWL during mitosis is essential for interaction with PPP2R2D (PR55-delta) and subsequent inactivation of PP2A. Phosphorylated by PKA (By similarity).
Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis. When phosphorylated at Ser-67 during mitosis, specifically interacts with PPP2R2D (PR55-delta) and inhibits its activity, leading to inactivation of PP2A, an essential condition to keep cyclin-B1-CDK1 activity high during M phase. Also acts as a stimulator of insulin secretion by interacting with sulfonylurea receptor (ABCC8), thereby preventing sulfonylurea from binding to its receptor and reducing K(ATP) channel currents (By similarity).
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.
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 (PubMed:1515147).
Heterodimer of chain A and chain B held by a disulfide bond. Binds to fibrin with high affinity. This interaction leads to an increase in the catalytic efficiency of the enzyme 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. Binds LRP1B; binding is followed by internalization and degradation. Forms heterodimer with SERPINA5 (By similarity). In complex with SERPINE1, interacts with SORL1 (By similarity).
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-308 catalyzed by plasmin, tissue kallikrein or factor Xa.
Interacts with CEP152 and CDK1; these interactions recruit both ligands to centrosomes. Interacts with CDK2, CDK5RAP2, WDR62, CEP90, KIAA0753/moonraker an CCDC14. CEP63, CDK5RAP2, CEP152, WDR62 are proposed to form a stepwise assdembled complex at the centrosome forming a ring near parental centrioles. Interacts with CCDC57; the interaction is required for their location to proximal end of centrioles (By similarity).
Required for normal spindle assembly. Plays a key role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication. Also recruits CDK1 to centrosomes (By similarity). Plays a role in DNA damage response. Following DNA damage, such as double-strand breaks (DSBs), is removed from centrosomes; this leads to the inactivation of spindle assembly and delay in mitotic progression (By similarity).
Phospholipid scramblase involved in autophagy. 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 from the cytoplasmic to the luminal leaflet of the bilayer, thereby driving autophagosomal membrane expansion.
Associates (via C-terminus) with actin (PubMed:11849295). Interacts with F-actin (By similarity). Interacts with SCARF1; the interaction occurs in embryonic dorsal root ganglions at 18 dpc and induces neurite-like outgrowth (By similarity). Interacts with PLCE1. Interacts with ACTR2 and ACTR3; associates with the ARP2/3 complex (By similarity).
Ca(2+)-regulated actin-binding protein which plays an important role in actin bundling. 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 (PubMed:11849295). 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 (By similarity).
Expressed in dorsal root ganglion (DRG) neurons and superior cervical ganglia (SCG) (PubMed:11849295). Expressed in podocytes (PubMed:29058690).
The C-terminal domain is necessary for the induction of long fine actin-containing filopodia-like structures in fibroblast and neurite-like outgrowth.
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 (By similarity). Involved in the regulation of cortical neuron migration and dendrite arborization (By similarity).
Binds three actin monomers via the three C-terminal RPEL repeats.
Interacts (via RPEL repeats) with ACTA1 and PPP1CA; ACTA1 and PPP1CA compete for the same binding site.
Selectively expressed in brain. High levels are found in the olfactory tubercle, nucleus accumbens core and shell, caudate-putamen, cerebral cortex, hippocampus and piriform cortex. Moderate to high levels in the olfactory bulb, arcuate and ventromedial hypothalamus, subthalamic nucleus, amygdala, lateral septum, habenula and thalamus. Low expression, if any, in substantia nigra pars compacta/pars reticula and globus pallidus (at protein level).
Binding to misfolded proteins is mediated by a hydrophobic patch forming a large groove within the first two TPR repeats.
Interacts with EIF2AK2 and EIF2AK3. Forms a trimeric complex with DNAJB1 and HSPA8. Interacts with THAP12 (By similarity).
Involved in the unfolded protein response (UPR) during ER stress. Co-chaperone of HSPA8/HSC70, it stimulates its ATPase activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity (By similarity).
The J domain mediates interaction with HSPA8.
Expressed in the perinuclear ring of spermatid manchettes within testis and in keratinocytes of the suprabasal layer of footpad epidermis (at protein level).
May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues. Plays a role in keratin filament assembly (By similarity). May be involved in spermatid nuclear shaping and sperm development.
There are two types of cytoskeletal and microfibrillar keratin, I (acidic) and II (neutral to basic) (40-55 and 56-70 kDa, respectively).
Probably involved in nervous system development and function.
Acts as a transcriptional regulator. Promotes transcription repression. Promotes transcription activation in differentiated myotubes. Binds to double- and single-stranded DNA sequences. Binds to the transcription suppressor CATR sequence of the COX5B promoter. 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 (By similarity).
Dimethylation of Arg-310 is probably of the asymmetric type.
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).
Upon glucose starvation, as well as treatment with tunicamycin.
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.
Found exclusively in the peripheral nervous system. Present in both myelinating and nonmyelinating Schwann cells. Found in the tumors of Schwann cell lineage where axons are present (neurofibromas) but not where axons are absent (schwannomas).
Levels increase between embryonic day 21 (21 dpc) and postnatal day 1 (P1) and then gradually increase up to P15. There is a slight increase between P15 and adulthood.
Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
Strongly down-regulated in the initial phase after sciatic nerve injury.
Interacts with HNRNPH1; the interaction in RNA-dependent. Interacts with PARN. Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Associates with polysomes.
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. 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. 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 (By similarity). May be a specific regulator of miRNA biogenesis. Binds to primary microRNA pri-MIR140 and, with CELF2, negatively regulates the processing to mature miRNA (By similarity).
RRM1 and RRM2 domains preferentially target UGU(U/G)-rich mRNA elements.
Broad spectrum monooxygenase that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including xenobiotics (PubMed:8504165). Catalyzes the S-oxygenation of hypotaurine to produce taurine, an organic osmolyte involved in cell volume regulation as well as a variety of cytoprotective and developmental processes (By similarity). In vitro, catalyzes the N-oxygenation of trimethylamine (TMA) to produce trimethylamine N-oxide (TMAO) and could therefore participate to the detoxification of this compound that is generated by the action of gut microbiota from dietary precursors such as choline, choline containing compounds, betaine or L-carnitine (PubMed:8504165).
Expressed in liver, lung and kidney and to a lesser extent in the heart and brain.
Belongs to the SLC35G solute transporter family.
Deglycase activity does not require glutathione as a cofactor, however, glycated glutathione constitutes a PARK7 substrate.
Glyoxalase activity has been reported. It may however reflect its deglycase activity.
Homodimer. Binds EFCAB6/DJBP and PIAS2. Part of a ternary complex containing PARK7, EFCAB6/DJBP and AR. Interacts (via N-terminus) with OTUD7B. Interacts with BBS1, HIPK1, CLCF1 and MTERF. Forms a complex with PINK1 and PRKN (By similarity). 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).
Mutants rear and groom less, they have a shorter stride length than their wild-type counterparts, but take more forelimb and hindlimb steps. They display deficits in short-term spatial memory as early as 4.5 months of age during place preference testing, as well as impaired coping strategies in the forced swim test.
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. Thus, functions as a protein deglycase that 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. 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. Also displays an apparent glyoxalase activity that in fact reflects its deglycase activity. Plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease; functions probably related to its primary function. 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. Eliminates hydrogen peroxide and protects cells against hydrogen peroxide-induced cell death. Required for correct mitochondrial morphology and function as well as for autophagy of dysfunctional mitochondria. 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. Regulates astrocyte inflammatory responses, may modulate lipid rafts-dependent endocytosis in astrocytes and neuronal cells (By similarity). 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. Metal-binding protein able to bind copper as well as toxic mercury ions, enhances the cell protection mechanism against induced metal toxicity (By similarity). 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 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 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. However, biochemical experiments showing that PARK7 is a bona fide deglycase have been performed.
Ubiquitous. Detected on epididymal sperm. Highly expressed in testis and prostate. Detected at lower levels in heart, lung, brain, liver, kidney, seminal vesicle, caput and corpus epididymis.
Undergoes cleavage of a C-terminal peptide and subsequent activation of protease activity in response to oxidative stress.
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 (By similarity).
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.
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 (By similarity).
Homopentamer; disulfide-linked. Pentraxin (or pentaxin) have a discoid arrangement of 5 non-covalently bound subunits. Two of the five chains form a dimer linked by two interchain disulfide bonds located in the C-terminal heptapeptide and specific to rat CRP. Interacts with FCN1; may regulate monocyte activation by FCN1 (By similarity).
The last two cysteines are involved either in interchain disulfide bonds or in an intrachain bond.
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.
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 (By similarity). Enhanced by DWORF; DWORF increases activity by displacing sarcolipin (SLN), phospholamban (PLN) and myoregulin (MRLN) (By similarity). Stabilizes SERCA2 in its E2 state (By similarity).
Interacts with sarcolipin (SLN); the interaction inhibits ATP2A2 Ca(2+) affinity. Interacts with phospholamban (PLN); the interaction inhibits ATP2A2 Ca(2+) affinity (By similarity). Interacts with myoregulin (MRLN) (By similarity). Interacts with DWORF (By similarity). Interacts with HAX1 (By similarity). Interacts with S100A8 and S100A9 (By similarity). Interacts with SLC35G1 and STIM1. Interacts with TMEM203 (By similarity). Interacts with TMEM64 and PDIA3 (By similarity). Interacts with TMX2 (By similarity). Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2. Interacts with ULK1 (By similarity). Interacts with S100A1 in a Ca(2+)-dependent manner (By similarity). 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 2 is highly expressed in heart and slow twitch skeletal muscle. Isoform 1 is widely expressed.
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. Involved in autophagy in response to starvation. Upon interaction with VMP1 and activation, controls ER-isolation membrane contacts for autophagosome formation. Also modulates ER contacts with lipid droplets, mitochondria and endosomes.
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.
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.
Endoplasmic reticulum (ER)-anchored autophagy regulator which exists in an inactive state under basal conditions but is activated following cellular stress. When activated, induces ER fragmentation and mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins. Required for collagen quality control in a LIR motif-independent manner.
Interacts with ATG8 family modifier proteins MAP1LC3A, MAP1LC3B, GABARAP, GABARAPL1 and GABARAPL2. Interacts with CANX.
The LIR motif interacts with ATG8 family proteins.
Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
Binds directly to activin and functions as an activin antagonist. Specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone (FSH).
Autophosphorylation at His-118 increases serine/threonine protein kinase activity of the enzyme. Interaction with the SET complex inhibits exonuclease activity (By similarity).
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.
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 (By similarity).
This protein is found in reduced amount in tumor cells of high metastatic potential.
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
Belongs to the metallo-dependent hydrolases superfamily. ATZ/TRZ family.
Catalyzes the hydrolytic deamination of guanine, producing xanthine and ammonia.
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 (By similarity). Component of the endosomal sorting complex required for transport II (ESCRT-II), composed of SNF8, VPS25 and VPS36 (PubMed:11278625). SNF8 is essential for the stability of the ESCRT-II complex. ESCRT-II interacts with ELL (By similarity).
Required for degradation of both endocytosed EGF and EGFR, but not for the EGFR ligand-mediated internalization (By similarity). 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 the exosomal release of SDCBP, CD63 and syndecan (By similarity).
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 peripheral neurons, but not in neurons of the central nervous system.
Forms pentahomomeric complex as well as pentaheteromeric complex with HTR3B; homomeric complex is functional but exhibits low conductance with modified voltage dependence and antagonist affinity.
N-glycosylation is required for membrane localization.
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.
Contains a short sequence motif (Phe-Xaa-Xaa-Phe-Tyr) that can bind to AR and may modulate AR activity.
Identified in the spliceosome C complex. May interact with AR.
Involved in the pre-mRNA splicing process. May play a role as regulator of AR transcriptional activity; may increase AR transcriptional activity.
Belongs to the small GTPase superfamily. Ras family. KappaB-Ras subfamily.
Binds 3 Ca(2+) ions per subunit. Two of the Ca(2+) ions are bound to the C2 domain.
Has no enzyme activity and acts as a negative regulator of phospholipase C, with a preference for thePLC-delta family.
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.
Increases at the transition from G1- to S-phase, and the continues to the end of M-phase. Almost disappears when cells reenter the next G1-phase.
Interacts with GRIP1 (By similarity). Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunit GNAI3 (inactive GDP-bound form); low-affinity interaction (By similarity).
Present at high level in testis. Also present in brain > skeletal muscle > thyroid gland > stomach > thymus > aorta > heart (at protein level). Highly expressed in regenerating liver. Isoform 4 is weakly expressed compared to other isoforms but is expressed at high level in some neural cells.
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 GBA (G-alpha binding and activating) motif mediates binding to the alpha subunits of guanine nucleotide-binding proteins (G proteins).
The PDZ-binding motif mediates the interaction with GRIP1.
The PH domain is not a critical determinant of the membrane localization. The PH domain of isoform 4 is necessary and sufficient to inhibit enzyme activity of other PLC-delta enzymes.
Interacts with ACHE, probably through disulfide bonds.
Isoforms 1 and 2 are expressed in the adult brain. In matured cortical neurons, only isoform 1 is detectable.
Required to anchor acetylcholinesterase (ACHE) to the basal lamina of the neuromuscular junction and to the membrane of neuronal synapses in brain. Organizes ACHE into tetramers (By similarity).
The proline-rich attachment domain (PRAD) binds the AChE catalytic subunits.
Up-regulated during the differentiation of in vitro cultured cortical neurons.
ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane. Plays an essential role in the selective transport of dietary plant sterols and cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile. Required for normal sterol homeostasis. The heterodimer with ABCG8 has ATPase activity.
Detected in liver (at protein level). Expressed only in liver and intestine.
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.
The polymorphism at position 583 is found in strains SHR, SHRSP and Wistar Kyoto which are both hypertensive and sitosterolemic. Strains which are hypertensive but not sitosterolemic do not contain a polymorphism at this position.
Component of a ribosome-associated translocon complex involved in multi-pass membrane protein transport into the endoplasmic reticulum (ER) membrane and biogenesis (By similarity). 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. 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. Participates in a large protein complex, which is not related to the gamma-secretase complex.
May antagonize Nodal signaling and subsequent organization of axial structures during mesodermal patterning.
Activated by phosphorylation on Thr-182 (By similarity). 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.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. AMPK subfamily.
By high salt diet and depolarization in brain.
Interacts (when phosphorylated on Thr-182 and Ser-186) with YWHAZ (By similarity). Interacts with ATP1A1.
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-577 by PKA promotes translocation to the cytoplasm (By similarity). 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 and CRTC2/TORC2. 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.
Belongs to the G-alpha family. G(12) subfamily.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with UBXD5. Interacts (in GTP-bound form) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RGS22. Interacts (via N-terminus) with NAPA; the interaction promotes CDH5 localization to plasma membrane. Interacts with CTNND1 (via N-terminus); the interaction regulates CDH1-mediated cell-cell adhesion. Interacts with PPP2R1A; the interaction promotes protein phosphatase 2A activation causing dephosphorylation of MAPT. Interacts (in GTP-bound form) with ARHGEF1. Interacts (in GTP-bound form) with ARHGEF11 (via RGS domain). Interacts (in GTP-bound form) with ARHGEF12 (via RGS domain).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:12176367, PubMed:21212405). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF12/LARG) (By similarity). GNA12-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (PubMed:21212405). GNA12-dependent Rho signaling also regulates protein phosphatese 2A activation causing dephosphorylation of its target proteins (By similarity). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway and up-regulating pro-inflammatory cytokine production. Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (By similarity). Together with NAPA promotes CDH5 localization to plasma membrane (By similarity). May play a role in the control of cell migration through the TOR signaling cascade (PubMed:12176367).
Expressed at high levels in vessels from developing heart from 12 dpc to P12. Expression decreases markedly from P12 to P17, and is no longer detectable at P30.
In the brain, by electrical or chemical seizures (at protein level).
May be involved in angiogenesis. May play a role in activity-dependent changes of brain vasculature. May affect blood-brain permeability.
Present at low levels in brain vascular cells (at protein level).
Abundantly expressed in the CNS and reproductive organs with the highest levels in the cerebrum, cerebellum, testis and ovary.
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 (By similarity).
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'.
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 with ECPAS. Interacts with DCC and ITGB5; the presence of DCC inhibits ITGB5 binding. Interacts with tubulin; ITGB5 or DCC binding inhibits tubulin binding. Interacts strongly with CALM3 and weakly with CALM, the CALM3 interaction is essential for function in filopodial extension and motility. Interacts with ITGB1, ITGB3 and ITGB5. Interacts with NEO1. Interacts with VASP (By similarity).
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 (By similarity). 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 (By similarity).
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 (By similarity).
Belongs to the glycosyl hydrolase 22 family.
Could be the product of a pseudogene. Lyz1 has been shown to be expressed, but not Lyz2.
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. In the intestine they may also have a digestive function.
Belongs to the Arg-specific ADP-ribosyltransferase family.
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 (PubMed:8188647, PubMed:9118951). 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 (Probable). Interacts with NEDD4; via the WW domains (PubMed:11323714). Interacts with NEDD4L; via the WW domains. Interacts with WWP1; via the WW domains. Interacts with WWP2; via the WW domains. Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (By similarity).
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 (PubMed:9118951, PubMed:8188647). Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells (PubMed:9118951, PubMed:8188647). 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 (By similarity). Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception (By similarity).
Ubiquitinated; this targets individual subunits for endocytosis and proteasome-mediated degradation.
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 DOCK3. Interacts with HERPUD1, FLNA and FLNB (By similarity).
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 (By similarity). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369).
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.
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. 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. 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. 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. 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. Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response. 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. Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation. Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs). 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. 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. In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (By similarity). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).
Expressed throughout the forebrain in discrete populations of neurons and is enriched in the cortex and hippocampus.
PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation. 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.
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.
Trimers composed of three different chains: alpha 1(XI), alpha 2(XI), and alpha 3(XI). Alpha 3(XI) is probably a post-translational modification of alpha 1(II).
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).
The cytoplasmic region mediates interaction with EPB41L1, DLG3, PALS2 and CASK.
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).
Defects in Dsg4 are the cause of an autosomal recessive phenotype lanceolate hair (lah). Lah rats pups develop only a few short hairs on the head and neck which form a lance head at the tip and disappear within one month. Hair regrows again a few days later, following a 29-day cycle of external growth and loss. Almost complete pelage hair loss occurs by 18 month.
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). Interacts with ATP7B, but not ATP7A, in a copper-dependent manner (By similarity). Interacts with ANK2; this interaction is required for localization at costameres (By similarity). Binds directly to the ACTR1A subunit of dynactin.
Expressed early in development (15 dpc), and gradually increases, reaching a peak at around 2 weeks after birth.
Monomer and homodimer. Interacts with CXADR. Interacts presynaptically with the glutamate receptors GRIA2, GRIA3, GRIK3, isoform 3 of GRIA4, isoform A of GRM4, GRM7 and GRM8; with NAPA and NAPB; and with BTG2. The interaction with NAPA and NAPB disrupts the interaction with GRIA2, conducting to the internalization of GRIA2. Interacts with PRKCA; with the amine transporters SLC6A2 and SLC6A3; with the channels ASIC1 and ASIC2; with the GTP-binding proteins ARF1 and ARF3; with the ephrin receptor tyrosine kinases EPHA7, EPHB1 and EPHB2; with ERBB2 and through its PDZ domain with the C-terminal tail of PRLHR (By similarity). Interacts with UNC5A. Interacts (via AH domain) with NCS1/FREQ; in a calcium-dependent manner. Interacts with F-actin and associates with the ARP2/3 complex. Interacts (via PDZ domain) with ARF1 (activated); the interaction blocks Arp2/3 complex inhibition.
Palmitoylation on Cys-414 is essential for long-term synaptic depression (LTD).
Phosphorylation at Thr-82 appears to inhibit the interaction with AMPA receptors.
Probable adapter protein that bind to and organize the subcellular localization of a variety of membrane proteins containing some PDZ recognition sequence. Involved in the clustering of various receptors, possibly by acting at the receptor internalization level. Plays a role in synaptic plasticity by regulating the trafficking and internalization of AMPA receptors. May be regulated upon PRKCA activation. May regulate ASIC1/ASIC3 channel. Regulates actin polymerization by inhibiting the actin-nucleating activity of the Arp2/3 complex; the function is competitive with nucleation promoting factors and is linked to neuronal morphology regulation and AMPA receptor (AMPAR) endocytosis. Via interaction with the Arp2/3 complex involved in regulation of synaptic plasicity of excitatory synapses and required for spine shrinkage during long-term depression (LTD). Involved in regulation of astrocyte morphology, antagonistic to Arp2/3 complex activator WASL/N-WASP function.
The AH domain mediates binding to F-actin.
The unoccupied PDZ domain is probably involved in allosteric modulation by forming an intramolecular bridge with the AH domain leading to a 'closed' formation. Binding of a PDZ ligand, such as GRIA2, allows enhanced interactions with F-actin and the Arp2/3 complex thus enhanced inhibition of actin polymerization.
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).
Expressed at highest levels early in development.
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 (By similarity).
Highest levels within the nervous system, expressed in different tissues, mostly in skeletal muscle.
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 (By similarity).
Ubiquitination at Met-1 leads to degradation by the proteasome pathway.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism (PubMed:12709059). Capable of activating medium-chain fatty acids with a preference for C6-12 fatty acids (PubMed:12709059).
Detected in all cell layers of the dorso-medial part of the embryonic olfactory placode and olfactory epithelium. First detected in olfactory placode on embryonic day 11.5. Detected in olfactory placode on embryonic day 12, 14, 16 and 18.
Belongs to the eukaryotic RPA49/POLR1E RNA polymerase subunit family.
Required for replication-independent chromatin assembly and for the periodic repression of histone gene transcription during the cell cycle.
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.
Catalyzes the covalent attachment of ubiquitin 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).
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.
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. 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 (By similarity). Interacts with RARA; the interaction requires prior phosphorylation of RARA on 'Ser-369' which then enhances interaction of RARA with CDK7 (By similarity).
Probable aspartic protease (By similarity). Seems to act as a proteasomal shuttle which links the proteasome and replication fork proteins like RTF2. 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 (By similarity).
Expression is restricted to the substantia nigra and ventral tegmental area in the midbrain. Expression increases in prenatally stressed adult offspring in the ventral tegmental area, whereas no changes are observed in the substantia nigra area (at protein level).
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).
Allosterically activated by magnesium, and possibly also other divalent metal cations. Allosterically activated by ATP, ADP or GTP (By similarity). Competitively inhibited by malonate.
Belongs to the serine/threonine dehydratase family.
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.
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 (By similarity).
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 (By similarity).
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 (By similarity).
The RRM domain is required for the formation of the ASAP complex.
Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling (By similarity).
Deiminated on Arg-4 in granulocytes upon calcium entry.
Down-regulated in hepatocytes after treatment with the procarcinogen N-nitrosodiethylamine (NDEA).
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.
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. 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. H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.
Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.
Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.
The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (By similarity).
Belongs to the type II (or gamma) interferon family.
Homodimer. Interacts with IFNGR1 (via extracellular domain); this interaction promotes IFNGR1 dimerization.
Released primarily from activated T lymphocytes.
Type II interferon produced by immune cells such as T-cells and NK cells that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation. Primarily signals through the JAK-STAT pathway after interaction with its receptor IFNGR1 to affect gene regulation. Upon IFNG binding, IFNGR1 intracellular domain opens out to allow association of downstream signaling components JAK2, JAK1 and STAT1, leading to STAT1 activation, nuclear translocation and transcription of IFNG-regulated genes. Many of the induced genes are transcription factors such as IRF1 that are able to further drive regulation of a next wave of transcription. Plays a role in class I antigen presentation pathway by inducing a replacement of catalytic proteasome subunits with immunoproteasome subunits. In turn, increases the quantity, quality, and repertoire of peptides for class I MHC loading. Increases the efficiency of peptide generation also by inducing the expression of activator PA28 that associates with the proteasome and alters its proteolytic cleavage preference. Up-regulates as well MHC II complexes on the cell surface by promoting expression of several key molecules such as cathepsins B/CTSB, H/CTSH, and L/CTSL (By similarity). Participates in the regulation of hematopoietic stem cells during development and under homeostatic conditions by affecting their development, quiescence, and differentiation (By similarity).
Type II interferon produced by immune cells such as T-cells and NK cells that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation. Primarily signals through the JAK-STAT pathway after interaction with its receptor IFNGR1 to affect gene regulation. Upon IFNG binding, IFNGR1 intracellular domain opens out to allow association of downstream signaling components JAK2, JAK1 and STAT1, leading to STAT1 activation, nuclear translocation and transcription of IFNG-regulated genes. Many of the induced genes are transcription factors such as IRF1 that are able to further drive regulation of a next wave of transcription. Plays a role in class I antigen presentation pathway by inducing a replacement of catalytic proteasome subunits with immunoproteasome subunits. In turn, increases the quantity, quality, and repertoire of peptides for class I MHC loading. Increases the efficiency of peptide generation also by inducing the expression of activator PA28 that associates with the proteasome and alters its proteolytic cleavage preference. Up-regulates as well MHC II complexes on the cell surface by promoting expression of several key molecules such as cathepsins B/CTSB, H/CTSH, and L/CTSL. Participates in the regulation of hematopoietic stem cells during development and under homeostatic conditions by affecting their development, quiescence, and differentiation.
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 (By similarity).
Is a phosphoprotein. While the DNA-binding activity is unaffected by the phosphorylation/dephosphorylation 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 (By similarity).
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).
Down-regulated by DTR via activation of EGFR.
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.
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.
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 and FBN1. Forms a ternary complex with FBN1 and FBLN2 or FBLN5. Interacts with MFAP4 in a Ca (2+)-dependent manner; this interaction promotes ELN self-assembly (By similarity). Interacts with EFEMP2 with moderate affinity (By similarity).
Involved in both the normal 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.
Expressed in osteoclasts and kidney cells.
Homodimer (By similarity). Interacts with BCL6 (By similarity). Interacts with RELA; involved in the control by RELA of the accessibility of target gene promoters (By similarity). Interacts with AR (via NR LBD domain); the interaction is direct and androgen-dependent (By similarity). Interacts with NCOR1 (By similarity). Interacts with NCOR2 (By similarity). Interacts with SMAD4; the interaction is direct and stimulated by TGFB1 (By similarity). Interacts with HDAC1 (By similarity). Interacts with SP1; ZBTB7A prevents the binding to GC-rich motifs in promoters and represses the transcriptional activity of SP1 (By similarity). Interacts with the DNA-dependent protein kinase complex/DNA-PKc (By similarity). Interacts with KHDRBS1; negatively regulates KHDRBS1 splicing activity (By similarity).
Sumoylated. Undergoes sumoylation with SUMO1 that may regulate its transcriptional activity.
The BTB domain mediates the interaction with the androgen receptor/AR and HDAC1. Also mediates the interaction with SP1.
Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation (By similarity) (PubMed:10477728). Directly and specifically binds to the consensus sequence 5'-[GA][CA]GACCCCCCCCC-3' and represses transcription both by regulating the organization of chromatin and through the direct recruitment of transcription factors to gene regulatory regions (By similarity) (PubMed:10477728). Negatively regulates SMAD4 transcriptional activity in the TGF-beta signaling pathway through these two mechanisms. That is, recruits the chromatin regulator HDAC1 to the SMAD4-DNA complex and in parallel prevents the recruitment of the transcriptional activators CREBBP and EP300 (By similarity). Collaborates with transcription factors like RELA to modify the accessibility of gene transcription regulatory regions to secondary transcription factors (By similarity). Also directly interacts with transcription factors like SP1 to prevent their binding to DNA. Functions as an androgen receptor/AR transcriptional corepressor by recruiting NCOR1 and NCOR2 to the androgen response elements/ARE on target genes. Thereby, negatively regulates androgen receptor signaling and androgen-induced cell proliferation. Involved in the switch between fetal and adult globin expression during erythroid cells maturation. Through its interaction with the NuRD complex regulates chromatin at the fetal globin genes to repress their transcription (By similarity). Specifically represses the transcription of the tumor suppressor ARF isoform from the CDKN2A gene. Efficiently abrogates E2F1-dependent CDKN2A transactivation. Regulates chondrogenesis through the transcriptional repression of specific genes via a mechanism that also requires histone deacetylation (By similarity). Regulates cell proliferation through the transcriptional regulation of genes involved in glycolysis. Involved in adipogenesis through the regulation of genes involved in adipocyte differentiation (By similarity). Plays a key role in the differentiation of lymphoid progenitors into B and T lineages. Promotes differentiation towards the B lineage by inhibiting the T-cell instructive Notch signaling pathway through the specific transcriptional repression of Notch downstream target genes (By similarity). Also regulates osteoclast differentiation (PubMed:10477728). May also play a role, independently of its transcriptional activity, in double-strand break repair via classical non-homologous end joining/cNHEJ. Recruited to double-strand break sites on damage DNA, interacts with the DNA-dependent protein kinase complex and directly regulates its stability and activity in DNA repair (By similarity). May also modulate the splicing activity of KHDRBS1 toward BCL2L1 in a mechanism which is histone deacetylase-dependent and thereby negatively regulates the pro-apoptotic effect of KHDRBS1 (By similarity).
Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde 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). 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). 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. The recruitment of the retriever complex to the endosomal membrane involves CCC and WASH complexes. Involved in GLUT1 endosome-to-plasma membrane trafficking; the function is dependent of association with ANKRD27.
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 (By similarity). 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. Component of the heterotrimeric retriever complex formed by VPS26C, VPS29 and VPS35L. Interacts with VPS35L (By similarity). Interacts with VPS26A, VPS35, SNX1, SNX2, SNX27, WASHC5, TBC1D5 (By similarity). Interacts with VPS26B and ANKRD27 (By similarity).
Binds DNA as a monomer (By similarity). Interacts with GRIP1, NCOA2 and NR0B2. Interacts (when sumoylated) with GPS2; interaction with GPS2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (By similarity).
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. 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 (By similarity). Activates the transcription of CYP2C38 (By similarity).
Sumoylated by SUMO1 at Lys-289 during the hepatic acute phase response, leading to promote interaction with GPS2 and prevent N-Cor corepressor complex dissociation.
Probable transcription factor which exert its primary action widely during early neural development and in a very limited set of neurons in the mature brain.
Calretinin is a calcium-binding protein which is abundant in auditory neurons.
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 (By similarity). 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). 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.
Highly expressed in small intestine and kidney, slightly in the liver. Expression was up-regulated when fed on a low inorganic phosphate diet.
Interaction with the C-terminus of CFTR could be mediated through independent binding of 1, 3 and 4 domains.
Interacts with PDZK1IP1 and ABCC2. Binds to the C-terminal region of SLC26A3. Interacts (via PDZ domains 1 and 3) with SCARB1 (C-terminal domain). Forms a heterodimeric complex with SLC9A3R1. Interacts with AKAP2, BCR, CFTR, SLCO1A1, 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 C-terminal PDZ domain) with SLC26A6 (via C-terminal domain). Interacts (via C-terminal PDZ domain) with SLC9A3 (via C-terminal domain). Interacts (via the first PDZ domain) with PTGIR (via non-isoprenylated C-terminus) (By similarity).
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.
By 12-O-tetradecanoylphorbol-13-acetate (TPA). Induced at higher levels by TPA and cycloheximide together. Also induced by redox changes after stimulation by hydrogen peroxide or menadione.
Overexpression impairs serum-induced cell cycle progression from the G0/G1 to S phase.
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. Dual-specificity tyrosine-regulated kinases (DYRKs) autophosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. 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. Does not mediate disassembly of all membraneless organelles: disassembly of P-body and nucleolus is not regulated by DYRK3. 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. 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. 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. Also acts as a negative regulator of EPO-dependent erythropoiesis: may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1: this in turn inhibits p53/TP53 activity and apoptosis.
Expressed predominantly in testis (PubMed:9748265). Expressed in late pachytene spermatocytes (PubMed:17292540).
Protein kinase activity is activated following autophosphorylation at Tyr-368.
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.
F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein (By similarity).
Homodimer; antiparallel. Interacts with MYOZ2, TTID and LPP (By similarity). Interacts with DDN (PubMed:16464232). Interacts with PSD. Interacts with MICALL2 (By similarity). Interacts with DNM2 and CTTN (PubMed:21210813). Interacts with PDLIM1 (PubMed:22659164). Interacts with PDLIM2 (PubMed:15505042). Interacts with PDLIM4 (via PDZ domain) (PubMed:14729062).
Activated by autophosphorylation on Thr-1381 and Thr-1393 following oligomerization.
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.
Binds both upstream activators and downstream substrates in multimolecular complexes through its N-terminus. Oligomerizes after binding MAP4K2 or TRAF2. Interacts (via the kinase catalytic domain) with STK38 (By similarity). Interacts with GRIPAP1 (PubMed:17761173).
Component of a protein kinase signal transduction cascade (PubMed:11784851). Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4 (PubMed:11784851). May phosphorylate the MAPK8/JNK1 kinase (By similarity). Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway (PubMed:11784851).
Most highly expressed in spleen, kidney and lung.
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. Beta-1/CHRNB1 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.
Expressed by natural killer cells and by resting thoracic duct CD4+ and CD8+ T-cells, but not by thymocytes or other hemopoietic cells. Expressed by DC cells.
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.
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. Can form disulfide-bonded heterodimer with CD94 (By similarity). Interacts with CEACAM1; recruits PTPN6 that dephosphorylates VAV1 (By similarity).
Is not capable of signal transduction by itself, but operates through the adapter protein HCST.
Monomer. Interacts with BTRC. Identified in a complex with CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the proteasomal degradation of DDIT4 (By similarity).
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. 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.
Strongly up-regulated by hypoxia. Up-regulated by dexamethasone in skeletal muscles. Up-regulated in various cellular models of Parkinson disease (at protein level).
Belongs to the fatty acyl-CoA reductase family.
Catalyzes the reduction of fatty acyl-CoA to fatty alcohols.
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).
In the ventral prostate, expressed in glandular epithelial cells.
Expressed in brain, kidney and liver. Expressed within the amygdala, brainstem, cerberal cortex, dorsal root ganglia, dorsal spinal cord, hippocampus, hypothalamus, retina, striatum and ventral spinal cord. Expressed within neurons of the caudate-putamen, olfactory tubercle, nucleus accumbens, hippocampus, interpeduncular nucleus and dorsal and medial raphe nuclei. Expressed in inner hair cells of the ear. Expressed at synaptic terminals within the lateral superior olive (LSO), a nucleus of the mammalian sound localization system, and in the medial nucleus of the trapezoid body (MNTB), which provides inhibitory input to the LSO.
Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, sodium and phosphate (PubMed:12097496, PubMed:12388773, PubMed:27133463). 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:12097496, PubMed:12388773, PubMed:27133463). 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:12388773, PubMed:12097496). 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 (PubMed:27133463). 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 (By similarity). The symporter activity is electrogenic (By similarity). Moreover, operates synergistically with SLC18A3/VACHT under a constant H(+) gradient, thereby allowing striatal vesicular acetylcholine uptake (PubMed:18278042).
The L-glutamate uniporter activity exhibits a biphasic dependence on chloride concentration (PubMed:12388773). Chloride channel activity is allosterically activated by lumenal H(+) and Cl(-) leading to synaptic vesicles acidification (PubMed:27133463). The glutamate transport activity is allosterically activated by lumenal H(+) and Cl(-), preventing non-vesicular L-glutamate release (PubMed:27133463).
Mitochondrial serine transporter that mediates transport of serine into mitochondria, an important step of the one-carbon metabolism pathway. 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.
Anchored to cell periphery via its N-terminal PDZ domain.
At 14 dpc expressed in mesenchymal tissue surrounding the cartilaginous anlage of immature bones, and in the future joint spaces. As endochondral ossification progresses, and the hypertrophic cartilage zone is replaced by mineralized bone, expression appears in the mineralizing portion of the bone. Expressed in mesoderm derived bones of the skull base and neural crest-derived endochondral bones such as the proximal mandible.
Binds via its LIM zinc-binding 3 domain (LIM 3) domain 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 2 domain (LIM 2). Probably part of a complex with SHC and the RET dimer. Interacts with TPM2, TBX4 and TBX5 (By similarity). Interacts (via LIM domains) with SIPA1L1.
Expressed in kidney, heart, brain, lung, and skeletal muscle. Overexpression results in the synthesis of an unidentified soluble factor which acts on cells in the osteoblast lineage causing them to differentiate and secrete BMP-2.
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.
The LIM zinc-binding 2 (LIM 2) 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).
Homooligomer (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. 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 ATP5MPL (PubMed:17575325). 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 (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. 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. They are expressed in a tissue-specific manner.
This protein 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.
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 (By similarity).
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.
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. INTS11 subfamily.
Catalytic 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. Mediates the snRNAs 3' cleavage. Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex.
The HXHXDH motif is essential for the endoribonuclease activity of the CPSF complex.
May be involved in the regulation of neurotransmitter release and synaptogenesis. Binds ATP with high affinity and ADP with a lower affinity. This is consistent with a catalytic role of the C-domain in which ADP would be dissociated by cellular ATP after bound ATP was hydrolyzed.
Phosphorylation at Ser-9 dissociates synapsins from synaptic vesicles.
The A region binds phospholipids with a preference for negatively charged species.
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.
Homopentamer. Interacts with HAX1. Interact with ATP2A2; the inhibition decreases ATP2A2 Ca(2+) affinity. Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2. Interacts with S100A1 in a Ca(2+)-dependent manner.
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 (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. ATP2A2 inhibition is alleviated by PLN phosphorylation. Controls intracellular Ca(2+) levels in elongated spermatids. May play a role in germ cell differentiation.
Interacts with PXN. Interacts with JKAMP. Interacts with STING1; the interaction of endogenous proteins is dependent on viral infection.
Membrane-bound E3 ubiquitin-protein ligase that mediates ubiquitination of target proteins. May function together with E2 ubiquitin-conjugating enzymes UBE2D1/UBCH5A and UBE2D2/UBC4. Mediates ubiquitination of PXN/paxillin,thereby regulating cell motility and localization of PXN/paxillin. Catalyzes ubiquitination of Salmonella type III secreted protein sopA. 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. 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. Catalyzes ubiquitination and subsequent degradation of ATG4B, thereby inhibiting autophagy.
Belongs to the Schlafen family. Subgroup III subfamily.
Interacts with TRIM3; the interaction positively affects motility of KIF21B (By similarity). Interacts with GABARAP and GABA(A) receptor subunits: GABRG2, GABRA1 and GABRA2 (PubMed:25172774). May interact with GABA(A) receptor subunits: GABRB2 and GABRB3 (PubMed:25172774).
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.
CRK-II is expressed in all tissues and cells whereas CRK-I is expressed at lower level and in limited cell-types.
Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (By similarity). Within the complex, interacts with SH2D3C (via C-terminus), and BCAR1/CAS (By similarity). Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (By similarity). 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. Isoform Crk-II interacts with KIT. Interacts with EPHA3; upon activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase activity-dependent. Interacts with EPHA3 (phosphorylated); mediates EFNA5-EPHA3 signaling through RHOA GTPase activation. Interacts with FLT4 (tyrosine-phosphorylated). Isoform Crk-II (via SH2 domain) interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). 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 (By similarity).
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:12198159). 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. 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 (By similarity). 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 (By similarity).
At 17 dpc, expressed in the auditory circuit, most prominently in the inferior colliculus, and later in the medial geniculate and the auditory cortex at P0. At P0, also expressed in targets of retinal projections, such as the superior colliculus, the suprachiasmatic nucleus, and the ventrolateral geniculate nucleus. At the same stage, detected in selected structures of the limbic circuit, including the anterior limbic thalamic nuclei, the hippocampus, amygdala and habenula.
Calcium-dependent cell-adhesion protein. May play a role in activity-induced synaptic reorganization underlying long term memory. 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.
Enriched in brain relative to peripheral tissues, with low expression in the testis. Expressed in hippocampal neurons (at protein level).
May be the only physiologically relevant isoform.
Rapidly and transiently induced by maximal electroconvulsive seizure in the hippocampal granule cells, and modestly induced in the pyramidal cells. Also induced by cAMP.
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.
Component of the XPC complex composed of XPC, RAD23B and CETN2. Interacts with NGLY1 and PSMC1. Interacts with ATXN3. Interacts with AMFR. Interacts with VCP; the interaction is indirect and mediated by NGLY1 (By similarity).
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 (By similarity).
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 (By similarity).
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:Rad22b induces a bend in DNA upon binding. Xpc:Rad23b stimulates the activity of DNA glycosylases Tdg and Smug1 (By similarity).
Interacts with CLK1, PNN and with the phosphorylated C-terminal domain of RNA polymerase II.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. May be implicated in the folding, transport, and assembly of proteins. May play an important role in the regulation of pre-mRNA splicing.
The RS domain is required for the interaction with the phosphorylated C-terminal domain of RNA polymerase II.
Interacts with ATP2B1; this interaction stabilizes ATP2B1 and increases ATPase activity; this interaction controls T cell calcium homeostasis following T cell activation. Interacts with XKR8; promoting its localization at the cell membrane.
Isoform 1 and isoform 2 are N-glycosylated.
Isoform 1 is detectable at all developmental stages starting from postnatal day 1. Isoform 2 is low at postnatal day 1, increases steadily until postnatal days 20-25 and then declines to an intermediate level.
Isoform 1 is ubiquitously expressed. Isoform 2 is brain-specific. In brain isoform 2 is highly expressed in hippocampus and cerebral cortex and weakly in cerebellum and lower brain regions. In the hippocampus isoform 2 is found in the dentate gyrus and CA1-CA4, the striatum oriens of CA3 shows the higher level.
Probable homophilic and heterophilic cell adhesion molecule involved in long term potentiation at hippocampal excitatory synapses through activation of p38MAPK (PubMed:10759566, PubMed:16925595). May also regulate neurite outgrowth by activating the FGFR1 signaling pathway (PubMed:10759566, PubMed:16925595). May play a role in synaptic plasticity (PubMed:10759566, PubMed:16925595). Also acts as a chaperone for ATP2B1; stabilizes ATP2B1 and increases its ATPase activity. Promotes localization of XKR8 at the cell membrane (By similarity).
Some isoforms lack the first Ig-like domain which may confer homophilic adhesion activity. However, they can bind and activate FGFR1.
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. Interacts with CLOCK and BMAL1 (By similarity).
Phosphorylated in vitro by CDC2 and PKC.
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 (By similarity).
Belongs to the PTEN phosphatase protein family.
Abundant in cortex and hypothalamus, and lower levels seen in the heart and intestine.
Belongs to the G-protein coupled receptor 1 family. Neurotensin receptor subfamily. NTSR2 sub-subfamily.
Expressed maximally in 7-day-old brain and expression decreases progressively until adulthood (35-day-old brain).
Receptor for the tridecapeptide neurotensin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Isoform Se-P1 contains several disulfide bridges and a selenide-sulfide bond between Sec-59 and Cys-62. These bonds are speculated to serve as redox-active pairs.
Might be responsible for some of the extracellular antioxidant defense properties of selenium or might be involved in the transport of selenium. May supply selenium to tissues such as brain and testis.
Plasma contains 4 isoforms, which are named isoforms Se-P10, Se-P6, Se-P2 and Se-P1, according to the number of selenocysteines they contain. All isoforms arise from the same mRNA. The 3 shortened isoforms terminated at the opal stop codons at positions 264, 282, 371, when selenocysteine has not been inserted.
The C-terminus is not required for endocytic uptake in the proximal tubule epithelium.
Widely expressed, mainly by the liver. Secreted in plasma.
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 (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. 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 (By similarity).
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM8A from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
By aldosterone, corticosterone and RU28362 in hippocampus. By corticosterone and RU28362 in cortex. The response to corticosterone is slow. Does not respond to vibratory stress. May be regulated by both the mineralocorticoid receptor and glucocorticoid receptor.
Detected mainly in brain and at lower levels in heart and lung (at protein level). Also detected in testis but not in kidney, liver or spleen.
Isoform 1 interacts with WASL (via WH1 domain), and monomeric and filamentous actin.
May have a role in spermatogenesis (By similarity). May be a regulator of cytoskeletal organization.
Suppress the growth and endocytosis defect of yeast lacking VRP1 without correcting the actin patch polarization defect.
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.
Homooligomer and heterooligomer (Probable). Interacts with titin/TTN. Interacts with myosins. Interacts with SQSTM1 and NBR1. Probably interacts with TRIM63 and TRIM54 (By similarity).
May regulate gene expression and protein turnover in muscle cells.
By lipopolysaccharide. Expression increases until 4 hours after treatment and then gradually decreases, remaining high 24 hours after stimulation.
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.
Channel activity is inhibited by mercury ions.
Detected in kidney medulla and papilla, in collecting duct cells (PubMed:7526388, PubMed:7517548). Detected in colon (PubMed:7517548).
Water channel required to promote glycerol permeability and water transport across cell membranes (PubMed:7526388, PubMed:7517548). 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).
Common component of the spliceosome and rRNA processing machinery.
Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells. Binds both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositolphosphatidylinol 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).
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.
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 (By similarity). 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 (By similarity). May play a role during development (By similarity).
Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation. Cytokine-binding is sufficient to activate LTK. In contrast, ALKAL2-driven activation of ALK is coupled with heparin-binding to ALK. Stimulation of ALK signaling is involved in neural development and regulation of energy expenditure.
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.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which hydrolyzes the 46-Lys-|-Leu-47 bond and probably inhibits neurotransmitter release (PubMed:8175689).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 45-Gln-|-Lys-46 bond and probably inhibits neurotransmitter release (PubMed:8175689).
(Microbial infection) Targeted and hydrolyzed by C.tetani toxin (tetX) which hydrolyzes the 63-Gln-|-Phe-64 bond and probably inhibits neurotransmitter release (PubMed:8175689).
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 (By similarity). Interacts with PICALM (By similarity).
SNARE involved in vesicular transport from the late endosomes to the trans-Golgi network.
Ubiquitinated by RNF167 at Lys-70, Lys-72 and Lys-81, regulating the recycling endosome pathway.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by RIGI in response to viral infection. Essential for viral activation of IRF3 (By similarity). Mediates ubiquitination of PEX5.
Interacts with SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex. Interacts with CNOT4 (via RING domain). Interacts with E3 ubiquitin-protein ligases CBLC, PJA1 and PJA2. Interacts with PDZRN3. Interacts with PPP1R11.
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9. Interacts with COQ8B and COQ7.
FAD-dependent monooxygenase required for the C5-ring hydroxylation during ubiquinone biosynthesis. Catalyzes the hydroxylation of 3-polyprenyl-4-hydroxybenzoic acid to 3-polyprenyl-4,5-dihydroxybenzoic acid. The electrons required for the hydroxylation reaction may be funneled indirectly from NADPH via a ferredoxin/ferredoxin reductase system to COQ6.
In the kidney, expressed almost exclusively in glomerular podocytes. In the inner ear, expressed in the spiral ganglion, as well as in stria vascularis and spiral ligament cells.
Interacts with EAF2. Associates with UBR5 and forms a transcription regulatory complex made of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription by recruiting their promoters.
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 (By similarity).
S-II binds to RNA-polymerase II in the absence of transcription.
Interacts with RAB11A; this interaction recruits TBC1D12 to RAB11A-positive recycling endosomes.
Knock-down promotes neurite outgrowth in a RAB11A-dependent manner.
RAB11A-binding protein that plays a role in neurite outgrowth.
Highly expressed in cornea and lung. Expressed at intermediate level in sclera and combined tissues of the eye irido-corneal angle. Specifically expressed in the corneal epithelial cells but not in other corneal layers.
Interacts with alpha-actinins ACTN1 and ACTN4, FLNA and MYH9 (PubMed:15505042). Interacts (via LIM zinc-binding domain) with MKRN2 (By similarity).
Probable adapter protein located at the actin cytoskeleton that promotes cell attachment. Necessary for the migratory capacity of epithelial cells. Overexpression enhances cell adhesion to collagen and fibronectin and suppresses anchorage independent growth. May contribute to tumor cell migratory capacity (By similarity).
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. It prevents sialic acids from being recycled and returning to the cell surface. Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway.
By prolactin, IL-2 and FGF-2 in prolactin-dependent lymphoid cells (at protein level).
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. 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).
Homodimer. Interacts with DAPK3 (PubMed:11884640). Component of the precatalytic, catalytic and postcatalytic spliceosome complexes (By similarity). Part of a spliceosomal 'core' complex consisting of CDC5L, PLRG1, SPF27, CCAP1, CCAP3 and CCAP6. Interacts with PLRG1, Lodestar/TTF2, and NIPP1/PPP1R8 (PubMed:10827081). Identified in the spliceosome C complex. 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 (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. Also interacts with CTNNBL1. Interacts with PRPF19 (via N-terminus) (PubMed:16352598). Interacts with USB1 (By similarity).
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 (By similarity). Phosphorylation enhances interaction with PPP1R8.
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 PSMC2 and few additional components. Interacts with NDC80 and SQSTM1. Interacts with PAAF1. Interacts with TRIM5.
Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
Activated by autophosphorylation. Prior phosphorylation at Tyr-511 by SRC inhibits ulterior autophosphorylation at Tyr-400. 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 brain cortex (at protein level).
Interacts with ITGB1, ITGB2, MS4A2/FCER1B and FCGR2. 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 (By similarity). Interacts with CLNK (By similarity).
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, FCER1G and FCGR2. 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 (By similarity). 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 FCGR2 engagement, cell adhesion and signaling by ITGB2 (By similarity). Prior phosphorylation at Tyr-511 by SRC inhibits ulterior autophosphorylation at Tyr-400.
Ubiquitinated. Becomes ubiquitinated in response to ITGB2 signaling; this does not lead to degradation (By similarity).
The BTB domain might play a role in targeting to acrosomal vesicles.
Expressed in the parotid and submandibular glands (at protein level) (PubMed:10600827). Expressed in the gastric mucosa (at protein level) (PubMed:8141271). Expressed in the choroid plexus epithelium (at protein level) (PubMed:2371270). Expressed in the liver and gallbladder (PubMed:22310983).
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:2371270). Plays an important role in osteoclast differentiation and function (By similarity). Regulates bone resorption and calpain-dependent actin cytoskeleton organization in osteoclasts via anion exchange-dependent control of pH (By similarity). Essential for intracellular pH regulation in CD8(+) T-cells upon CD3 stimulation, modulating CD8(+) T-cell responses (By similarity).
Belongs to the 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. In addition to its role as a glycolytic enzyme, it seems that PGK-1 acts as a polymerase alpha cofactor protein (primer recognition protein). May play a role in sperm motility.
RAB2B effector protein required for accurate acrosome formation and normal male fertility. In complex with RAB2A/RAB2B, seems to suppress excessive vesicle trafficking during acrosome formation.
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. Interacts with PRKAR1A and PRKAR2B (By similarity). The cAMP-dependent protein kinase catalytic subunit binds PJA2. Interacts with GPKOW.
Asn-3 is deaminated to Asp in more than 25% of the proteins, giving rise to 2 major isoelectric variants, called CB and CA respectively (0.4 pH unit change). Deamidation proceeds via the so-called beta-aspartyl shift mechanism and yields either 'D-Asp-2' (major) or 'D-isoAsp-2' (minor), in addition to L-isomers. Deamidation occurs after the addition of myristate. The Asn-3 form reaches a significantly larger nuclear/cytoplasmic ratio than the 'Asp-2' form.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily.
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. Phosphorylates GPKOW which regulates its ability to bind RNA.
Belongs to the mitochondrion-specific ribosomal protein mL43 family.
Developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN), which has heparin binding activity. Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation. Involved in neointima formation after arterial injury, possibly by mediating leukocyte recruitment. Also involved in early fetal adrenal gland development (By similarity).
Expressed at a low level in arteries, and at higher levels in newly formed neointima. In brain, expressed in the caudate nucleus and the brain stem.
Homodimer. Interacts with ALK. Interacts with LRP1; promotes neuronal survival. Interacts with LRP2. Interacts with NCAM1. Interacts (via C-terminal) with PTPRZ1 (via chondroitin sulfate chains); this interaction is inhibited by PTN; this interaction promotes neuronal migration. Interacts with NCL; this interaction promotes NCL clustering and lateral movements of this complex into lipid rafts leading to MDK internalization. Interacts with LRP6 and LRP8: this interaction is calcium dependent. Interacts with ITGA4. Interacts with ITGA6. Interacts with ITGB1. Interacts with ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation. Interacts with ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth. Interacts with NOTCH2; this interactio mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3. Interacts with GPC2 (via heparan sulfate chain); this interaction is inhibited by heparin followed by chondroitin sulfate E; this interaction induces GPC2 clustering through heparan sulfate chain; this interaction induces neuronal cell adhesion and neurite outgrowth. Interacts with SDC3; this interaction induces SDC3 clustering; this interaction induces neuronal cell adhesion and neurite outgrowth (By similarity). Interacts with SDC1 (By similarity). Interacts with CSPG5; this interaction promotes elongation of oligodendroglial precursor-like cells (By similarity).
In arteries 3 days after injury. Expression continues to increase until day 7 after injury and decreases slightly by day 14.
In the cortices of the adrenal glands, expressed at 12.5 dpc, decreases considerably at 15.5 dpc and is almost undetectable in the newborn stage. In brain, expressed at low levels in early embryos, expression peaks between 12 dpc and 14 dpc, and rapidly falls until birth when expression is barely detectable.
Secreted protein that functions as cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors. Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups. Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration. Participates in inflammatory processes by exerting two different activities (By similarity). Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression (PubMed:10683378). This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively. Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation (By similarity). Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis. Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation. Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans (By similarity). Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival. Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion. Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2 (By similarity). Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells (By similarity). Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth. Binds LRP1; promotes neuronal survival. Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation. Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation. Promotes epithelial to mesenchymal transition through interaction with NOTCH2 (By similarity). During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation. Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts (By similarity). In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system (By similarity) (PubMed:11136554).
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.
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.
Phosphorylated on a cytoplasmic Ser residue.
Two types of rat hepatic lectin have been identified, RHL-1 and RHL-2/3, having a relative abundance of 4:1.
Receptor for UDP-glucose coupled to G-proteins.
Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol.
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.
Belongs to the short-chain dehydrogenases/reductases (SDR) family. 2,4-dienoyl-CoA reductase subfamily.
Probable kinase that may be involved in a calcium-signaling pathway controlling neuronal migration in the developing brain. May also participate in functions of the mature nervous system (By similarity).
Cytochromes P450 are a group of heme-thiolate monooxygenases. This isozyme seems to be implicated in olfaction.
Forms a ternary complex with DKK1 and LRP6. Interacts with LRP6 in a DKK1-dependent manner. Interacts with DKK1 and RSPO1 (via FU repeats).
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.
Belongs to the AB hydrolase superfamily. LDAH family.
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.
RNA-binding protein implicated in the regulation of several post-transcriptional events. Involved in pre-mRNA alternative splicing, mRNA translation and stability. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of TNNT2 in embryonic, but not adult, skeletal muscle. Activates TNNT2 exon 5 inclusion by antagonizing the repressive effect of PTB. Acts as both an activator and repressor of a pair of coregulated exons: promotes inclusion of the smooth muscle (SM) exon but exclusion of the non-muscle (NM) exon in actinin pre-mRNAs. Promotes inclusion of exonS 21 and exclusion of exon 5 of the NMDA receptor R1 pre-mRNA. Involved in the apoB RNA editing activity. Increases COX2 mRNA stability and inhibits COX2 mRNA translation in epithelial cells after radiation injury. Modulates the cellular apoptosis program by regulating COX2-mediated prostaglandin E2 (PGE2) expression. Binds to (CUG)n triplet repeats in the 3'-UTR of transcripts such as DMPK. Binds to the muscle-specific splicing enhancer (MSE) intronic sites flanking the TNNT2 alternative exon 5. Binds preferentially to UG-rich sequences, in particular UG repeat and UGUU motifs. Binds to apoB mRNA, specifically to AU-rich sequences located immediatly upstream of the edited cytidine. Binds AU-rich sequences in the 3'-UTR of COX2 mRNA. Binds to an intronic RNA element responsible for the silencing of exon 21 splicing. Binds to (CUG)n repeats (By similarity). May be a specific regulator of miRNA biogenesis. Binds to primary microRNA pri-MIR140 and, with CELF1, negatively regulates the processing to mature miRNA (By similarity).
Strongly expressed in forebrain regions, including the cerebral cortex and hippocampus. Moderately expressed in hindbrain regions, including the cerebellum and spinal cord.
Histone deacetylase that catalyzes 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. Also functions as deacetylase for non-histone proteins.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ4 subfamily.
Detected in kidney distal convoluted tubules (at protein level). Widely expressed throughout the brain. Also found in some peripheral tissues.
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. 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).
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.
Highly expressed in all regions of the small intestine and colon studied in suckling animals. However, after weaning, when iron absorption declines significantly, strong expression is retained only in the duodenum. Also expressed in respiratory epithelium.
Plasma membrane reductase that uses cytoplasmic ascorbate as an electron donor to reduce extracellular Fe(3+) into Fe(2+). Probably functions in dietary iron absorption at the brush border of duodenal enterocytes by producing Fe(2+), the divalent form of iron that can be transported into enterocytes. It is also able to reduce extracellular monodehydro-L-ascorbate and may be involved in extracellular ascorbate regeneration by erythrocytes in blood. May also act as a ferrireductase in airway epithelial cells (By similarity). May also function as a cupric transmembrane reductase (By similarity).
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family.
Binds to RTN4R (By similarity). Interacts with ATL1 (PubMed:19665976). Interacts with TMEM170A (By similarity). 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:12037567, PubMed:12843238, PubMed:20573699). Regulates the radial migration of cortical neurons via an RTN4R-LINGO1 containing receptor complex. 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 (By similarity). Interacts with BAD/Bcl-xl and BCL2. Interact with RTN3 (By similarity). Interacts with NGBR (By similarity). Interacts with SPTLC1 (By similarity). Interacts with GRAMD4 (By similarity). Interacts with CDH5 (By similarity). Interacts with BACE1 and BACE2 (By similarity). Interacts with REEP5 (By similarity). Interacts with RETREG3 (By similarity).
Interacts in trans with CNTNAP1 (PubMed:14592966). Interacts with REEP5 (By similarity).
Interacts with BACE1 and BACE2 (By similarity). Interacts with TMEM33 (By similarity).
Isoforms A, B and C are present in optic nerve, spinal cord and cerebral cortex. Isoforms A and B are present in dorsal root ganglion, sciatic nerve and PC12 cells after longer exposure. Isoforms B and C are detected in kidney, cartilage, skin, lung and spleen. Isoform C is expressed at high level in skeletal muscle. In adult animals isoform A is expressed mainly in the nervous system.
Mainly function in endothelial cells and vascular smooth muscle cells, is also involved in immune system regulation (By similarity). 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. With isoform C, inhibits BACE1 activity and amyloid precursor protein processing (By similarity).
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 (By similarity).
Required to induce the formation and stabilization of endoplasmic reticulum (ER) tubules. They regulate membrane morphogenesis in the ER by promoting tubular ER production. They influence nuclear envelope expansion, nuclear pore complex formation and proper localization of inner nuclear membrane proteins. However each isoform have specific functions mainly depending on their tissue expression specificities.
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.
Implicated in development of the cochlea.
Interacts (via SIM domains) with SUMO1 and SUMO2.
Belongs to the FMN-dependent alpha-hydroxy acid dehydrogenase family.
Homotetramer (PubMed:8508789). Could also form homooctamer.
Is inhibited in vitro by CCPST (4-carboxy-5-(4-chlorophenyl)sulfanyl-1,2,3-thiadiazole).
Oxidase that catalyzes the oxidation of medium and long chain hydroxyacids such as 2-hydroxyhexadecanoate, 2-hydroxyoctanoate, 2-hydroxyhexanoate and 2-hydroxybutanoate, to the correspondong 2-oxoacids (PubMed:15683236, PubMed:3061453, PubMed:8508789). Its role in the oxidation of 2-hydroxy fatty acids may contribute to the general pathway of fatty acid alpha-oxidation (By similarity). Can also use mandelate as substrate (PubMed:3061453). 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:15683236, PubMed:3061453, PubMed:8508789).
Binds to heparan sulfate proteoglycans on the surface of fibroblast cells.
Lacks key residues involved in peptide docking, suggesting that this is a non-classical MHC class I protein which does not play a role in antigen presentation.
Ubiquitously expressed in neonatal and adult tissues.
Forms a DNA-binding heterodimer with transcription factor PBX1.
Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
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.
Predominantly expressed in testis. Present in early developing spermatids. Not present in spermatogonia, spermatocytes or somatic cells (i.e. peritubular, Leydig, and Sertoli cells). Present in early round spermatids at step 4, remains until step 11, then it decreases at steps 12-15, and diminishes after step 16 (at protein level). Also expressed at lower level in brain.
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.
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.
Expressed in embryonic calvaria and femur, and in adult aorta, costa, femur, kidney, lung, ovary, spleen and trachea (PubMed:8605043). Widely expressed throughout the adult central nervous system, including most neurons and their axons (PubMed:27130896).
Expression increases in mesenchymal cells at fracture sites during healing. Also highly expressed in chondrocytes and osteoblasts at newly formed cartilage and bone.
Negatively regulates bone density. Antagonizes the ability of certain osteogenic BMPs to induce osteoprogenitor differentitation and ossification (By similarity).
Component of the transition zone in primary cilia. Required for ciliogenesis.
Cerulenin, a potent non-competitive pharmacological inhibitor of FAS, binds covalently to the active site of the condensing enzyme region, inactivating a key enzyme step in fatty acid synthesis (PubMed:16969344). Another inhibitor, though less efficient, is C75, a member of the alpha-methylene-gamma-butyrolactone chemical class, also proposed as an antitumour and anti-obesity agent (PubMed:15715522).
Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH. This multifunctional protein contains 7 catalytic activities and a site for the binding of the prosthetic group 4'-phosphopantetheine of the acyl carrier protein ([ACP]) domain.
Homodimer which is arranged in a head to tail fashion (By similarity). Interacts with CEACAM1; this interaction is insulin and phosphorylation-dependent; reduces fatty-acid synthase activity (PubMed:16054098).
S-nitrosylation of Fatty acid synthase at cysteine residues Cys-1464 or Cys-2085 is important for the enzyme dimerization. In adipocytes, S-nitrosylation of Fatty acid synthase occurs under physiological conditions and gradually increases during adipogenesis.
Up-regulated in livers of rats fed on a high carbohydrate diet.
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). Heterodimer with ZHX1 (via homeobox domain 1). Heterodimer with ZHX2 (via homeobox domain 1). Heterodimerization with ZHX1 is a prerequisite for repressor activity. Interacts with NFYA.
Cortex, hippocampus, pituitary gland, colon, kidney, and adrenal gland. In the developing nervous system, expressed from E12 when it is restricted to postmitotic neuronal populations leaving the ventricular zone. From E12 on, expressed in migrating neuronal populations in numerous developing regions including the cerebral cortex, hippocampus and ganglionic eminences. Also detected in the deep part of the external granular layer of the cerebellum, the rostral migratory stream and a subset of axons and neurons. Expressed in the medial forebrain bundle, rostral migratory stream and cerebellum during development but not in adulthood.
Homodimer and heterodimer with SSTR3 and SSTR5. Heterodimerization with SSTR3 inactivates SSTR3 receptor function. Heterodimerization with SSTR5 is enhanced by agonist stimulation of SSTR2 and increases SSTR2 cell growth inhibition activity. Following agonist stimulation, homodimers dissociate into monomers which is required for receptor internalization. Interacts with beta-arrestin; this interaction is necessary for receptor internalization and is destabilized by heterodimerization with SSTR5 which results in increased recycling of SSTR2 to the cell surface. Interacts (via C-terminus) with SHANK1 (via PDZ domain).
Phosphorylated on serine and threonine residues in response to agonist stimulation, leading to receptor desensitization and rapid internalization. Phosphorylated to a greater extent on serine than threonine residues. Threonine phosphorylation is required for arrestin binding and receptor endocytosis but is not necessary for desensitization.
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase. In addition it stimulates phosphotyrosine phosphatase and PLC via pertussis toxin insensitive as well as sensitive G proteins. Inhibits calcium entry by suppressing voltage-dependent calcium channels. Acts as the functionally dominant somatostatin receptor in pancreatic alpha- and beta-cells where it mediates the inhibitory effect of somatostatin-14 on hormone secretion. Inhibits cell growth through enhancement of MAPK1 and MAPK2 phosphorylation and subsequent up-regulation of CDKN1B. Stimulates neuronal migration and axon outgrowth and may participate in neuron development and maturation during brain development. Mediates negative regulation of insulin receptor signaling through PTPN6. Inactivates SSTR3 receptor function following heterodimerization.
A homodimer structure has been reported; however it is unclear whether the protein form a homodimer in vivo. Identified in a complex with the COP9 signalosome complex (CSN). Interacts with SMAD1, SMAD2 and SMAD3; the interaction is direct. Forms a complex with SMURF2 and SMAD7. Interacts with TGFBR1. Interacts with SART3; the interaction is direct. May interact with RNF20 and RNF40. May interact with PRKN. Interacts with INCA1.
Highly expressed in testis and spleen, and at lower level 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. 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. 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. Able to mediate deubiquitination of monoubiquitinated substrates, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B. 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. 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. 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. Acts as a negative regulator of antifungal immunity by mediating 'Lys-27'-linked deubiquitination of CARD9, thereby inactivating CARD9.
Phosphorylated. Phosphorylation protects against ubiquitination and subsequent degradation by the proteasome.
Ubiquitinated, leading to degradation by the proteasome.
Belongs to the learning-associated protein family.
Expressed in intestine, liver and kidney. Weakly expressed in brain, thymus, lung, spleen, heart and skin. In brain, it is expressed in cerebellum, especially in the granular layer, in hippocampus and cortex. In kidney, it is expressed in cortex and medulla with relatively more abundance in the cortical-medullary junction. In heart, it is expressed in myocardium and valves. Expressed labyrinthine zone of the placenta.
Inhibited by desipramin > DMA > procainamide > cimetidine.
It is unclear whether it transports carnitine in vivo.
Sodium-ion dependent transporter of various organic cationic compounds. A key substrate of this transporter is ergothioneine (ET). Able to transport carnitine, probably moving one sodium ion with one molecule of carnitine (By similarity). Also transports tetraethylammonium (TEA) without the involvement of sodium.
Expressed in heart, lung, kidney and testis.
Inhibited by dephosphorylation by PTPN6.
Interacts with PTPN11; may activate the PI3 kinase-mTOR signaling pathway. Interacts with VAV3; constitutive interaction mediating VAV3 phosphorylation. Interacts with PTPN6 (via SH2 1 domain); the interaction is direct and promotes ROS1 dephosphorylation (By similarity).
Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2 (By similarity).
Phosphorylated. Probably autophosphorylates. Phosphorylation at Tyr-2266 is required for the interaction with PTPN6 that mediates ROS1 dephosphorylation. Phosphorylation at Tyr-2266 stimulates the kinase activity and the activation of the ERK1 signaling cascade. Phosphorylation at Tyr-2266 and/or Tyr-2325 recruits PTPN11 (By similarity).
Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation (PubMed:21802374). Binds phosphatidylinositol 3-phosphate (PtdIns3P). Activated by the STK11/AMPK signaling pathway upon starvation, WDR45 is involved in autophagosome assembly downstream of WIPI2, regulating the size of forming autophagosomes. Together with WIPI1, promotes ATG2 (ATG2A or ATG2B)-mediated lipid transfer by enhancing ATG2-association with phosphatidylinositol 3-monophosphate (PI3P)-containing membranes. Probably recruited to membranes through its PtdIns3P activity (By similarity).
Interacts with WIPI1. Interacts with WIPI2. Interacts with ATG2A and ATG2B. Interacts with ULK1. May interact with the PRKAA1, PRKAA2, PRKAB1 and PRKAG1 subunits of the AMPK kinase. May interact with NUDC.
Facilitates the differentiation and the cornification of keratinocytes.
Phosphorylation at Thr-5 significantly suppresses homodimerization and promotes association with NCL/nucleolin which induces nuclear translocation.
Catalyzes the NADPH-dependent reduction of a variety of substrates including aromatic and aliphatic aldehydes, quinones, ketones, dicarbonyl compounds and 17-ketosteroids (PubMed:17574202). Catalyzes the NADP(+)-dependent oxidation of aromatic, alicyclic and aliphatic alcohols, and 17beta-hydroxysteroids (PubMed:17574202). To a lesser extent, can also catalyze the reduction of some aldoses and ketoses and the oxidation of some sugar alcohols (PubMed:17574202). In the stomach, lung and colon tissues, mediates the reduction of farnesal and geranylgeranial into farnesol and geranylgeraniol respectively (PubMed:21187079). By reducing 4-hydroxy-2-nonenal (HNE), produced during lipid peroxidation, into 1,4-dihydro-2-nonene (DHN), protects vascular endothelial cells from damage elicited by oxidized lipoproteins (PubMed:21187080).
Expressed in lung, specifically in bronchiolar club cells, type II alveolar cells and epithelial cells of the duct of the bronchial gland (at protein level) (PubMed:17574202, PubMed:7511002, PubMed:21187079). Expressed in gastric parietal cells and in epithelial cells of the large intestine and colon (at protein level) (PubMed:17574202, PubMed:21187079). Expressed in brown adipocytes (at protein level) (PubMed:17574202). Expressed in vascular endothelial cells (at protein level) (PubMed:17574202).
The dehydrogenase activity is inhibited by 3',3'',5',5''-tetraiodophenolphthalein, phenolphthalein, genistein, quercetin, zearalenone and diethylstilbestrol.
Expressed in brain. High levels found in hippocampus, thalamic nuclei, neocortex, and molecular and granule cell layers of the cerebellum.
Oligomer. Interacts with KCNA1 within a complex containing KCNA1, KCNA4 and KCNAB1. Can bind to ADAM11 and ADAM23 (By similarity). Part of a complex containing ADAM22, DLG4/PSD95 and CACNG2 (stargazin).
Plays a role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway (By similarity). 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.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. GDP-mannose 4,6-dehydratase subfamily.
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.
Can hydrolyze NAD but cannot hydrolyze nucleotide di- and triphosphates (By similarity). May play a role in neuronal cell communication. Lacks nucleotide pyrophosphatase and lysopholipase D activity in vitro (PubMed:12927778).
Phosphorylation by PKA at Ser-209 is required for endoplasmic reticulum retention function.
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.
Upon ligand binding the receptor oligomerizes and interacts with components of the transport machinery such as ARFGAP1 and ARF1.
Brain, enriched in the striatum, nucleus accumbens, and periaqueductal gray.
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 (By similarity).
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).
Ca(2+) or Mg(2+). Has lower efficiency with Mg(2+).
Canalicular ectonucleoside NTPDase responsible for the main hepatic NTPDase activity. Ectonucleoside NTPDases catalyze the hydrolysis of gamma- and beta-phosphate residues of nucleotides, playing a central role in concentration of extracellular nucleotides. Has activity toward ATP, ADP, UTP and UDP, but not toward AMP (By similarity).
Present in liver, and at lower level in jejunum and kidney. Limited to the canalicular domain of hepatocytes (at protein level).
The transmembranous domains are involved in regulation of enzyme activity.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family.
Expression was restricted to the intermediate and anterior lobes of the pituitary.
May play a role as physiological regulators of gastrointestinal, cardiovascular bioactivities mediated by the CALCRL/RAMPs receptor complexes. Activates the cAMP-dependent pathway.
Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37.
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). Substance P is also cleaved and degraded by Angiotensin-converting enzyme (ACE) and neprilysin (MME).
Belongs to the cyclin-dependent kinase 5 activator family.
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 (By similarity). Interacts with EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4 (PubMed:17143272). Interacts with RASGRF2 (PubMed:15128856). The complex p35/CDK5 interacts with CLOCK (By similarity).
Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35 (By similarity).
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.
Ubiquitinated, leading to its degradation: degradation of p35 by proteasome results in down-regulation of CDK5 activity. During this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Ubiquitinated by the CRL2(FEM1B) complex, which recognizes the -Gly-Leu-Asp-Arg C-degron at the C-terminus, leading to its degradation.
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.
Expressed in the early gut and pancreatic epithelium, at 15 dpc day localized to cells that will eventually become exocrine. Expressed in choroid plexus, developing myocardium, pancreatic epithelium and dorsal root ganglia.
Highly expressed in testis followed by pancreas, kidney, heart and brain. Not expressed in skeletal muscle, liver, lung and spleen.
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-318 by PRKCQ. Autophosphorylation at Thr-240 positively regulates its activity.
The phosphorylated form forms a complex with WNK2 (By similarity). Interacts with RELT (By similarity). Interacts with SORL1 (via cytosolic C-terminus) (By similarity).
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.
Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Required for normal platelet aggregation and blood coagulation.
The transmembrane domain is composed of seven transmembrane helices; most of these are not strictly perpendicular to the plane of the membrane, but are tilted and/or kinked. Agonist binding promotes a conformation change in the extracellular loops that leads to an inward movement of the transmembrane helices. Antagonists can bind to an overlapping site, but block the inward movement of the transmembrane helices (By similarity).
Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (By similarity). Positively regulates MAPK signal transduction pathway (By similarity). Dephosphorylates GAB1, ARHGAP35 and EGFR (By similarity). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity (By similarity). Dephosphorylates CDC73 (By similarity). Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification (By similarity). Dephosphorylates tyrosine-phosphorylated NEDD9/CAS-L (By similarity).
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily.
Inhibited by orthovanadate, molybdate and spermidine.
Interacts with phosphorylated SIT1, LIME1, BCAR3 and MZPL1. Interacts with FCRL4, FCRL6, ANKHD1, SHB, INPP5D/SHIP1 and CD84 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2 (By similarity). Interacts with PTPNS1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with GAB2 (By similarity). Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. Interacts with PDGFRA (tyrosine phosphorylated). Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity (By similarity). Interacts with ROS1; this mediates PTPN11 phosphorylation. 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) (By similarity). Interacts with SIGLEC10 (By similarity). Interacts with CLEC12B (via ITIM motif); this interaction triggers dephosphorylation and activation of PTPN11. Interacts (via SH2 domains) with NEDD9/CAS-L; the interaction is enhanced when NEDD9/CAS-L is tyrosine phosphorylated (By similarity).
Phosphorylated on Tyr-542 and Tyr-580 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated upon activation of the receptor-type kinase PDGFRA. Phosphorylated by activated PDGFRB (By similarity).
The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme.
Cilium-specific protein required for the stability of the ciliary architecture. Plays a role in cytoplasmic preassembly of dynein arms (By similarity). Involved in regulation of microtubule-based cilia and actin-based brush border microvilli (By similarity).
Cilium-specific protein required for the stability of the ciliary architecture. Plays a role in cytoplasmic preassembly of dynein arms (By similarity). Involved in regulation of microtubule-based cilia and actin-based brush border microvilli.
Androgen-regulated, increases in concentration with zinc uptake.
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. Cleaved by CTSL in lysosome thus regulating the maturation and turnover of progranulin within the lysosome.
Inhibits epithelial cell proliferation and induces epithelial cells to secrete IL-8.
Progranulin is secreted as a homodimer. Interacts with SLPI; interaction protects progranulin from proteolysis. Interacts (via region corresponding to granulin-7 peptide) with CTSD; stabilizes CTSD and increases its proteolytic activity. 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. Interacts with PSAP; facilitates lysosomal delivery of progranulin from the extracellular space and the biosynthetic pathway. Forms a complex with PSAP and M6PR; PSAP bridges the binding between progranulin and M6PR. 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. 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. Interacts (via region corresponding to granulin-7 peptide) with HSPA1A; mediates recruitment of HSPA1A to GBA1 and prevents GBA1 aggregation in response to stress.
Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation (By similarity). Regulates protein trafficking to lysosomes and, also the activity of lysosomal enzymes (By similarity). Facilitates also the acidification of lysosomes, causing degradation of mature CTSD by CTSB (By similarity). 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 (By similarity). Moreover, modulates inflammation in neurons by preserving neurons survival, axonal outgrowth and neuronal integrity (By similarity).
Stabilizes CTSD through interaction with CTSD leading to maintain its aspartic-type peptidase activity.
Ubiquitous; most abundant in the spleen and several tissues of endocrine significance.
Homotetramer. Interacts with PTEN upstream reading frame protein MP31.
Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+).
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.
Belongs to the glycosyl hydrolase 84 family.
Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:8034696). Does not bind acetyl-CoA and does not have histone acetyltransferase activity.
Detected in spleen (at protein level). Ubiquitous. Expressed at highest levels in the brain and spleen.
Inhibited by Cu(2+), Hg(2+), Cd(2+) and Zn(2+) at 1 mM. Not inhibited by Co(2+), Mg(2+), Ca(2+), Mn(2+), Fe(3+) and EDTA. Also inhibited by sodium chloride at 1M and 2-amino-2-hydroxymethyl-1,3-propanediol (trishydroxymethylaminomethane) at 75 mM.
Monomer. Interacts with CLOCK (By similarity).
Proteolytically cleaved by caspase-3 during apoptosis. The fragments interact with each other; cleavage does not decrease enzyme activity.
Was initially identified as a bi-functional protein that has an N-terminal domain with O-GlcNAcase activity and a C-terminal domain that has histone acetyltransferase activity (PubMed:15485860). The protein has apparent histone acetyltransferase activity when expressed in mammalian cells, but not when expressed in bacterial cells (PubMed:15485860), suggesting that the histone acetyltransferase activity might be due to the presence of a contaminant. Characterization of the human ortholog shows that this protein does not bind acetyl-CoA and therefore cannot have acetyltransferase activity.
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.
Belongs to the STXBP/unc-18/SEC1 family.
Brain and spinal cord. Highly enriched in axons.
Faint levels are detectable at embryonic day 14, with levels rising at later embryonic ages and peaking at postnatal day 7.
Interacts with SYTL4 (PubMed:12058058). Interacts with STX1A (PubMed:10746715). Interacts with alpha-synuclein/SNCA; this interaction controls SNCA self-replicating aggregation (By similarity). Interacts with RAB3A; this interaction promotes RAB3A dissociation from the vesicle membrane (PubMed:21689256). Interacts with CABP5 (By similarity).
Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins (PubMed:21689256). 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.
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.
Homodimer; the filamin repeat 24 and the second hinge domain are important for dimer formation (By similarity). Interacts with FLNB, KCND2, INPPL1, ITGB1A, MYOT, MYOZ1 and MYOZ3 (By similarity). Interacts with sarcoglycans SGCD and SGCG (By similarity). Interacts (via filament repeats 17-18, 20-21 and 24) with USP25 (isoform USP25m only) (By similarity). Interacts with FBLIM1 (By similarity). Interacts with KY (By similarity). Interacts with IGFN1 (By similarity). Interacts with MICALL2 (By similarity). Interacts with XIRP1; this interaction is mediated by filamin 20 repeat (By similarity). Interacts with ANK3. Interacts with SYNPO2 (By similarity).
Muscle-specific filamin, which plays a central role in sarcomere assembly and organization. Critical for normal myogenesis, it probably functions as a large actin-cross-linking protein with structural functions at the Z lines in muscle cells. May be involved in reorganizing the actin cytoskeleton in response to signaling events.
Ubiquitinated by FBXL22, leading to proteasomal degradation.
Based on x-ray crystallography data, the protein would be constituted of 4 tandem ACT domains instead of the 2 predicted from the sequence.
Forms homodimers and heterodimers with CASTOR2 (By similarity). Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by arginine (By similarity). Interacts with TM4SF5; the interaction is positively regulated by leucine and is negatively regulated by arginine (By similarity).
Functions as an intracellular arginine sensor within the amino acid-sensing branch of the TORC1 signaling pathway. As a homodimer or a heterodimer with CASTOR2, binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1. Binding of arginine to CASTOR1 allosterically disrupts the interaction of CASTOR1-containing dimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway.
Phosphorylation at Ser-14 by AKT1, promoting the interaction between CASTOR1 and RNF167.
Ubiquitinated by RNF167 via 'Lys-29'-polyubiquitination, leading to its degradation, releasing the GATOR2 complex. Ubiquitination by RNF167 is promoted by phosphorylation at Ser-14 by AKT1.
Down-regulated upon infection with rat cytomegalovirus.
Receptor for KLRB1B that protects target cells against natural killer cell-mediated lysis.
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. Might also be a target for novel lipid activators that are elevated during nutrient-stimulated insulin secretion (By similarity).
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 (PI3K) 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. Downstream of PI3K is required for insulin-stimulated glucose transport. Activates RAB4A and promotes its association with KIF3A which is required for the insulin-induced SLC2A4/GLUT4 translocation in adipocytes. Is essential in early embryogenesis and development of differentiating photoreceptors by playing a role in the establishment of epithelial and neuronal polarity (By similarity). Involved in early synaptic long term potentiation phase in CA1 hippocampal cells and short term memory formation (PubMed:27498875).
Expressed in dorsal hippocampus (at protein level).
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. Interacts with WDFY2 (via WD repeats 1-3) (By similarity).
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 (By similarity). 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 (By similarity). Phosphorylated at Thr-564 during the initial phase of long term potentiation (PubMed:27498875).
RNAi-mediated knockdown in the dorsal hippocampus impairs the early phase of long-term potentiation and the formation of short term memory.
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.
Plays a key role in maintaining the cardiac electrical stability by modulating cell surface expression of SCN5A. May play a role i the modulation of anxiety behavior by regulating GABAergic neuronal system in the nucleus accumbens.
Belongs to the class-II fumarase/aspartase family. Fumarase subfamily.
Catalyzes the dehydration of L-malate to fumarate. 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). 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) (By similarity).
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 (By similarity). Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other (Probable).
Phosphorylation at Thr-233 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs).
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.
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-46, Ser-196 and Ser-214 by CaMK2 does not change kinetic parameters.
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 (By similarity). Enhances phosphorylation of translation initiation factors and active polysome formation.
Interacts with RPL4. Associates with the 60S ribosomal subunits.
Phosphorylated. Isoform 2 is methylated.
Widely expressed in the brain. Highly expressed in the cerebellum and olfactory bulb (at protein level). Expressed in neurons and glial cells.
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. Negatively regulates protein transport to the cilium and ciliogenesis through the inhibition of RAB8A.
Interacts with RHOH. 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. Interacts with RAB8A (GDP-bound inactive form); prevents RAB8A activation. Interacts with DZIP1; negatively regulates the interaction of GDI2 with GDP-bound RAB8A.
Belongs to the ATP:guanido phosphotransferase family.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A9 subfamily.
Found in the gray matter of CNS as well as in macrophages and mast cells in peripheral tissues.
Found only in the white matter of the CNS.
Interacts with EXOC1; interaction increases the transporter capacity of SLC6A9 probably by promoting its insertion into the cell membrane (PubMed:16181645). Interacts with EXOC3 and EXOC4 (PubMed:16181645).
Sodium- and chloride-dependent glycine transporter (PubMed:1534013, PubMed:16181645). Essential for regulating glycine concentrations at inhibitory glycinergic synapses (By similarity).
Belongs to the X(+)/potassium ATPases subunit beta family.
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.
Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN. Stabilizes and organizes elastic fibers in the skin, lung and vasculature. 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. May act as an adapter that mediates the interaction between FBN1 and ELN.
Homodimer. Monomer, homodimerizes in presence of Ca(2+). Interacts with ELN. Interacts (via N-terminus) with the integrins ITGAV/ITGB3, ITGAV/ITGB5 and ITGA9/ITGB1. Interacts with FBN1 (via N-terminal domain). Forms a ternary complex with ELN and FBN1. Interacts with EFEMP2 with moderate affinity (By similarity).
Belongs to the cyclin family. Cyclin AB subfamily.
Interacts with the CDK2 and the CDC2 protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Does not bind CDK4 and CDK5 (in vitro). The cyclin A1-CDK2 complex interacts with transcription factor E2F-1 and RB proteins. Found in a complex with CDK2, CABLES1 and CCNE1. Interacts with INCA1 and KLHDC9 (By similarity).
May be involved in the control of the cell cycle at the G1/S (start) and G2/M (mitosis) transitions. May primarily function in the control of the germline meiotic cell cycle and additionally in the control of mitotic cell cycle in some somatic cells (By similarity).
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 (By similarity).
Belongs to the peroxiredoxin family. Prx5 subfamily.
S-palmitoylated. Depalmitoylated by ABHD10.
S-palmitoylated. Palmitoylation occurs on the active site, inhibiting its reactivity; therefore PRDX5 palmitoylation status determines its antioxidant capacity.
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.
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 (By similarity).
It is uncertain whether Met-1 or Met-4 is the initiator.
Displays low metallophosphoesterase activity (in vitro) (PubMed:19004815, PubMed:21824479). May play a role in the development of the nervous system (Probable).
Expressed in fetal brain (at protein level). detected in fetal and adult brain.
Inhibited by nmolar levels of AMP and GMP.
This protein has a low affinity for cofactor and demonstrates very restricted substrate specificity. The enzyme may need additional interacting proteins to show full activity, or may be losing its activity and acquiring the role of a scaffolding protein.
Contains a putative mitochondrial transit peptide at positions 1-20.
In the N-terminal section; belongs to the thiolase-like superfamily. Thiolase family.
Interacts with PEX5; the interaction is essential for peroxisomal import.
Liver > intestine > brain > lung, colon, stomach, spleen, kidney, heart and ovary.
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 (By similarity). Stimulates the microsomal conversion of 7-dehydrocholesterol to cholesterol (PubMed:8063752). 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 (PubMed:9553048) (By similarity). Isoforms SCP2 and SCPx cooperate in peroxisomal oxidation of certain naturally occurring tetramethyl-branched fatty acyl-CoAs (PubMed:9553048).
Plays a crucial role in the peroxisomal oxidation of branched-chain fatty acids (PubMed:9325339, PubMed:8063752). 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:9325339, PubMed:8063752). Also active with medium and long straight chain 3-oxoacyl-CoAs (PubMed:9325339, PubMed:10706581). Stimulates the microsomal conversion of 7-dehydrocholesterol to cholesterol and transfers phosphatidylcholine and 7-dehydrocholesterol between membrances, in vitro (PubMed:8063752). Isoforms SCP2 and SCPx cooperate in peroxisomal oxidation of certain naturally occurring tetramethyl-branched fatty acyl-CoAs (PubMed:9553048).
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.
Interacts with IL8. Interacts with GNAI2.
Phosphorylated upon ligand binding; which is required for desensitization.
Receptor for interleukin-8 which is a powerful neutrophil chemotactic factor. 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. Binds to IL-8 with high affinity. Also binds with high affinity to CXCL3, GRO/MGSA and NAP-2.
Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM5 sub-subfamily.
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
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 (By similarity).
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.
Belongs to the AB hydrolase superfamily. Monoacylglycerol lipase family.
Converts monoacylglycerides to free fatty acids and glycerol (PubMed:12136125). Hydrolyzes the endocannabinoid 2-arachidonoylglycerol, and thereby contributes to the regulation of endocannabinoid signaling, nociperception and perception of pain (PubMed:12136125, PubMed:17649977). Regulates the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth (By similarity).
Requires non-ionic detergent for solubilization.
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.
Ubiquitous. Highly expressed in adipose tissue, adrenal gland, ovary, heart, spleen, lung, skeletal muscle, kidney and testis. Highly expressed throughout the brain.
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).
Expressed in brain. Within brain, expressed in hippocampus, cerebellum, olfactory bulb and forebrain (at protein level).
Lacks a cytoplasmic PDZ-binding domain, which has been implicated in function of related LRFN proteins.
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 commited step in the biosynthesis of AMP from IMP.
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 of purine nucleotide biosynthesis.
May play a role in the development and maintenance of the nervous system (By similarity). Exhibits a limited synaptogenic activity in vitro, restricted to excitatory presynaptic differentiation.
Detected in brain and adipose tissue, and at much lower levels in testis. Detected in liver when rats are kept on a fat-free diet, but not when their food contains unsaturated fatty acids.
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:20228221). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:20228221). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides, especially during embryonic development and in neonates. Important for normal permeability barrier function of the skin in neonates.
Up-regulated in liver in the absence of dietary unsaturated fatty acids(PubMed:1982442). Expression in adipose tissue seems to be constitutive (PubMed:1982442).
Component of the dolichol-phosphate mannose (DPM) synthase complex.
Stabilizer subunit of the dolichol-phosphate mannose (DPM) synthase complex; tethers catalytic subunit to the ER.
Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids (PubMed:28003429). Propionate is the preferred substrate but can also utilize acetate and butyrate with a much lower affinity (PubMed:28003429).
Expressed in a wide range of tissues, with the highest levels observed in the liver followed by kidney.
Binds synaptic Ca(2+) with its cytoplasmic domain.
Directly interacts with APBA2. Forms a tripartite complex with APBA2 and APP. Interacts with low affinity with KLC1 (By similarity).
May modulate calcium-mediated postsynaptic signals. 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.
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-beta 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 gamma-secretase (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers (PubMed:19465910). 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. Implicated in neuronal migration (By similarity).
Transfers N-acetylgalactosamine onto globotriaosylceramide. Plays a critical role in preimplantation stage embryonic development.
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.
Belongs to the class I fructose-bisphosphate aldolase family.
Catalyzes the hydrolysis of triacylglycerols to yield free fatty acids, diacylglycerol, monoacylglycerol, and glycerol (PubMed:3839077). Shows a preferential hydrolysis at the sn-3 position of triacylglycerol (By similarity).
Secreted by the serous (von Ebner's) glands at the back of the rat tongue.
Interacts with RAB11A, MYO5B and RAB11FIP2. Interaction with RAB11A, MYO5B and RAB11FIP2 is required for proper transport to the plasma membrane upon cholesterol depletion (By similarity). Interacts with NPC2 (By similarity). Interacts with LIMA1 (By similarity).
Plays a major role in cholesterol homeostasis (PubMed:17135346). Critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte (PubMed:17135346). Involved in plant sterol absorption, it transports sitosterol, although at lower rates than cholesterol (PubMed:17135346). 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 (By similarity). May be involved in caveolin trafficking from the plasma membrane (By similarity). Acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation (By similarity).
Small intestine showed the highest level of expression (PubMed:14976318). Expression in other tissues including gall bladder, liver, testis and stomach is also observed (PubMed:14976318). Along the duodenum-ileum axis, the levels vary in different segments of the intestine with peak expression in the proximal jejunum (PubMed:14976318). Protein expression is confined to the enterocyte (PubMed:14976318). Discrete localization to the epithelial layer bordering the luminal space along the crypt-villus axis (PubMed:14976318). Protein expression in the enterocyte is observed closest to the luminal space. Expression in enterocytes from the proximal (jejunum) but not in the distal (ileum) region (PubMed:14976318).
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).
At 12 dpc, detected in the developing brain, eye, lateral lip of the dermomyotome, somites and branchial arch.
Detected in brain (at protein level) (PubMed:22405201). Detected in brain neurons, especially in basal ganglia, hippocampus dentate gyrus and CA3 region, cerebellum and in olfactory bulb (PubMed:14706654, PubMed:15485775).
Functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners. Plays a role in the spatial organization of brain neurons. Plays a role in vascular development in the retina (By similarity). Plays a role in cell-cell adhesion via its interaction with ADGRL3 and probably also other latrophilins that are expressed at the surface of adjacent cells (By similarity). Interaction with the intracellular domain of ROBO1 mediates axon attraction towards cells expressing NTN1. Mediates axon growth cone collapse and plays a repulsive role in neuron guidance via its interaction with UNC5B, and possibly also other UNC-5 family members (By similarity). Promotes neurite outgrowth (in vitro) (By similarity). Mediates cell-cell contacts that promote an increase both in neurite number and in neurite length (PubMed:15485775). Plays a role in the regulation of the density of glutamaergic synapses (PubMed:22405201). Plays a role in fibroblast growth factor-mediated signaling cascades. Required for normal morphogenesis during embryonic development, but not for normal embryonic patterning. Required for normal ventral closure, headfold fusion and definitive endoderm migration during embryonic development. Required for the formation of a normal basement membrane and the maintenance of a normal anterior visceral endoderm during embryonic development (By similarity).
Monomer and homodimer. Self-associates (via leucine-rich repeats), giving rise to homooligomers. Interacts with FGFR1 (By similarity). Interacts (via extracellular domain) with ADGRL1/LPHN1 and ADGRL3 (via olfactomedin-like domain) (PubMed:22405201). Interacts (via extracellular domain) with LPHN2 (via olfactomedin-like domain). Interacts (via extracellular domain) with UNC5B (via Ig domain). May also interact (via extracellular domain) with UNC5A and UNC5C. Interacts (via extracellular domain) with UNC5D (via extracellular domain). Identified in complexes composed of FLRT3, ADGRL3 and UNC5B, respectively FLRT3, ADGRL3 and UNC5D (By similarity). Interacts (via cytoplasmic domain) with ROBO1 (By similarity).
Proteolytic cleavage in the juxtamembrane region gives rise to a soluble ectodomain. Cleavage is probably effected by a metalloprotease.
Up-regulated in neurons in dorsal root ganglia in response to peripheral nerve injury (at protein level) (PubMed:15485775). Up-regulated in neurons in dorsal root ganglia in response to peripheral nerve injury (PubMed:15485775).
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. Forms a multimeric complex together with LRPAP1 (PubMed:1400426). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats) (PubMed:22649097). Interacts with LRP2BP. Interacts (via NPXY motif) with DAB2; the interaction is not affected by tyrosine phosphorylation of the NPXY motif (By similarity). Interacts with MB (PubMed:12724130). 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 (PubMed:17324488). Interacts with ALB (PubMed:18466341). Interacts with the antiapoptotic protein BIRC5/survivin (By similarity). Interacts with matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). 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 (PubMed:23836931). 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).
In the brain, expression is high after birth and gradually decreases from postnatal day 4 until the end of the first postnatal week.
In the inner ear, expressed in the lumen of the endolymphatic sac where it localizes to macrophage-like cells as well as to mitochondria-rich and ribosome-rich epithelial cells (at protein level) (PubMed:17063000). In the inner ear, expressed in marginal cells of the stria vascularis, epithelial cells at the spiral prominence, epithelial cells of Reissner's membrane facing the cochlear duct, and Kolliker's organ (at protein level) (PubMed:19202329). Expressed in the choroid plexus epithelium in the brain (at protein level) (PubMed:17324488). In the brain, also expressed in astrocytes (at protein level) (PubMed:18466341). Expression also detected in epithelial cells of the kidney glomerulus and proximal tubule, lung, epididymis and yolk sac (PubMed:7510321).
Multiligand endocytic receptor. 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 (PubMed:7544804, PubMed:19202329). 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 (PubMed:17324488). 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 (PubMed:17462596). 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 (PubMed:12724130). Mediates renal uptake and subsequent lysosomal degradation of APOM (PubMed:16099815). 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 (By similarity). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (PubMed:11964399, PubMed:16801528). Also mediates ShhN transcytosis (PubMed:16801528). 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 (PubMed:18466341). 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 (PubMed:16143106). Mediates endocytosis of angiotensin-2 (PubMed:15467006). Also mediates endocytosis of angiotensin 1-7 (PubMed:16380466). 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 (PubMed:17846082).
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.
Cross-linked by interchain disulfide bonds around the DNA-helix.
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.
Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM (By similarity). 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.
Belongs to the V-ATPase E 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:32165585). 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:32165585).
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex (PubMed:32165585). 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:32165585). 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:32165585). Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity). Interacts with ALDOC (By similarity). Interacts with RAB11B (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 (By similarity).
Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry. Interacts with NSFL1C-like protein p37; the complex has membrane fusion activity and is required for Golgi and endoplasmic reticulum biogenesis. Interacts with RHBDD1 (via C-terminal domain). 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. 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 SPRTN; leading to recruitment to stalled replication forks. 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. 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 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 (By similarity). Interacts (via the PIM motif) with RNF31 (via the PUB domain) (By similarity). 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 (By similarity). Interacts with BAG6 (By similarity). Interacts with UBXN10 (By similarity). Interacts with UBXN6; the interaction with UBXN6 is direct and competitive with UFD1 (By similarity). Forms a ternary complex with CAV1 and UBXN6. Interacts with PLAA, UBXN6 and YOD1; may form a complex involved in macroautophagy (By similarity). Interacts with ANKZF1 (By similarity). Interacts with ubiquitin-binding protein FAF1 (By similarity). Interacts with ZFAND2B (via VIM motif); the interaction is direct (By similarity). Interacts with ZFAND1 (via its ubiquitin-like region); this interaction occurs in an arsenite-dependent manner (By similarity). Interacts with CCDC47 (By similarity). Interacts with LMBR1L and UBAC2 (By similarity). Interacts with ATXN3 (By similarity). Interacts with TEX264; bridging VCP to covalent DNA-protein cross-links (DPCs) (By similarity).
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) (PubMed:10930451, PubMed:12411482). Vesicle budding from the tER is an ATP-dependent process (PubMed:10930451, PubMed:12411482). 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 (PubMed:10930451, PubMed:12411482). 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. Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response (By similarity). 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. 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. Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis. Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex. Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal (By similarity). Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation. Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy. 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 (By similarity). May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation (By similarity). May more particularly play a role in caveolins sorting in cells (By similarity). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (By similarity).
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.
Expressed in the regions of the hypothalamus involved in reproductive control, such as medial preoptic area, arcuate nucleus and ventromedial nucleus.
Probable E3 ubiquitin protein ligase involved in the proteasome-mediated ubiquitin-dependent degradation of target proteins. Through the degradation of CTNNB1, functions downstream of FOXF2 to negatively regulate the Wnt signaling pathway. Probably plays a role in the development of the central nervous system and in neuronal maintenance (By similarity). Also acts as a transcriptional regulator of genes controlling female reproductive function. May play a role in gene transcription by transactivating GNRH1 promoter and repressing PENK promoter.
Up-regulated during puberty in the hypothalamus, but not in the cerebral cortex.
Catalyzes the degradation of hydrogen peroxide (H(2)O(2)) generated by peroxisomal oxidases to water and oxygen, thereby protecting cells from the toxic effects of hydrogen peroxide. Promotes growth of cells including T-cells, B-cells, myeloid leukemia cells, melanoma cells, mastocytoma cells and normal and transformed fibroblast cells.
Homotetramer. Interacts (via microbody targeting signal) with PEX5, monomeric form interacts with PEX5, leading to its translocation into peroxisomes.
Belongs to the G-protein coupled receptor 1 family. Bradykinin receptor subfamily. BDKRB1 sub-subfamily.
By lipopolysaccharide (LPS), four hours after treatment levels show an increase in many tissues. After 12 hours maximum levels are observed in the heart.
Expressed in bladder, lung, duodenum, kidney, uterus, thymus, salivary gland, testis, prostate, macrophages, aorta, spleen and heart.
This is a receptor for bradykinin. Could be a factor in chronic pain and inflammation.
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. In concert with CIC and ATXN1L, involved brain development.
Homooligomer. Interacts with CIC. Interacts with ANP32A, PQBP1, UBQLN4, ATXN1L and USP7. Directly interacts with RBPJ; this interaction is disrupted in the presence of Notch intracellular domain. Competes with ATXN1L for RBPJ-binding. Found in a complex with CIC and ATXN1L.
Phosphorylation at Ser-749 increases the pathogenicity of proteins with an expanded polyglutamine tract.
Sumoylation is dependent on nuclear localization and phosphorylation at Ser-749. It is reduced in the presence of an expanded polyglutamine tract.
The AXH domain is required for interaction with CIC.
The rat poly-Gln region is very limited in comparison to human ATXN1 and is not polymorphic.
Ubiquitinated by UBE3A, leading to its degradation by the proteasome.
Binds to WNT proteins and inhibits their activities. May be involved in mesoderm segmentation.
Induced during the differentiation of CG-4 cells.
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 (By similarity).
Neurotrophic factor that regulates central nervous development and function. May play an important role in dopaminergic neurons in the substantia nigra.
Preferentially expressed in brain; substantia nigra pars compacta.
Binds to linker H1 histones but not to core histones (By similarity). Interacts with histones H2A, H2B, H3 and H4 (By similarity). Interacts with histone H3.3 (By similarity). Also binds to HSP90 in the cytoplasm. This interaction stimulates binding of NASP to H1-6/H1T (By similarity).
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.
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.
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.
Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine (PubMed:9165094). May also function as a transporter of branched chain alpha-keto acids (PubMed:8428987).
Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit (By similarity). 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. The elongin BC complex is part of a complex with VHL and hydroxylated HIF1A. Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC. Interacts with VHL. Interacts with TMF1. Interacts with SPSB1. Interacts with SPSB1. Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component. Interacts with NOS2 in the presence of SPSB1 or SPSB2 or SPSB4 (By similarity).
Ubiquitinated by the DCX(AMBRA1) complex, leading to its degradation by the proteasome.
Belongs to the complex I NDUFB8 subunit family.
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.
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.
Expressed by neurons, oligodendrocytes and their progenitors (at protein level). Myelination regulates the expression being down-regulated when neurons are in contact with Schwann cells.
Monomer (By similarity). Interacts with NOTCH1 (By similarity). Interacts with CNTNAP1 in cis form and TNR (PubMed:9118959, PubMed:9081628). Binds to the carbonic-anhydrase like domain of PTPRZ1 (PubMed:7628014). Detected in a complex with NRCAM and PTPRB (By similarity). Interacts with TASOR (By similarity).
Acts as a ligand for PILRA in neuronal tissues, where it may be involved in immune regulation.
O-glycosylation at Thr-136 is essential for recognition by PILRA.
Arginine hydroxylase involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages. Acts by mediating hydroxylation of 'Arg-111' of NDUFS7. May also have methyltransferase activity.
Interacts with NDUFAF8, leading to stabilize NDUFAF5. Interacts with NDUFS7.
Belongs to the vacuolar ATPase subunit S1 family.
Belongs to the shaker potassium channel beta subunit family.
Cytoplasmic potassium channel subunit that modulates the characteristics of the channel-forming alpha-subunits (PubMed:9763623, PubMed:21357749). 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 (PubMed:10896669, PubMed:16770729, PubMed:18003609, PubMed:21357749). Promotes potassium channel closure via a mechanism that does not involve physical obstruction of the channel pore (PubMed:21357749). Modulates the functional properties of KCNA4 (PubMed:9763623). Modulates the functional properties of KCNA5 (By similarity). Enhances KCNB2 channel activity (By similarity). Binds NADPH and has NADPH-dependent aldoketoreductase activity (PubMed:18672894, PubMed:21209188). 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) (PubMed:18672894).
Detected in brain (PubMed:9334400, PubMed:21357749). Detected in the middle third of the molecular layer of the dentate gyrus in hippocampus (PubMed:9334400). Detected in neurons in the deep cerebellar nucleus (PubMed:23318870). Detected in globus pallidus and pars reticulata of the substantia nigra (PubMed:9334400). Detected in cerebellum (PubMed:23318870). Detected at axon terminal plexuses of cerebellar granule cells (PubMed:9334400). Detected in the juxtaparanodal region of nodes of Ranvier in cerebellum (at protein level) (PubMed:9334400). Detected in mesenteric arteries (PubMed:15618540).
Homotetramer (PubMed:10884227, PubMed:16002581, PubMed:18004376, PubMed:18806782, PubMed:20534430, PubMed:20360102, PubMed:23705070). Interaction with tetrameric potassium channel alpha subunits gives rise to a heterooctamer (PubMed:10884227, PubMed:16002581, PubMed:18004376, PubMed:18806782, PubMed:20534430, PubMed:20360102, PubMed:23705070). Identified in potassium channel complexes containing KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNAB1 and KCNAB2 (PubMed:9334400). Interacts with KCNA1 (PubMed:23318870, PubMed:10884227). Interacts with KCNA2 (PubMed:18003609, PubMed:21357749, PubMed:23318870, PubMed:16002581, PubMed:18004376, PubMed:18806782, PubMed:20534430, PubMed:20360102, PubMed:23705070). Interacts with KCNA4 and KCND3 (PubMed:12860406). Interacts with KCNA5 (By similarity). Interacts with KCNB2 (By similarity). Interacts (in unphosphorylated form) with MAPRE1 (PubMed:21357749). Forms a ternary complex with SQSTM1 and PRKCZ (PubMed:10477520).
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.
Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes.
Homodimer; disulfide-linked. Forms phosphorylated oligomer aggregates on Wnt-signaling.
Autophosphorylated on serine and threonine residues; this autophosphorylation represses activity. Reactivated by phosphatase-mediated dephosphorylation. May be dephosphorylated by PP1.
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 (By similarity). Exhibits substrate-dependent heparin activation.
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 (By similarity).
Expressed in most tissues, including heart, brain, testis, kidney, spleen and lung.
Monomer (By similarity). 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 (By similarity). Interacts directly with PER1 and PER2 which may lead to their degradation (By similarity). Interacts with MAPT/TAU, SNAPIN, DBNDD2, AIB1/NCOA3 and ESR1 (By similarity). Interacts with AKAP9/AKAP450; this interaction promotes centrosomal subcellular location (By similarity). Binds to tubulins in mitotic cells upon DNA damage (By similarity). Interacts with GJA1 (By similarity). Interacts with MAP1A (PubMed:15961172). Interacts with DDX3X; this interaction enhances CSNK1D kinase activity in vitro, but it is unclear whether this interaction is physiologically relevant (By similarity).
The autoinhibitory domain is involved in regulating enzyme activity through autophosphorylation and possibly, through heparin binding.
Belongs to the universal ribosomal protein uS8 family.
Structural component of the ribosome. Required for proper erythropoiesis.
By activation of lymphocytes by mitogens. By estrogen in the uterine epithelium of ovariectomized animals.
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 (By similarity). 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 (By similarity).
Expressed in the skeletal muscle, liver, small intestine, kidney, testis, brain, heart and spleen (PubMed:8425897). Also present in various immature cells and endothelia (PubMed:2009910).
Homooligomer (By similarity). Interacts with NXNL1, SLC2A1 and SLC16A1/GLUT1 (By similarity). Interacts with XKR8; promoting its localization at the cell membrane (By similarity).
Homooligomer (Probable). Interacts with SLC16A1; interaction mediates SLC16A1 targeting to the plasma membrane (PubMed:10921872). Interacts with SLC16A3; interaction mediates SLC16A3 targeting to the plasma membrane (PubMed:11719518). Interacts with VEGFA, KDR/VEGFR2, PPIA/CYPA, SLC16A12, SLC16A11, ATP1B2, MAG, L1CAM and AJAP1 (By similarity). Interacts with PPIL2; regulates BSG transport to the cell membrane (By similarity).
In uterus during peri-implantation period strongly expressed in the luminal epithelium on day 1 of pregnancy and gradually decreased to a basal concentration from day 3 to day 5 of pregnancy. Strongly expressed in the implanting blastocyst and primary decidua on day 6 of pregnancy.
Signaling receptor for cyclophilins, essential for PPIA/CYPA and PPIB/CYPB-dependent signaling related to chemotaxis and adhesion of immune cells (By similarity). Plays an important role in targeting the monocarboxylate transporters SLC16A1/GLUT1 and SLC16A3 to the plasma membrane (PubMed:10921872). Acts as a coreceptor for vascular endothelial growth factor receptor 2 (KDR/VEGFR2) in endothelial cells enhancing its VEGFA-mediated activation and downstream signaling (By similarity). Promotes angiogenesis through EPAS1/HIF2A-mediated up-regulation of VEGFA and KDR/VEGFR2 in endothelial cells (By similarity). Plays an important role in spermatogenesis; mediates interactions between germ cells and Sertoli cell and is essential for the development/differentiation of germ cells to round spermatids (By similarity).
Belongs to the major facilitator superfamily. Proton-dependent oligopeptide transporter (POT/PTR) (TC 2.A.17) family.
Interacts (via extracellular domain region) with trypsin.
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. In addition to the major A:B and C:C dimer bands, rat, unlike human C1q, contained minor dimer species.
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.
Highest levels in spleen, lung and brain. Weaker expression in kidney and liver. In the spleen, localized mainly to the red pulp, in cells mainly of monocyte-macrophage lineage. In white pulp, localized in specific dendritic cells such as those from the periarteriolar lymphatic sheath (PALS).
Hydroxylated on lysine and proline residues. Hydroxylated lysine residues can be glycosylated.
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 (By similarity).
Homooligomer and heterooligomer with TMEM120B.
Ion channel involved in sensing mechanical pain. Contributes to mechanosensitive currents in nocireceptors and detecting mechanical pain stimuli. May also be required for efficient adipogenesis.
Interacts with CECR2, HEBP2, MAP1S, UXT, PPARGC1A and FOXO1. 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).
Widely expressed. Expressed in liver, brain and a subset of small diameter sensory neurons in the dorsal root ganglion (at protein level).
Binds tightly to hydroxyapatite. Appears to form an integral part of the mineralized matrix. Probably important to cell-matrix interaction. Promotes Arg-Gly-Asp-dependent cell attachment.
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.
Oligomeric complex of 6 set of homotrimers.
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.
Belongs to the actin family. ARP5 subfamily.
Expressed a low levels in pancreas at birth, expression increases through the suckling-weanling period to reach adult levels by the time of weaning.
Expressed by the pancreas (PubMed:8203536). Pancreatic secretory (zymogen) granule.
Forms a 1:1 stoichiometric complex with (pro)colipase/CLPS.
Inhibited by bile salts, is reactivated by (pro)colipase/CLPS.
Plays an important role in fat metabolism. It preferentially splits the esters of long-chain fatty acids at positions 1 and 3, producing mainly 2-monoacylglycerol and free fatty acids, and shows considerably higher activity against insoluble emulsified substrates than against soluble ones.
Highly active in the 7-alpha-hydroxylation of testosterone, progesterone and androstenedione.
Major acute phase reactant. Apolipoprotein of the HDL complex.
Contains three transmembrane domains, including a tandem transmembrane domain insertion into its glycosyltransferase-A fold. Transmembrane domain 1 functions as a signal for Golgi targeting.
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. Required for the initial step of GPI-GalNAc biosynthesis, transfers GalNAc to GPI in the Golgi after fatty acid remodeling by PGAP2.
The conserved DXD motif is involved in enzyme activity.
Lipid transfer protein that promotes intermembrane transfer of phosphatidylcholines but no other phospholipids. Binds a single lipid molecule. May play a role in hepatocellular selection and transport of phosphatidylcholines during bile formation.
Expressed in both head and flagellum of epididymal sperm.
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-33 with sheath components.
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.
Enzymatic activity is induced by 25-hydroxycholesterol, cholestyramine and lovastatin.
Expression in liver is reduced by 70% in 2 years old rats compare to 3 weeks old.
May be required for cellular fusion during osteoclastogenesis.
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.
May negatively affect PAX8-induced thyroglobulin/TG transcription.
Cytokine that plays important roles in allergic inflammation and immune response to parasite infection (PubMed:9366558). Synergizes with IL2 in regulating interferon-gamma synthesis. Stimulates B-cell proliferation, and activation of eosinophils, basophils, and mast cells (By similarity). 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 (PubMed:9366558). 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. 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. Aside from IL13RA1, another receptor IL13RA2 acts as a high affinity decoy for IL13 and mediates internalization and depletion of extracellular IL13 (By similarity).
The C-terminus is necessary for localization to the cell membrane.
Widely expressed, with much higher levels in fetal tissues than in adult ones. Highly expressed in newborn brain.
Acts as a GTPase-activating protein (GAP) for ARL2 with low specific activity.
At P02, in the organ of Corti, expressed in the stereocilia of outer hair cells and in the kinocilia of both outer and inner hair cells. Also concentrated at the cuticular plate level of auditory hair cells. However, before P07, expression in the inner hair cell stereocilia is very weak. By P07, in auditory hair cells, patchy expression detected along the length of stereocilia, but absent from the very tip. Later in development, detected in the stereocilia bundles and microvilli of sensory cells and also in the supporting cell bodies (at protein level).
Expressed in the cochlea and in the organ of Corti, as well as in the supporting cells, including pillar and Dieters' cells (at protein level).
Belongs to the phosphatidylethanolamine-binding protein family.
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 (By similarity).
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.
Has a tendency to form dimers by disulfide cross-linking. 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 (By similarity).
Major component of epididymal secretions and sperm plasma membranes. It is present in cytosols from a variety of other tissues. Highly expressed in brain.
Seems to be associated with memory and learning disorder.
Belongs to the WD repeat BOP1/ERB1 family.
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12. 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. The PeBoW complex associates with DDX27, BOP1 interacts directly with DDX27.
Component of the PeBoW complex, which is required for maturation of 28S and 5.8S ribosomal RNAs and formation of the 60S ribosome.
Belongs to the DNA polymerase type-Y family.
Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.
Belongs to the glycosyl hydrolase 59 family.
5'->3' DNA exonuclease which digests single-stranded DNA (ssDNA) (By similarity). Regulates inflammatory cytokine responses via the degradation of nucleic acids, by reducing the concentration of ssDNA able to stimulate TLR9, a nucleotide-sensing receptor in collaboration with PLD4 (By similarity). May be important in myotube formation. Plays a role in lysosomal homeostasis. Involved in the regulation of endosomal protein sorting (By similarity).
It was initially thought that PDL3 has phospholipase D activity due to its HKD motifs. The second HKD motif contains Glu instead of the canonical Asp. Its enzyme activity is therefore unsure. Catalytic phospholipase D activity is still controversial (By similarity). Its closest homolog PLD4, exhibits no phospholipase activity (By similarity).
Proteolytically processed to a soluble form that is stable within endosomes and lysosomes. During transport through the secretory pathway becomes proteolysed by cysteine proteases, thereby releasing a stable soluble lysosomal lumenal polypeptide, whereas the transmembrane-bound fragment is rapidly degraded. Its transport route to lysosomes involves ubiquitination and the ESCRT complex.
Ubiquitinated. Ubiquitination mediates sorting into lysosomes.
May function as inhibitor of dietary triglyceride digestion. Lacks detectable lipase activity (in vitro) (By similarity).
Was originally thought to be the pancreatic lipase.
Acts specifically as a negative regulator of skeletal muscle growth.
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.
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 (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 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 (By similarity).
Down-regulated in kidney but not in stomach following feeding with 2-amino-4,5-diphenylthiazole.
Bradykinin is inactivated by ACE, which removes the dipeptide Arg-Phe from its C-terminus.
Bradykinin is released from kininogen by plasma kallikrein.
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.
Phosphorylated by FAM20C in the extracellular medium.
Rats express four types of kininogens: the classical HMW/LMW kininogens and two additional LMW-like kininogens: T-I and T-II.
The active peptide bradykinin is a potent vasodilatator that is released from HMW-kininogen shows a variety of physiological effects: (A) influence in smooth muscle contraction, (B) induction of hypotension, (C) natriuresis and diuresis, (D) decrease in blood glucose level, (E) it is a mediator of inflammation and causes (E1) increase in vascular permeability, (E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action).
Interacts with 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 (By similarity).
May be a allosteric regulator of serine/threonine-protein phosphatase 2A (PP2A). 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 (By similarity).
Acts as a chaperone for the angiogenic VEGF receptor KDR/VEGFR2, increasing its abundance by inhibiting its ubiquitination and degradation (By similarity). Inhibits the folding activity of the chaperonin-containing T-complex (CCT) which leads to inhibition of cytoskeletal actin folding (By similarity). Acts as a chaperone during heat shock alongside HSP90 and HSP40/70 chaperone complexes (PubMed:27496612). Modulates the activation of caspases during apoptosis (By similarity).
Interacts (via thioredoxin fold region) with KDR/VEGFR2 (via juxtamembrane domain) (By similarity). Forms ternary complexes with the chaperonin CCT complex and actin substrate, leading to inhibition of actin folding (By similarity). Interacts with XIAP (via BIR 3 and RING domain) (By similarity). Interacts with HSP90AA1 and HSP90AB1 (PubMed:27496612).
N-terminal methionine acetylation destabilizes the protein.
Expressed in the brain, specifically in neurons of the cerebellum, cortex, hippocampus, olfactory bulb, brainstem and spinal cord (at protein level).
Homodimer (By similarity). Can also form heterodimers (By similarity). Interacts with SYT1 (PubMed:17190793).
Phosphorylation of Ser-97 is required for mossy-fiber long-term potentiation.
Synaptic vesicle phosphoprotein that enhances spontaneous neurotransmitter release but does not effect induced neurotransmitter release (PubMed:17190793). Unlike other synaptotagmins, it does not bind Ca(2+) or phospholipids (PubMed:17190793). Essential for mossy-fiber long-term potentiation in the hippocampus (By similarity).
Unlike classical synaptotagmins, lacks Ca(2+)-binding sequences and does not bind phospholipids.
Associates with spermatozoa in the epididymal fluid but does not bind tightly to them. Binds both all-trans and 9-cis retinoic acid. May act as a retinoid carrier protein which is required for epididymal function and/or sperm maturation.
Synthesized exclusively in the proximal part (caput epididymidis) of the epididymis. It makes up a substantial part of the total protein in the epididymal luminal fluid and binds to the sperm membrane.
The N-terminus of form C is probably blocked.
There are two similar, immunologically cross-reacting forms of this protein, designated B and C, which probably result from different processing of the amino end.
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.
Enzyme activity is increased by phosphate, due to increased kcat and increased substrate affinity.
Homotetramer, dimer of dimers. Tetramer composed of 68 and 65 kDa peptides in a 1:3 ratio. Can assemble into higher oligomers (in vitro), but the physiological significance of this is not clear (PubMed:23935106). Interacts with RAF1 and MAP2K2 (By similarity). Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity.
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.
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). Interacts with activated CSPG4 and with BAIAP2. Interacts with DOCK11/Zizimin2; the interaction activates CDC42 by exchanging GDP for GTP. Interacts with DOCK9; the interaction activates CDC42 by exchanging GDP for GTP. Interacts with DOCK8 (via DHR-2 domain); the interaction activates CDC42 by exchanging GDP for GTP. Interacts with IQGAP1. Interacts with NET1 and ARHGAP33/TCGAP. Part of a complex with PARD3, PARD6A or PARD6B and PRKCI or PRKCZ. The GTP-bound form interacts with CCPG1. Interacts with USP6. Interacts with NEK6. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with ITGB1BP1. Interacts with ARHGDIA; this interaction inactivates and stabilizes CDC42. Interacts with ARHGDIB; this maintains CDC42 in the inactive, GDP-bound form. Interacts in (GTP-bound form) with FNBP1L and ABI1, but only in the presence of FNBP1L.
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 (PubMed:25498153). Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase (By similarity). Regulates cell migration (By similarity). In neurons, plays a role in the extension and maintenance of the formation of filopodia, thin and actin-rich surface projections (By similarity). Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. Facilitates filopodia formation upon DOCK11-activation (By similarity). Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (PubMed:21423166, PubMed:25498153). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups (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 (Probable). Inhibited by GAPs such as ARHGAP44 (PubMed:25498153).
Belongs to the ribonucleoside diphosphate reductase large chain family.
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
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. Forms a complex with KMT2A and CREBBP (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 of Ser-119 allows CREBBP binding. Stimulated by phosphorylation. Phosphorylation of both Ser-128 and Ser-119 in the SCN regulates the activity of CREB and participate in circadian rhythm generation (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. 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 (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). Phosphorylated by TSSK4 on Ser-119 (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 (By similarity).
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 (By similarity).
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination (By similarity).
Expressed in the brain, including in the hippocampus (at protein level).
Identified in the spliceosome C complex (By similarity). Component of the mRNA splicing-dependent exon junction complex (EJC), which contains at least CASC3, EIF4A3, MAGOH, NXF1 and RBM8A/Y14. Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro) (By similarity). Forms homooligomers (PubMed:12843282). Interacts with STAU in an RNA-dependent manner (PubMed:12843282). Interacts with DHX34; the interaction is RNA-independent (By similarity).
Required for pre-mRNA splicing as component of the spliceosome (By similarity). 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 (By similarity). Component of the dendritic ribonucleoprotein particles (RNPs) in hippocampal neurons. May play a role in mRNA transport.
The coiled coil domain may be involved in oligomerization.
Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation.
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. Is not be required for the stability of the complex. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. 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. Required for recruitment of telomeres to PML nuclear bodies. Required for sister chromatid cohesion during prometaphase and mitotic progression.
Sumoylated, possibly via autosumoylation.
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. Selectively expressed in the spermatids of seminiferous tubules and in flagella of epididymal sperm.
Was originally thought to be a selenoprotein and was known as sperm mitochondrial capsule selenoprotein.
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. 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. 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. Acts as a regulator of ribosome biogenesis following stress.
Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and ACVR1B/ALK4.
Monomer (By similarity). Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP. 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 (By similarity). Interacts with GEMIN5; the interaction is direct (By similarity). Interacts (via C-terminus) with SMN1; the interaction is direct (By similarity). Interacts with GEMIN5; the interaction is direct (By similarity). Interacts with SNRPD1; the interaction is direct (By similarity). Interacts with SNRPD2; the interaction is direct (By similarity). Interacts (via N-terminus) with SNRPF; the interaction is direct (By similarity). Interacts (via N-terminus) with SNRPE; the interaction is direct (By similarity). Interacts (via N-terminus) with SNRPG; the interaction is direct (By similarity).
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 (By similarity). 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) (By similarity). 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 (By similarity). To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A (By similarity). 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 (By similarity). 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 (By similarity).
Autophosphorylated (By similarity). Phosphorylated by ATM in response to DNA damage. Phosphorylated by LRRK2 (By similarity).
Proteolytically processed by caspase-3 (CASP3).
Self-associates. Interacts with MAP2K3. Interacts with SPRED1 (PubMed:18216281). Interacts with TESK1; the interaction inhibits TAOK1 kinase activity (PubMed:18216281). Interacts with MAP3K7 (By similarity).
Serine/threonine-protein kinase activity is inhibited by SPRED1.
Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability. Phosphorylates MAP2K3, MAP2K6 and MARK2. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade by mediating phosphorylation and subsequent activation of the upstream MAP2K3 and MAP2K6 kinases. Involved in G-protein coupled receptor signaling to p38/MAPK14. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of MAP2K3 and MAP2K6. Acts as a regulator of cytoskeleton stability by phosphorylating 'Thr-208' of MARK2, leading to activate MARK2 kinase activity and subsequent phosphorylation and detachment of MAPT/TAU from microtubules. Also acts as a regulator of apoptosis: regulates apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation via activation of the MAPK8/JNK cascade. During fetal development, it plays an essential role in the regulation of neuronal differentiation and migration to the cortical plate (By similarity).
Component of nuclear RNase P and RNase MRP ribonucleoproteins. RNase P consists of a catalytic RNA moiety and about 10 protein subunits; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40. 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. 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.
Transcription factor required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs.
Expressed at much higher levels in the adipocytes of lean Zucker rats than in obese Zucker rats. Expression is higher is the adipocytes of male Zucker rats than in female Zucker rats.
Repressed by 3,3',4,4',5-pentachlorobiphenyl (PenCB) and 3-methylchlantherene (3MC).
S-glutathionylated in hepatocytes under oxidative stress.
S-thiolated both by thiol-disulfide exchange with glutathione disulfide and by oxyradical-initiated S-thiolation with reduced glutathione.
Belongs to the CDP-alcohol phosphatidyltransferase class-II family.
Functions in the biosynthesis of the anionic phospholipids phosphatidylglycerol and cardiolipin.
Carboxypeptidase that catalyzes the release of a C-terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro (By similarity). Catalyzes the conversion of leukotriene C4 to leukotriene F4 via the hydrolysis of an amide bond (By similarity).
Monomer. May form a complex with proelastase 2.
Multiubiquitin chain receptor involved in modulation of proteasomal degradation. Involved in nucleotide excision repair.
Highly expressed in the spleen, testis and kidney. Also found in the heart, liver, lung and brain.
Interacts with RB1; the interaction disrupts RB1 binding to E2F1 (PubMed:9697699). Interacts with RBL1 and RBL2 (PubMed:9697699).
Serine hydrolase whose substrates have not been identified yet (By similarity). May negatively regulate basal or autocrine TGF-beta signaling by suppressing SMAD2-SMAD3 phosphorylation (By similarity). 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).
Found to be expressed in developing spermatocytes, but not in terminally differentiated spermatozoa.
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
Highest expression is found in testis. Ubiquitously expressed in extragonadal tissues.
E3 ubiquitin-protein ligase (By similarity). May facilitate apoptosis by inhibiting APC/C-Cdh1-mediated poly-ubiquitination and subsequent proteasome-mediated degradation of the pro-apoptotic protein MOAP1 (By similarity). Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21 (By similarity). 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 (By similarity).
Interacts with MOAP1 (By similarity). Interacts with CDKN1A (By similarity).
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.
Interacts with GRIK2 and GRIK3, but neither with AMPA-nor with NMDA-sensitive glutamate receptors.
Expression detected in trophoblast giant cells (TGCs), the placenta-derived cell lineage aligned at the boundary between the uterus and placenta, at embryonic days 12.5 (12.5 dpc). However, expression is faint and only observed in some of these cells, and disappears by 15.5 dpc.
Highest expression levels in the cerebrum and cecum. Moderate expression in the ovary, colon and placenta. Low levels in the uterus, small intestine, and thymus. Expressed only moderately in the placenta. No expression in kidney tissues. Has a complex and abundant central nervous system expression pattern. Expressed in brain regions such as pons, midbrain, thalamus, hypothalamus, hippocampus, amygdala, cortex, frontal cortex, and striatum. No expression in the cerebellum. Persistent expression is detected in hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female. Hypothalamic expression changed throughout the estrus cycle and is significantly increased after gonadectomy, a rise that is prevented by sex steroid replacement both in males and females.
Receptor for metastin, a C-terminally amidated peptide of KiSS1. KiSS1 is a metastasis suppressor protein. Activation of the receptor inhibits cell proliferation and cell migration, key characteristics of tumor metastasis. 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. 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.
Although related to peptidase S1 family, lacks the conserved active Ser residue in position 339 which is replaced by a Thr, suggesting that it has no protease activity.
Cleaved into an alpha and beta chain by autocatalysis; this activates the enzyme (PubMed:2775174). The N-terminal residue of the beta subunit is responsible for the nucleophile hydrolase activity (By similarity).
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.
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. 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).
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. Metabolizes also benzaldehyde. Low activity towards acetaldehyde and 3,4-dihydroxyphenylacetaldehyde. May not metabolize short chain aldehydes. Can use both NADP(+) and NAD(+) as electron acceptor. May have a protective role against the cytotoxicity induced by lipid peroxidation.
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 (By similarity).
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 (By similarity).
Phosphorylated on Tyr-202 upon EGF stimulation. Phosphorylation is required for interaction with CD2AP and CIN85/SH3KBP1 (By similarity).
Homomultimers may associate with EGR1 bound to DNA.
Calcium-binding protein that plays a role in various cellular processes including motility, angiogenesis, cell differentiation, apoptosis, and autophagy. Increases cell motility and invasiveness by interacting with non-muscle myosin heavy chain (NMMHC) IIA/MYH9 (By similarity). 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 (By similarity). 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 (By similarity).
Homodimer. Interacts with PPFIBP1 in a calcium-dependent mode. Interacts with PGLYRP1; this complex acts as a chemoattractant that promotes lymphocyte movement. Interacts with MYH9; this interaction increases cell motility. Interacts with Annexin 2/ANXA2. Interacts with TP53; this interaction promotes TP53 degradation. Interacts with CCR5 and CXCR3. Interacts with FCGR3A; this interaction inhibits PKC-dependent phosphorylation of FCGR3A.
Catalyzes the inactivation of reactive sulfate esters in carcinogenic arylmethanols (PubMed:2114406). Highest activity towards ethacrynic acid and cumene hydroperoxide (PubMed:2114406).
Highest values found in liver followed by testis, adrenal gland, kidney, lung, brain and skeletal muscle. In liver, highest expression found in central vein limiting plate hepatocytes. In lung, expressed mainly in club cells of the bronchiolar epithelium and, at low levels, in type II alveolar cells.
Part of the multisubunit TRAPP (transport protein particle) complex.
Autophosphorylated on Ser/Thr. Phosphorylated in cytosol under basal conditions and dephosphorylated when membrane-associated (By similarity).
Homodimer (By similarity). Interacts with MBIP (By similarity).
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. 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. 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.
An interaction between Thr-414 and Asp-48 is essential for kinase activity and dimerization.
Autophosphorylated. Phosphorylation at Tyr-722 reduces its binding to RHOA and is crucial for focal adhesion dynamics. Dephosphorylation by PTPN11 stimulates its RHOA binding activity (By similarity).
Cleaved by granzyme B during apoptosis. This leads to constitutive activation of the kinase and membrane blebbing.
Highly expressed in brain, lung, liver, skeletal muscle, kidney and testis.
Homodimer (By similarity). Interacts with IRS1 (PubMed:11739394). Interacts with RAF1 (PubMed:15753127). Interacts with RHOA (activated by GTP), RHOB, RHOC (PubMed:7493923, PubMed:8816443). Interacts with PPP1R12A (PubMed:19131646). Interacts with EP300 (By similarity). Interacts with CHORDC1 (By similarity). Interacts with BRCA2 (By similarity). Interacts with NPM1; this interaction enhances its activity (By similarity). Interacts with SORL1 (By similarity). Interacts with PJVK (By similarity).
May play a role in hypertension. ROCK-inhibitors lower the blood pressure in spontaneous hypertensive, renal hypertensive and deoxycorticosterone acetate-induced hypertensive rats, but not in normal rats.
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 a role in placental homeostasis during the perinatal period. 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.
Citrullination at Arg-53 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance.
In normoxia, is hydroxylated on Asn-851 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.
In normoxia, is probably hydroxylated on Pro-405 and Pro-530 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 HIF3A2. 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. Interacts with CREBBP (By similarity). Interacts with EGLN1. Interacts with VHL (By similarity).
Phosphorylated on multiple sites in the CTAD.
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 APEX seems to activate CTAD (By similarity).
Belongs to the glycosyl hydrolase 35 family.
Belongs to the ATP-dependent DNA ligase family.
DIDS- and thiosulfate- sensitive anion exchanger mediating chloride, sulfate and oxalate transport.
Component of the oligosaccharyltransferase (OST) complex (By similarity). 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 (By similarity). 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. Interacts with DDI2 (By similarity). Interacts with TMEM35A/NACHO (By similarity).
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.
A phosphoprotein adapter involved in the XPO1-mediated U snRNA export from the nucleus. Bridge components required for U snRNA export, the cap binding complex (CBC)-bound snRNA on the one hand and the GTPase Ran in its active GTP-bound form together with the export receptor XPO1 on the other. Its phosphorylation in the nucleus is required for U snRNA export complex assembly and export, while its dephosphorylation in the cytoplasm causes export complex disassembly. It is recycled back to the nucleus via the importin alpha/beta heterodimeric import receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Its compartmentalized phosphorylation cycle may also contribute to the directionality of export. Binds strongly to m7G-capped U1 and U5 small nuclear RNAs (snRNAs) in a sequence-unspecific manner and phosphorylation-independent manner. Also plays a role in the biogenesis of U3 small nucleolar RNA (snoRNA). Involved in the U3 snoRNA transport from nucleoplasm to Cajal bodies. Binds strongly to m7G-capped U3, U8 and U13 precursor snoRNAs and weakly to trimethylated (TMG)-capped U3, U8 and U13 snoRNAs. Binds also to telomerase RNA (By similarity).
Expressed in dorsal root ganglia and sensory neuron cell bodies.
Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA. Part of a precomplex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20 and m7G-capped RNA. Interacts with NCBP1/CBP80. Found in a complex with snoRNA. Interacts with NCBP2/CBP20 (By similarity).
Phosphorylated in the nucleus. Dephosphorylated in the cytoplasm.
Probably catalyzes the deacetylation of acetylated carbohydrates an important step in the degradation of oligosaccharides.
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.
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.
Expressed in liver, spleen and olfactory epithelium. Weaker expression is seen in skeletal muscle, cardiac muscle, eye and brain tissue.
Forms homodimers or heterodimers with TCF3 gene products E12 and E47. These dimers bind to the E-box site, however, heterodimer with MYOD1 does not bind target DNA.
Lacks a classic transcription activation domain and instead possesses an N-terminal region capable of inhibiting heterologous activators.
Plays a role in controlling the transcriptional activity of MyoD, ensuring that expanding myoblast populations remain undifferentiated. Repression may occur through muscle-specific E-box occupancy by homodimers. May also negatively regulate bHLH-mediated transcription through an N-terminal repressor domain. Serves as a key regulator of acinar cell function, stability, and identity. Also required for normal organelle localization in exocrine cells and for mitochondrial calcium ion transport. May function as a unique regulator of gene expression in several different embryonic and postnatal cell lineages. Binds to the E-box consensus sequence 5'-CANNTG-3' (By similarity).
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 and SF potentiate and sensitize ASIC2 and ASIC3 channels.
Homodimer (By similarity). The CSTF complex is composed of CSTF1 (50 kDa subunit), CSTF2 (64 kDa subunit) and CSTF3 (77 kDa subunit) (By similarity). Interacts (via repeats WD) directly with CSTF3 (By similarity). Interacts (via repeat WD6) with BARD1 (By similarity). Interacts with ERCC6 (By similarity).
One of the multiple factors required for polyadenylation and 3'-end cleavage of mammalian pre-mRNAs (By similarity). May be responsible for the interaction of CSTF with other factors to form a stable complex on the pre-mRNA (By similarity).
Receptor for GRF, coupled to G proteins which activate adenylyl cyclase. Stimulates somatotroph cell growth, growth hormone gene transcription and growth hormone secretion.
Belongs to the proteasome subunit S5A family.
In all organs tested, highest levels in liver.
Tautomerization of D-dopachrome with decarboxylation to give 5,6-dihydroxyindole (DHI).
Detected in liver, kidney, spleen and macrophages (at protein level).
Extensively N-glycosylated (PubMed:1794981, PubMed:18644871). Contains a minor proportion of O-linked glycans (PubMed:1794981). Contains sialylated glycans (PubMed:1794981).
Monomer (PubMed:18644871). Forms large homooligomers (PubMed:11082038, PubMed:18644871). Interacts (via its cytoplasmic region) with HSPA8 (PubMed:18644871). Interacts with HSP90 in the lysosome lumen; this enhances LAMP2 stability (PubMed:18644871). Interacts with MLLT11 (By similarity). Interacts with ABCB9 (By similarity). Interacts with FURIN (By similarity).
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). Binds target proteins, such as GAPDH, and targets them for lysosomal degradation (PubMed:8662539, PubMed:11082038, PubMed:18644871). Plays a role in lysosomal protein degradation in response to starvation (PubMed:11082038). Required for the fusion of autophagosomes with lysosomes during autophagy. 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. Required for normal degradation of the contents of autophagosomes. 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. Is not required for efficient MHCII-mediated presentation of endogenous antigens (By similarity).
Expressed at high levels at 20.5 dpc. Expressed at lower levels at P2 and P6 and in adults (at protein level).
Expressed in brain, heart, kidney, liver and thymus. Within the brain expression is high in the cerebral cortex, hippocampus and olfactory bulb and is also seen at lower levels in the cerebellum (at protein level).
Interacts with NDEL1 (PubMed:17035248). 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. Interaction with microtubules may be mediated in part by TRAF3IP1. Interacts (via C-terminal) with PCNT. Interacts with CHCHD6 (By similarity). 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 (By similarity). 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 (By similarity).
Involved in the regulation of multiple aspects of embryonic and adult neurogenesis (PubMed:17035248). Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus. Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance. 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. Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A. Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development. 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 (By similarity).
Ubiquitinated. Ubiquitination with 'Lys-48'-linked polyubiquitin chains leads to its proteasomal degradation.
Hydrolyzes oligopeptides such as neurotensin, bradykinin and dynorphin A (PubMed:7836437). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:12500972, PubMed:18077343).
Highly expressed in cortex, Purkinje cells of the cerebellum, hippocampus, striatum and olfactory bulb. Isoform 1 and isoform 3 are expressed in skeletal and cardiac muscle.
In the developing hippocampus, the expression of isoform 1 is high at P8, then decreased with progression of hippocampal development. Isoform 3 expression was constitutively low, and not regulated during hippocampal development.
Induced in the hippocampus, by seizure and synaptic mechanisms in association with long-term potentiation (LTP). It is also induced in the striatum by drugs that alter dopamine signaling.
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. Differentially regulates the functions of the calcium activated channel ryanodine receptors RYR1 and RYR2. Isoform 1 decreases the activity of RYR2, and increases the activity of RYR1, whereas isoform 3 counteracts the effects by competing for binding sites. Isoform 1 regulates the trafficking and surface expression of GRM5. Isoform 3 acts as a natural dominant negative, in dynamic competition with constitutively expressed isoform 1, and isoform 2 to regulate synaptic metabotropic glutamate function. Isoform 3, may be involved in the structural changes that occur at synapses during long-lasting neuronal plasticity and development. Forms a high-order complex with SHANK1, which in turn is necessary for the structural and functional integrity of dendritic spines (PubMed:19345194). 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 (By similarity).
Tetramer; this tetrameric structure is critical for forming the high-order complex with SHANK1, which in turn is necessary for the structural and functional integrity of dendritic spines (PubMed:19345194). Interacts with GRM1, GRM5, ITPR1, DYN3, RYR1, RYR2 and SHANK3 (PubMed:10433269, PubMed:10798399, PubMed:12810060, PubMed:12887973, PubMed:9069287, PubMed:9808458, PubMed:9808459, PubMed:9727012). Interacts with IFT57 and OPHN1 (PubMed:15034583). Isoform 1 and isoform 2 encode coiled-coil structures that mediate homo- and heteromultimerization. Interacts with SHANK1; forms high-order polymerized complex with a mesh-like network structure, at least composed of SHANK1, HOMER1 and DLGAP1; the complex formation is SHANK1 multimerization dependent (PubMed:10433269, PubMed:19345194). Interacts with NFATC4 (By similarity). Interacts with DAGLA (via PPXXF motif); this interaction is required for the cell membrane localization of DAGLA (PubMed:17584991). Interacts with SRGAP2 (By similarity).
The WH1 domain interacts with the PPXXF motif in GRM1, GRM5, RYR1, RYR2, ITPR1, SHANK 1 and SHANK3. The coiled-Coil domain forms an antiparallel tetrameric arrangement (PubMed:19345194).
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. 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. 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 (By similarity).
Interacts with RAC1. 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. Interacts with CD2AP and CGNL1; probably part of a complex at cell junctions. Interacts with CAPZA1; recruits CAPZA1 to forming cell junctions. May interact with AFDN. Interacts with PLXND1; they dissociate upon SEMA3E binding to PLXND1 allowing SH3BP1 to transduce downstream signal through RAC1 inactivation. Interacts with ABL1, GRB2 and SRC (via SH3 domain).
The BAR domain mediates interaction with the exocyst components EXOC4 and EXOC8 and is required for the function in cell migration. It also mediates the interaction with PLXND1.
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. Reduces all-trans-retinal and 9-cis retinal. Reduces 3-ketosteroids and benzil into 3alpha-hydroxysteroids and S-benzoin, respectively, in contrast to the stereoselectivity of primates DHRS4s which produce 3beta-hydroxysteroids and R-benzoin. In the reverse reaction, catalyzes the NADP-dependent oxidation of 3alpha-hydroxysteroids and alcohol, but with much lower efficiency. Involved in the metabolism of 3alpha-hydroxysteroids, retinoid, isatin and xenobiotic carbonyl compounds.
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.
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, Phe-177, Leu-180 and Asn-196 are conserved between non-primate mammals whereas the respective residues are serine, phenylalanine and threonine in primates. The two residues at positions 177 and 180 are molecular determinants responsible for the stereoselective reduction of 3-ketosteroids and benzil. The presence of an asparagine at position 196 is important for the maintenance of the quaternary structure resulting in stability at cold temperature and improved catalytic activity toward retinal.
Acetylation at Lys-413 dramatically reduces catalytic activity. Deacetylated by SIRT3 (By similarity).
Binds 1 Mg(2+) or Mn(2+) ion per subunit.
On the 2D-gel the determined pI of this protein (spot P8) is: 9.0, its MW is: 42 kDa.
Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
Anion antiporter that mediates the transport of nicotinate (PubMed:35144162). Possibly involved in nicotinate intestinal reabsorption (By similarity). In contrast with human ortholog, not able to transport urate and orotate (PubMed:35144162).
Belongs to the type I cytokine receptor family. Type 2 subfamily.
Monomer. Interacts with AZGP1 (By similarity).
Expressed in liver and testis. Up-regulated in regenerating liver after partial hepatectomy.
Regulates the adhesive and proliferative status of intestinal epithelial cells. Can mediate density-dependent cell proliferation (By similarity).
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.6/SCN8A subfamily.
Isoform 1 is highly expressed in brain, moderately in spinal cord, and at low levels in dorsal root ganglia, nodose ganglia and superior cervical ganglia. Not detected in sciatic nerve and non-neuronal tissues. Isoform 2 is hardly detectable, if at all, in brain, expressed at low levels in spinal cord and at highest levels in dorsal root ganglia.
May be due to competing donor splice site.
Phosphorylation at Ser-1495 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:15282281). Interacts with FGF14, GBG3, GBB2 and SCN1B (By similarity). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with CALM1; the interaction modulates the inactivation rate of SCN8A (By similarity).
Belongs to the complex I NDUFB3 subunit family.
E3 ubiquitin-protein ligase that plays a role in various biological processes such as lung development or innate immunity. Seems to utilize UBE2E1. Promotes innate antiviral response by catalyzing 'Lys-63'-linked ubiquitination of IRF7. Inhibits also hepatitis C virus assembly by directly binding to viral E1 envelope glycoprotein to disrupt its interaction with E2.
Forms a ternary complex with CDKN1A/p21 and HSP90AB1/Hsp90.
May be involved in response to X-ray. Regulates p21 protein stability by binding to Hsp90 and p21.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.
Associates with the mTORC2 complex that regulates cellular processes including survival and organization of the cytoskeleton. Regulates the activity of the mTORC2 complex in a substrate-specific manner preventing for instance the specific phosphorylation of PKCs and thereby controlling cell migration. Plays a role in the stimulation of ZFP36-mediated mRNA decay of several ZFP36-associated mRNAs, such as TNF-alpha and GM-CSF, in response to stress. Required for ZFP36 localization to cytoplasmic stress granule (SG) and P-body (PB) in response to stress.
Interacts with the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with RFFL. Interacts (via C-terminus) with ZFP36 (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress. Interacts with RICTOR.
Ubiquitinated. Ubiquitination by RFFL promotes proteasomal degradation of PRR5L thereby modifying the substrate-specific activity of the mTORC2 complex. Ubiquitination by RFFL is stimulated by LPA/lysophosphatidic acid (By similarity).
Essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
Interacts with NDUFAF4, NDUFS2 and NDUFS3.
Gln-310 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.
Polyglycylase which modifies both tubulin and non-tubulin proteins, generating polyglycine side chains of variable lengths on the gamma-carboxyl groups of specific glutamate residues of target proteins. Involved in the elongation step rather than the initiation step of the polyglycylation reaction. Polyglycylates alpha-tubulin and beta-tubulin. Polyglycylates non-tubulin proteins such as nucleosome assembly protein NAP1.
Gamma-tubulin complex is necessary for microtubule nucleation at the centrosome.
Phosphorylation of Ser-329 and Ser-330 is a key step in agonist-dependent desensitization and loss of surface P2RY4. This phosphorylation does not involve PKC, nor other calcium-activated kinases (By similarity).
Receptor for ATP and UTP coupled to G-proteins that activate a phosphatidylinositol-calcium second messenger system. Not activated by ADP or UDP.
Widely expressed at low levels. In brain, higher expression in the pineal gland and ventricular system.
Phosphorylated. Phosphorylation of the protein kinase-like domain is required for full activation by CNP.
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.
Detected in extracts of several brain regions including striatum, pons, cerebellum and cortex. Not detected in numerous peripheral tissue extracts, except in testis. In the brain, detected in cortical structures including the anterior cingulate area, posterior cingulate and the frontoparietal, somatosensory and piriform cortices. Prominent also in the olfactory tubercle, the islands of Calleja, ventromedial and posterior nuclei of the hypothalamus, the medial septal nucleus, nucleus of the diagonal band and the ventral tegmental area. Localized also to hippocampal structures, with signals strongest over the CA2 and CA3 regions of Ammon's horn and less so over the dentate gyrus. Expressed in the caudate putamen only in its most caudal portion, with a decreasing gradient of signal from the dorsal to ventral aspect. Strong expression associated with a single pontine structure, the inferior olivary nucleus.
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 (By similarity).
Interacts with CDC42 (in GTP-bound form). Interacts weakly with RAC1 and not at all with RHOA (By similarity).
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 (By similarity).
The CRIB domain mediates interaction with CDC42.
Interacts with HSP90AA1, HSP90AB1, PPP5C, ROCK1 and ROCK2.
Regulates centrosome duplication, probably by inhibiting the kinase activity of ROCK2. Proposed to act as co-chaperone for HSP90. May play a role in the regulation of NOD1 via a HSP90 chaperone complex. In vitro, has intrinsic chaperone activity. This function may be achieved by inhibiting association of ROCK2 with NPM1. 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 (By similarity). Involved in stress response. Prevents tumorigenesis (By similarity).
As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.
Belongs to the adaptor complexes medium subunit family.
Probably part of the adaptor protein complex 5 (AP-5) a tetramer composed of AP5B1, AP5M1, AP5S1 and AP5Z1.
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.
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.
Up-regulated in denerved muscles cells. Down-regulated in soleus muscle in an electrical activity-dependent manner.
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.
Interacts with RIMS2, RPH3A and RPH3AL (By similarity). Interacts with RIMS1 (PubMed:9252191). Interacts with GDI2 and CHM; phosphorylation at Thr-86 disrupts these interactions (By similarity). 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 RAB GDP dissociation inhibitor GDI2.
Protein transport. Probably involved in vesicular traffic (By similarity).
Protein transport. Probably involved in vesicular traffic.
Functions as guanine nucleotide exchange factor (GEF) with specificity for RAB11A and RAB25. 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.
Interacts with BTK (PubMed:15158451). Interacts with all isoforms of MAPK8, MAPK9, MAPK10 and MAPK12 (PubMed:15158451). Interacts with GDP-bound and nucleotide-free forms of RAB11A (By similarity).
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. Interacts with ELAVL1; this interaction occurs in a RNA-dependent manner. Interacts with HAVCR2; this interaction promotes ILF3 ubiquitination and subsequent degradation (By similarity).
Methylated by protein arginine N-methyltransferase 1.
Phosphorylated at Thr-188 and Thr-315 by PKR in response to 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. 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 (By similarity). Upon viral infection, ILF3 accumulates in the cytoplasm and participates in the innate antiviral response. 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.
Asymmetrically dimethylated on arginine residues by PRMT1.
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. CPSF7 activates directly the mRNA 3'-processing machinery. Binds to pA signals in RNA substrates.
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. The cleavage factor Im (CFIm) complex associates with the CPSF and CSTF complexes to promote the assembly of the core mRNA 3'-processing machinery. Interacts with NUDT21/CPSF5. 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.
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.
Expressed in testis, unpreganant uterus and cardiac myocytes.
Ubiquitous with high level in testis, placenta and cardiac myocytes.
Up-regulated by DNA damaging agents like H(2)O(2) in cardiac myocytes.
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. ADRA2A sub-subfamily.
Mid to late gestation (gestation day 15).
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 (By similarity). May be involved in T-cell proliferation by regulating LIF secretion (By similarity). May play a role in lysosome homeostasis (By similarity).
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:11341836, PubMed:11179967). Preferentially fucosylates gangliosides GA1 and GM1 in the antrum, cecum and colon and in the female reproductive organs. Fucosylated host glycoproteins or glycolipids mediate interaction with intestinal microbiota influencing its composition (By similarity). 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:11179967).
In rat, there are three genes (Fut1/Fta, Fut2/Ftb and Ftc) which encode galactoside 2-L-fucosyltransferase. They are expressed in a tissue-specific manner and Ftc may have no enzymatic activity.
Belongs to the G-protein coupled receptor 2 family. Adhesion G-protein coupled receptor (ADGR) subfamily.
Highly expressed in the lung and to a much lesser extent in the kidney and heart. Dense localization in alveolar walls of the lung and in the intercalated cells of the collecting duct of the kidney.
Homodimer; disulfide-linked (PubMed:10391944). 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 (PubMed:11973329). Fragment generates by the processing enzyme furin remains attached to the extracellular N-terminal fragment (PubMed:16882675). Interacts (via N-terminal extracellular domain) with SFTPD (By similarity).
Proteolytically cleaved at multiple sites: one in the GPS domain (S1 site) and the other in the SEA domain (S2 site). The proteolytic cleavage at S1 site generates an extracellular subunit and a seven-transmembrane subunit. The proteolytic cleavage at S2 site generates a fragment that undergoes proteolytic cleavage by the processing enzyme furin.
Receptor that plays a critical role in lung surfactant homeostasis. May play a role in controlling adipocyte function.
It is uncertain whether Met-1 or Met-5 is the initiator.
Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport. The light chain may function in coupling of cargo to the heavy chain or in the modulation of its ATPase activity.
Oligomeric complex composed of two heavy chains and two light chains. Interacts with SPAG9. Interacts with ATCAY; may link mitochondria to KLC1 and regulate mitochondria localization into neuron projections. Interacts (via TPR repeats) with TOR1A; the interaction associates TOR1A with the kinesin oligomeric complex. Interacts with BORCS5 (By similarity). Interacts with MAPK8IP3/JIP3 and NTRK2/TRKB; interaction with NTRK2/TRKB is mediated by MAPK8IP3/JIP3 (PubMed:21775604).
Brain (olfactory bulb and central thalamic regions), and esophagus.
Receptor for neuromedin-B (PubMed:1848080). 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 (PubMed:26855425). 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 (By similarity). 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).
Belongs to the clathrin heavy chain family.
Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network (By similarity). 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). The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (By similarity). Plays a role in early autophagosome formation (By similarity).
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 (By similarity). Interacts with HIP1 (By similarity). Interacts with DENND1A, DENND1B and DENND1C (By similarity). Interacts with OCRL (By similarity). Interacts with ERBB2 (By similarity). Interacts with FKBP6 (By similarity). 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 (By similarity). Interacts with ATG16L1 (via N-terminus) (By similarity). Interacts with RFTN1; the interaction occurs in response to pathogens (By similarity). Interacts with USP2 isoform 2 (By similarity). Interacts with TMEM106B (via N-terminus) (By similarity).
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.
Belongs to the pterin-4-alpha-carbinolamine dehydratase family.
Homotetramer and homodimer (PubMed:1763325, PubMed:8444860, PubMed:10966642, PubMed:7744010, PubMed:8897596). Heterotetramer with HNF1A; formed by a dimer of dimers (PubMed:10966642). Interacts with HNF1B (via HNF-p1 domain); the interaction increases HNF1B transactivation activity (By similarity).
Involved in tetrahydrobiopterin biosynthesis (PubMed:8444860, PubMed:8618906). Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2 (PubMed:8444860). Coactivator for HNF1A-dependent transcription (PubMed:1763325). Regulates the dimerization of homeodomain protein HNF1A and enhances its transcriptional activity (PubMed:1763325). Also acts as a coactivator for HNF1B-dependent transcription (By similarity).
Predominantly synthesized during the later stage of gestation.
Extended rod-like protein with coiled-coil domains.
Golgin which probably tethers transport vesicles to the trans-Golgi network (TGN) and regulates vesicular transport between the endosomes and the Golgi. As a RAB9A effector it is involved in recycling of the mannose 6-phosphate receptor from the late endosomes to the TGN. May also play a role in transport between the recycling endosomes and the Golgi. Required for maintenance of the Golgi structure, it is involved in the biogenesis of noncentrosomal, Golgi-associated microtubules through recruitment of CLASP1 and CLASP2 (By similarity).
Homodimer. Interacts (via GRIP domain) with RAB6A (preferentially in its GTP-bound form). May interact (RAB6A-dependent) with ARL1; might be involved in GCC2 Golgi localization. Interacts with CLASP1 and CLASP2; recruits both proteins to membranes of the TGN. Interacts with STX16 (By similarity). Interacts (probably via GRIP domain) with RAB9A (preferentially in its GTP-bound form).
Anchoring protein that mediates the subcellular compartmentation of cAMP-dependent protein kinase (PKA type II) (PubMed:8125992). 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. May help to deliver cyclin D/E to CDK4 to facilitate cell cycle progression. 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. Involved in nuclear retention of RPS6KA1 upon ERK activation thus inducing cell proliferation. May be involved in regulation of DNA replication by acting as scaffold for MCM2. 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. May be involved in recruitment of active CASP3 to the nucleus in apoptotic cells. May act as a carrier protein of GJA1 for its transport to the nucleus. 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. 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 dimeric RII-alpha regulatory subunit of PKA during mitosis (PubMed:8125992). Interacts (via C-terminus) with FIGN (By similarity). Interacts with NCAPD2, CCND1, CCND3, MCM2, RPS6KA1, PDE4A, CASP3 (By similarity). Interacts with DDX5, CCNE1 (PubMed:11279182, PubMed:16721056). 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. Interacts with DPY30; mediating AKAP8 association with at least the MLL4/WBP7 HMT complex. Interacts with HDAC3; increased during mitosis. 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 (By similarity).
Phosphorylated on tyrosine residues probably by SRC subfamily protein kinases; multiple phosphorylation is leading to dissociation from nuclear structures implicated in chromatin structural changes.
Widely expressed. The protein has been detected in liver, fibroblasts, granulosa, myoblast, lymphoma and Sertoli cells.
Expressed at high levels in brain and is also found at lower levels in several other tissues.
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 (By similarity). Catalyzes the last of the four reactions of the long-chain fatty acids elongation cycle (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Catalyzes the saturation step of the sphingosine 1-phosphate metabolic pathway, the conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA (By similarity).
Belongs to the phosphohexose mutase family.
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.
Component of the mitochondrial ribosome large subunit (39S) which comprises a 16S rRNA and about 50 distinct proteins. Interacts with GADD45A, GADD45B and GADD45G. Interacts with NR4A1 via the NR4A1 AB domain. Interacts with ATAD3A and ATAD3B.
This gene is coded entirely within the intron of Mettl9 which is transcribed in the opposite strand of the DNA.
Belongs to the WD repeat coronin family.
Forms homooligomers, but does not form complexes with the other coronins. Interacts with Arp2/3 complex components, including ACTR2, ARPC1B and ARPC2. Binds actin (By similarity).
Phosphorylation on Ser-2 regulates the interaction with the Arp2/3 complex and cell motility in fibroblasts. Phosphorylation does not seem to affect subcellular location (By similarity).
Regulates leading edge dynamics and cell motility in fibroblasts. May be involved in cytokinesis and signal transduction (By similarity).
Regulates leading edge dynamics and cell motility in fibroblasts. May be involved in cytokinesis and signal transduction.
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 compared to '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. 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 (By similarity).
Interacts with RNF128. Forms a ternary complex with RNF128 and USP8. Interacts with FUS, ESR1 and RACK1. Interacts with UBE2N/UBC13 (By similarity).
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 (By similarity).
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 with higher activity toward C18 acyl-CoAs, especially C18:0 acyl-CoAs. 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.
Highly expressed in small intestine and colon.
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 (By similarity).
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 (By similarity).
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). Interacts with NPM1.
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 Atrial natriuretic peptide-converting enzyme, 180 kDa soluble fragment (Probable).
Activated through proteolytic processing by a trypsin-like protease; cleaved into a N-terminal propeptide and an activated corin protease fragment. Atrial natriuretic peptide-converting enzyme, 180 kDa soluble fragment is produced by cleavage by ADAM10. Cleavage by ADAM10 to produce soluble 180 kDa soluble fragment takes place after the transmembrane region and before FZ 1 (Probable).
Down-regulated upon experimental heart failure.
N-glycosylated; required for processing and activation.
Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) processing (PubMed:17660514). Converts through proteolytic cleavage the non-functional propeptide NPPA into the active hormone, thereby regulating blood pressure in heart and promoting natriuresis, diuresis and vasodilation (By similarity). Proteolytic cleavage of pro-NPPA also plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus (By similarity). Also acts as a regulator of sodium reabsorption in kidney (PubMed:20613715). May also process pro-NPPB the B-type natriuretic peptide (By similarity).
Specifically expressed in heart. Also detected in kidney, aorta, brain and testis. In kidney, present in epithelial cells, with segmental expression in the proximal tubule, thick ascending limb, connecting tubule, and throughout the collecting duct (at protein level).
Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5'-CANNTG-3' (By similarity). 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 (By similarity). 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 (By similarity). Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification (By similarity). Also required for dendrite morphogenesis and maintenance in the cerebellar cortex (PubMed:14741104). 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. Heterodimer with TCF3/E47; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element. Interacts with EP300; the interaction is inhibited by NR0B2 (By similarity). Interacts with RREB1 (By similarity). Interacts with ATOH8 (By similarity).
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). Phosphorylated. In islet cells, phosphorylated on Ser-274 upon glucose stimulation; which may be required for nuclear localization. In activated neurons, phosphorylated on Ser-336 by CaMK2; which promotes dendritic growth.
Up-regulated by fentanyl. Down-regulated by miR-190.
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.
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).
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. Probably interacts with PPP2CB. No complex with PPP2CB is detected when NMDARs are stimulated by NMDA. 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 (PubMed:24297929).
Isoform 1 and isoform 2 are expressed in olfactory bulb, frontal occipital, entorhinal and pyriform cortices, hippocampus, striatum, thalamus, cerebellum and spinal cord.
Isoform 1 and isoform 2 are expressed in spinal cord, medulla, pons, tegmentum, thalamus and hypothalamus at 15 dpc onwards (PubMed:7472412, PubMed:7472413, PubMed:9891978). In the brain cortex and in the hippocampus, strongly expressed during periods of synapse/spine reorganization at postnatal day 8 (P8) to P15. Expression declines after P25 (at protein level) (PubMed:24297929).
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 (PubMed:25009255, PubMed:24297929). May also play a role in PPP2CB-NMDAR mediated signaling mechanism.
Belongs to the POU transcription factor family. Class-2 subfamily.
Interacts with POU2AF1; the interaction increases POU2F1 transactivation activity. Interacts with NR3C1, AR, PGR and HCFC1.
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.
May be involved (but not essential) in spermatogenesis.
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.
Belongs to the nucleotide-sugar transporter family. SLC35A subfamily.
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).
Expressed in neurons of the V2 secondary visual cortex area (at protein level). Expressed at high levels in the brain cortex, hippocampus, striatum, thalamus and substantia nigra, in the lung, and spleen. Low expression has been found in heart, liver, skeletal muscle and testis.
Interacts with GNAI1, GNAI2 and GNAI3 (PubMed:11387333, PubMed:16870394, PubMed:17603074, PubMed:21158412, PubMed:11976690). Interacts with GNAO1 (By similarity). 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. 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. Associates with microtubules (By similarity). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14 (PubMed:19319189). Interacts with RIC8A (via C-terminus) (PubMed:21158412). 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 (PubMed:19878719). 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) (PubMed:19319189).
Phosphorylated by PKC. Phosphorylation is increased in presence of forskolin and may enhance the GDI activity on G(i) alpha subunit 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. Besides, modulates signal transduction via G protein alpha subunits by functioning as a GDP-dissociation inhibitor (GDI) (PubMed:11976690). 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 completion of the first mitotic division of the embryo. Involved in visual memory processing capacity; when overexpressed in the V2 secondary visual cortex area. Involved in hippocampal-based learning and memory; acts as a suppressor of synaptic plasticity in CA2 neurons. Required for the nerve growth factor (NGF)-mediated neurite outgrowth. Involved in stress resistance.
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.
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 (By similarity).
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 (By similarity).
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 (By similarity). Phosphorylation of the PRBH motif by aPKC inhibits the association of the protein with the cortical membrane (By similarity).
Catalyzes the NADPH-dependent reduction of carbonyl compounds to their corresponding alcohols. Has low NADPH-dependent oxidoreductase activity (PubMed:18983987). Acts on several orthoquinones, acts as well on non-quinone compounds, such as isatin or on the anticancer drug oracin. Best substrates for CBR3 is 1,2- naphthoquinone, hence could play a role in protection against cytotoxicity of exogenous quinones. Exerts activity toward ortho-quinones but not paraquinones. No endogenous substrate for CBR3 except isatin has been identified (By similarity).
There are conflicting results on the ability of CBR3 to metabolize menadione. Although menadione was originally reported as a good substrate of CBR3 (By similarity). Results of later studies showed that CBR3 possesses very low or no activity toward menadione (PubMed:18983987).
Heterodimer (via coiled-coil domain) with GMNN (via coiled-coil domain); targets GMNN to the nucleus. Can form homodimers (in vitro, via coiled-coil domain), but these are much less stable than the heterodimer formed with GMNN.
Detected in forbrain (at protein level).
Highly expressed in forebrain during the first 15 days after birth, a period of intense synaptogenesis.
Interacts with CADM1. Interacts with RAC1.
Intramolecular interaction between the DH domain and the PH domains can stabilize the protein in an autoinhibited conformation.
May play a role in semaphorin signaling (By similarity). Functions as guanine nucleotide exchange factor for RAC1. 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.
Single-stranded DNA-binding protein recruited to replication forks to maintain genome stability. Prevents fork collapse by antagonizing the accumulation of RAD51 at forks to ensure the proper balance of fork remodeling and protection without interfering with the capacity of cells to complete homologous recombination of double-strand breaks.
Belongs to the N-acetylmuramoyl-L-alanine amidase 2 family.
Highly expressed in the small intestine where it shows a proximal-distal graded expression.
Interacts with MTTP (By similarity). Interacts with MAD1L1 (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 (By similarity). Involved in p53/TP53-dependent cell survival after DNA damage (By similarity).
Central component of a redox-sensitive mitochondrial intermembrane space import machinery which is required for the biogenesis of respiratory chain complexes. Functions as chaperone and catalyzes the formation of disulfide bonds in substrate proteins, such as COX17, COX19, MICU1 and COA7. 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. 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. Reduced CHCHD4/MIA40 is then reoxidized by GFER/ERV1 via a disulfide relay system. Mediates formation of disulfide bond in MICU1 in the IMS, promoting formation of the MICU1-MICU2 heterodimer that regulates mitochondrial calcium uptake.
Forms intrachain disulfide bridges, but exists in different redox states.
Monomer. Can form homooligomers. Interacts with GFER and forms transient disulfide bonds with GFER. Interacts with MICU1. Interacts with COX19 forming transient intermolecular disulfide bridges. Interacts with COA7 through transient intermolecular disulfide bonds. Interacts with AIFM1; the interaction increases in presence of NADH. Interacts with NDUFB10.
The CHCH domain contains a conserved twin Cys-X(9)-Cys motif which is required for import and stability of MIA40 in mitochondria.
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.
Accepts the ubiquitin-like proteins SUMO1, SUMO2 and SUMO3 from the UBLE1A-UBLE1B E1 complex and catalyzes their covalent attachment to other proteins with the help of an E3 ligase such as RANBP2, CBX4 and ZNF451 (By similarity). Can catalyze the formation of poly-SUMO chains (By similarity). Essential for nuclear architecture and chromosome segregation (By similarity). Necessary for sumoylation of FOXL2 and KAT5 (By similarity). Sumoylates p53/TP53 at 'Lys-386' (By similarity). Mediates sumoylation of ERCC6 which is essential for its transcription-coupled nucleotide excision repair activity (By similarity).
Broadly expressed, with highest levels in spleen and lung (at protein level).
Forms a complex with SENP6 and UBE2I in response to UV irradiation (By similarity). Forms a tight complex with RANGAP1 and RANBP2 (By similarity). Identified in a complex with SUMO2 and UBE2I, where one ZNF451 interacts with one UBE2I and two SUMO2 chains, one bound to the UBE2I active site and the other to another region of the same UBE2I molecule (By similarity). Interacts with SETX (By similarity). Interacts with HIPK1 and HIPK2 (By similarity). Interacts with PPM1J (By similarity). Interacts with RASD2 (PubMed:19498170). Interacts with TCF3 (PubMed:9013644). Interacts with NR2C1; the interaction promotes its sumoylation (By similarity). Interacts with SIAH1 (By similarity). Interacts with PARP (By similarity). Interacts with various transcription factors such as TFAP2A, TFAP2B, and TFAP2C (By similarity). Interacts with AR (By similarity). Interacts with ETS1 (By similarity). Interacts with SOX4 (By similarity). Interacts with RWDD3; the interaction enhances the sumoylation of a number of proteins such as HIF1A and I-kappa-B (By similarity). Interacts with FOXL2 (By similarity). Interacts with DNM1l (via its GTPase and B domains); the interaction promotes sumoylation of DNM1L, mainly in its B domain (By similarity). Interacts with NFATC2IP; this inhibits formation of poly-SUMO chains (By similarity). Interacts with FHIT (By similarity). Interacts with PRKRA and p53/TP53 (By similarity). Interacts with UHRF2 (By similarity). Interacts with NR3C1 and this interaction is enhanced in the presence of RWDD3 (By similarity). Interacts with MTA1 (By similarity). Interacts with ZNF451 (By similarity). Interacts with CPEB3 (By similarity). Interacts with SUMO1, SUMO2, and SUMO3 (By similarity). Interacts with IPO13 (By similarity). Interacts with DNMT1 (By similarity).
Phosphorylation at Ser-71 significantly enhances SUMOylation activity.
'Secern' is an archaic English term meaning 'secrete'.
Belongs to the peptidase C69 family. Secernin subfamily.
Regulates exocytosis in mast cells. Increases both the extent of secretion and the sensitivity of mast cells to stimulation with calcium (By similarity).
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 (By similarity). 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) (By similarity).
On embryonic days 15 (15 dpc) and 18 dpc, expression is seen in the mantle and ventricular germinal zones throughout the neuraxis. On postnatal days 0 (P0) and P7, expression is seen in the cerebral neocortex, olfactory mitral and granule cell layers, hippocampal pyramidal and dentate granule cells and the striatum. A lower expression is seen in gray matter in di-, mes- and met-encephali. In the cerebellum, the expression is evident in the external and internal granule cell layers and Purkinje cell layer. On P14, a decreased expression is seen in the di-, mes- and met-encephali. On P21 and thereafter, expression is seen in the olfactory mitral and granule cells, dentate granule cells and the cerebellar granule cells and Purkinje cells.
Present in all tissues tested, with highest protein levels in brain and adrenal.
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.
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.
Interacts with CDT1 and ATPase VCP/p97. Interacts (via UBA domain) with FAS (via death domain). Interacts (via UBA domain) with NLRP12 (via DAPIN/PYRIN domain).
Ubiquitin-binding protein. Required for the progression of DNA replication forks by targeting DNA replication licensing factor CDT1 for degradation. Potentiates but cannot initiate FAS-induced apoptosis.
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. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. 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. 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. LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin. The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis.
Expressed in brain, spleen, lung, heart, skeletal muscle, kidney and testis (at protein level). Expressed in heart and testis.
Monomer and homodimer (PubMed:11178875). Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31 (By similarity). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (By similarity). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (By similarity). Interacts with EYA1, EYA2, SHANK1 and SHANK3 (via ANK repeats) (PubMed:11178875, PubMed:23897824).
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 (By similarity).
The Ubiquitin-like domain is required for the interaction with RNF31.
Belongs to the potassium channel family. V (TC 1.A.1.2) subfamily. Kv8.1/KCNV1 sub-subfamily.
Detected in brain, in neocortex, olfactory tubercle, hippocampus, dentate gyrus, piriform cortex and amygdala. Detected in Purkinje cells and granular cells of the cerebellum, in hippocampal CA4 neurons and neocortex pyramidal cells.
Heteromultimer with KCNB1 and KCNB2. Interacts with KCNC4 and KCND1 (By similarity).
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 (By similarity).
Homodimer. Homotetramer. 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. Binds subunits of the NuRD/MeCP1 complex. Interacts with FSHR; interaction is independent of follicle stimulating hormone stimulation. Interacts with APPL1; the interaction is decreased by adiponectin in a time-dependent manner. 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. 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. Interacts with ANXA2; targets APPL2 to endosomes and acting in parallel to RAB5A. 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 (By similarity). Interacts with PIK3R1; forms a complex with PIK3R1 and APPL1. 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. Interacts (via BAR domain) with ADIPOR2; ADIPOQ dissociates this interaction (By similarity).
Increases with aging and decreases by short-term exercise training in aging skeletal muscle.
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. Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex (By similarity). 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 (By similarity). Plays a role in cell metabolism by regulating adiponecting ans insulin signaling pathways and adaptative thermogenesis (By similarity). In muscle, negatively regulates adiponectin-simulated glucose uptake and fatty acid oyidation 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 (By similarity). 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 (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 (By similarity). 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 (By similarity). The PH and PID domains mediate phosphoinositide binding. The PID domain mediates phosphatidylserine binding and allows localization to cytosolic membrane structures and nucleus. The PH domain allows localization to the plasma membrane, cytosolic vesicles and distinct nuclear and perinuclear structures and is sufficient for RUVBL2 interaction (By similarity).
GTP-binding protein involved in transport from the endoplasmic reticulum to the Golgi apparatus. Activated by the guanine nucleotide exchange factor PREB. 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 (By similarity).
Homodimer. Binds PREB. Part of the COPII coat complex. Binds to the cytoplasmic tails of target proteins in the endoplasmic reticulum (By similarity). Interacts with SURF4 (By similarity).
Interacts with CDCP1. May interact with TMEFF1.
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.
Belongs to the BPI/LBP/Plunc superfamily. BPI/LBP family.
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.
Belongs to the SMC family. SMC5 subfamily.
A beta-galactoside alpha2-3 sialyltransferase primarily involved in terminal sialylation of ganglio and globo series glycolipids (PubMed:8144500). 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. Sialylates GM1/GM1a, GA1/asialo-GM1 gangliosides to form GD1a and GM1b, respectively (PubMed:8144500). Together with ST3GAL3, primarily responsible for biosynthesis of brain gangliosides that function as ligand for myelin-associated glycoprotein MAG on axons, regulating MAG expression and axonal myelin stability and regeneration (By similarity). Responsible for the sialylation of the pluripotent stem cell- and cancer stem cell-associated antigen SSEA3, forming SSEA4 (By similarity). Sialylates with low efficiency asialofetuin, presumably onto O-glycosidically linked Galbeta-(1->3)-GalNAc-O-Ser (PubMed:8144500).
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.
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. Acts by specifically binding and stimulating NPR2 to produce cGMP. Binds the clearance receptor NPR3 (By similarity).
May participate in the recruitment of inflammatory cells by injured or infected tissue.
Expressed at highest level in testis. Expressed at lower level in thymus. Also expressed in stomach, kidney, liver, brain and heart. Weakly expressed in spleen and lung (PubMed:16676351). Within testis, most abundantly present in spermatocytes: present from pachytene spermatocytes to early spermatids (at protein level) (PubMed:15229132, PubMed:16676351). Also present in non-germinal tissues (PubMed:16676351).
Homodimer; probably only forms homodimers in testis. Heterodimer; heterodimerizes with RFX1 and RFX3.
Transcription factor that acts as a key regulator of spermatogenesis (By similarity). Acts by regulating expression of genes required for the haploid phase during spermiogenesis, such as genes required for cilium assembly and function (By similarity). Recognizes and binds the X-box, a regulatory motif with DNA sequence 5'-GTNRCC(0-3N)RGYAAC-3' present on promoters (PubMed:14743396, PubMed:15526285, PubMed:16676351, PubMed:18247329). Probably activates transcription of the testis-specific histone gene H1-6 (PubMed:14743396, PubMed:15526285, PubMed:16676351, PubMed:18247329).
Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.
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:12390248). Interacts (via homeobox domain) with EP300; acetylates ALX1 and stimulates its transcriptional activity (PubMed:12929931).
Expressed in condensed prechondrocytic mesenchymal cells and in early chondrocytes of cartilage primordia. Expression is lower in mature chondrocytes.
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:12929931). Most probably regulates the expression of genes involved in the development of mesenchyme-derived craniofacial structures (By similarity). Early on in development, it plays a role in forebrain mesenchyme survival (By similarity). May also induce epithelial to mesenchymal transition (EMT) through the expression of SNAI1 (By similarity).
The OAR motif may negatively regulate DNA-binding and therefore transcriptional activity. It is found in the C-terminal transactivation domain that stimulates transcription.
Unable to bind DNA and activate transcription. Acts as a dominant negative through dimerization with isoform 1.
GRP proteins have a marked affinity for hydroxyapatite. They may play a role in the formation of the protective acquired pellicle at the saliva-tooth interface.
Binds (via the RRM domain) to the 3' untranslated region (UTR) of p21 mRNA.
Found in a signaling complex consisting of at least ARHGEF2, NOD2 and RIPK2.
Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains.
After cleavage of the signal peptide, the N-terminus is probably further processed by CTSC. Processing by CTSC is probably required for accumulation in cytoplasmic granules; in the absence of CTSC the protein does not accumulate.
Serine protease that cleaves preferentially after Arg residues. Can also cleave after citrulline (deimidated arginine) and methylarginine residues.
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. Essential for survival of retinal photoreceetors.
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 (By similarity).
Mediates the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (PubMed:7531435). 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 (PubMed:7531435). Plays a role in actin reorganization and cell migration (By similarity).
The SH3 domain mediates interaction with CLNK (By similarity). The SH3 domain also mediates interaction with RALGPS1 (By similarity).
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 (By similarity).
Ubiquitinated by CBLB in activated T-cells.
Has apparently no steroid dehydrogenase activity.
Belongs to the dermatan-sulfate isomerase family.
Belongs to the replication factor A protein 3 family.
Belongs to the enhancer of polycomb family.
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 (PubMed:9726963, PubMed:11311135). Interacts with LAPTM4B; this recruits the heterodimer formed by SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (By similarity).
Expressed in hepatoma but not in normal liver. Also expressed in placenta, testis, brain, ovary, spleen, mammary gland, and uterus. In brain expressed on capillary endothelia in cerebral cortex. Expressed in jejunum mucosa and the epithelial cells of the jejunum, ileum and colon. Also expressed in the intestinal epithelial cell line IEC-6. Expressed in the brain, retina, inner blood-retinal barrier of retina, retinal vascular endothelial cells, and in the retinal capillary endothelial cell line TR-iBRB2.
Expression induced in normal hepatic cells cultured in arginine-depleted medium.
L-leucine uptake by TR-iBRB2 cells was inhibited by L-leucine, L-phenylalanine, L-methionine, L-isoleucine, L-valine, L-tyrosine, L-tryptophan, D-leucine, D-phenylalanine, D-methionine and by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) (a specific inhibitor of system L transport).
The heterodimer with SLC3A2 functions as sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, L-DOPA, histidine, methionine, valine and alanine (By similarity). The heterodimer with SLC3A2 mediates the uptake of leucine, isoleucine and tryptophan (PubMed:9726963, PubMed:11311135, PubMed:12614332, PubMed:15980244). Functions as an amino acid exchanger (By similarity). 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 (By similarity). May mediate blood-to-retina L-leucine transport across the inner blood-retinal barrier (Probable). Can mediate the transport of thyroid hormones diiodothyronine (T2), triiodothyronine (T3) and thyroxine (T4) across the cell membrane. 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. Involved in the uptake of toxic methylmercury (MeHg) when administered as the L-cysteine or D,L-homocysteine complexes. Involved in the cellular activity of small molecular weight nitrosothiols, via the stereoselective transport of L-nitrosocysteine (L-CNSO) across the membrane (By similarity).
Nitration of Tyr-450 is irreversible and interferes with normal dynein intracellular distribution.
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. Binds specific activated tyrosine residues of the leptin, EPO, IL12, GSCF and gp130 receptors. Interaction with CSNK1E stabilize SOCS3 protein. Component of the probable ECS(SOCS3) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SOCS3. Interacts with CUL5, RNF7, ELOB and ELOC. Interacts with FGFR3 (By similarity). 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 (By similarity).
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 (By similarity).
The ESS and SH2 domains are required for JAK phosphotyrosine binding. Further interaction with the KIR domain is necessary for signal and kinase inhibition.
The SOCS box domain mediates the interaction with the Elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes.
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 (By similarity).
Detected in kidney, heart, brain, lung, skin, spleen and thymus.
Interacts with PLK1 (By similarity). Interacts with CDK1. Interacts with SMAD3 (By similarity).
Modulates the activity of cell cycle-specific kinases. Enhances CDK1 activity. May contribute to the regulation of the cell cycle. Fibrogenic factor contributing to the pathogenesis of renal fibrosis through fibroblast activation (By similarity).
Up-regulated in oligodendrocytes in response to complement activation.
Belongs to the teashirt C2H2-type zinc-finger protein family.
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 (By similarity). Interacts (via homeobox domain) with APBB1 (via PID domain 1).
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). 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 TALE/PBX homeobox family.
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.
Belongs to the peptidase C65 family. Otulin subfamily.
Belongs to the eukaryotic diacylglycerol kinase family.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids. 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. Also plays an important role in the biosynthesis of complex lipids. Does not exhibit an acyl chain-dependent substrate specificity among diacylglycerol species. Can also phosphorylate 1-alkyl-2-acylglycerol in vitro but less efficiently and with a preference for alkylacylglycerols containing an arachidonoyl group (By similarity). 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 (By similarity). Through the same mechanism could also positively regulate insulin-induced translocation of SLC2A4 to the cell membrane (By similarity). Regulates RASGRP1 activity (By similarity).
Interacts (via PDZ-binding motif) with the PDZ domain of the syntrophin SNTG1 and that of SNX27 (By similarity). 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). Forms a signaling complex with RASGRP1 and HRAS (By similarity).
The PDZ-binding motif mediates interaction with PDZ domain-containing proteins like SNTG1 and SNX27.
Sodium-independent transporter of chloride and iodide.
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.
PubMed:15635094 reported that the initiator methionine is coded by an unusual start codon, CTG.
Unusual initiator. The initiator methionine is coded by a non-canonical CTG leucine codon.
Detected at high levels in brain throughout embryonic development (at protein level). Levels are lower in neonates and decrease during the first days after birth (at protein level).
Detected in lung, uterus and placenta (at protein level). Detected in heart, lung, kidney, adrenal gland, intestine, testis, skeletal muscle and aorta. Detected at low levels in adult brain, in particular in brain stem and spinal cord, but also in hippocampus, olfactory bulb and striatum (at protein level).
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 (By similarity).
Implicated in the level of global muscle contraction and cardiac function (By similarity). Phosphorylates a specific serine in the N-terminus of a myosin light chain.
Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
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. 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. May play a role in the regulation of innate and adaptive immunity.
Monomer. Homodimer. Interacts with ITM2B and TNF.
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.
Expressed in neural stem cells (at protein level). Expressed in the dorsal telencephalon.
Interacts with DVL1 (PubMed:19001364). Interacts with RBPJ (By similarity).
May indirectly participate in activation of the NF-kappa-B and MAPK pathways (By similarity). Required for DNA damage-induced ATM phosphorylation, p53 activation and cell cycle arrest. Involved in myelopoiesis (By similarity). Acts as a mediator of BMP4-mediated modulation of canonical Wnt signaling activity in neural stem cells (PubMed:19001364). Binds to the oxygen responsive element of COX4I2 and represses its transcription under hypoxia conditions (4% oxygen), as well as normoxia conditions (20% oxygen) (By similarity). May repress COX4I2 transactivation induced by CHCHD2 and RBPJ (By similarity). Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG (By similarity).
The CXXC zinc finger mediates binding to CpG-DNA.
By lipopolysaccharides (LPS) and inflammation.
Has chemotactic activity for neutrophils. Contributes to neutrophil activation during inflammation.
Enhances DNA synthesis and may play a role in cell proliferation.
Belongs to the DEAD box helicase family. DDX18/HAS1 subfamily.
Interacts (via C-terminus) with DNAAF11 (via CS domain); this interaction stabilizes DNAAF11 at the protein level. Interacts (via C-terminus) with DNAL1; this interaction stabilizes DNAL1 at the protein level. Interacts with DNAAF4, HSPA8, IQUB, RUVBL2 and DYNTL5.
Plays a role in axonemal structure organization and motility. 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).
Present in spinal cord dorsal horn neurons and in developing teeth (at protein level). In the tooth, higher expression is found in the ameloblasts during the transition and maturation phases of amelogenesis; reduced eypression in the odontoblasts.
Probable metal transporter. The interaction with the metal ion chaperone COX11 suggests that it may play a role in sensory neuron functions. May play a role in biomineralization and retinal function.
Shares weak sequence similarity with the cyclin family, hence its name. However, it has no cyclin-like function in vivo.
Forms a tight complex with SCAP, the SCAP-SREBP complex, in the endoplasmic reticulum membrane. Interacts (via C-terminal domain) with RNF139.
Homodimer; efficient DNA binding of the soluble transcription factor fragment requires dimerization with another bHLH protein. Interacts with LMNA.
Key transcription factor that regulates expression of genes involved in cholesterol biosynthesis. 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'). Regulates transcription of genes related to cholesterol synthesis pathway.
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. 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.
Processed in the Golgi apparatus, releasing the protein from the membrane. At low cholesterol the SCAP-SREBP complex is recruited into COPII vesicles for export from the endoplasmic reticulum. In the Golgi, complex SREBPs are cleaved sequentially by site-1 (MBTPS1, S1P) and site-2 (MBTPS2, S2P) proteases. 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. Apoptosis triggers cleavage by the cysteine proteases caspase-3 and caspase-7. Cleavage and activation is induced by mediated cholesterol efflux.
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:15927954, PubMed:16120769). Interacts with LYPD6 (By similarity). Interacts with the alpha-conotoxin RgIA (PubMed:25740413). Interacts with alpha-conotoxins ImI and ImII (By similarity). Interacts with CANX (By similarity).
Belongs to the protease inhibitor I35 (TIMP) family.
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 (By similarity).
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. Also stimulates steroidogenesis by Leydig and ovarian granuloma cells; procathepsin L is required for maximal activity.
The activity of TIMP1 is dependent on the presence of disulfide bonds.
Belongs to the poly(ADP-ribose) glycohydrolase family.
Interacts with PCNA. Interacts with NUDT5.
Poly(ADP-ribose) glycohydrolase that degrades poly(ADP-ribose) by hydrolyzing the ribose-ribose bonds present in poly(ADP-ribose). PARG acts both as an endo- and exoglycosidase, releasing poly(ADP-ribose) of different length as well as ADP-ribose monomers. 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. Poly(ADP-ribose) is synthesized after DNA damage is only present transiently and is rapidly degraded by PARG. Required to prevent detrimental accumulation of poly(ADP-ribose) upon prolonged replicative stress, while it is not required for recovery from transient replicative stress. 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. 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. Involved in the synthesis of ATP in the nucleus, together with PARP1, NMNAT1 and NUDT5. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming.
The PIP-box mediates interaction with PCNA and localization to replication foci.
Expressed in brain. Found in the granular cell and Purkinje cell layers in the cerebellum; and in the hippocampal pyramidal cells, dentate granule cells and pyramidal granule cells of the cerebral cortex in the cerebrum.
In the PI-PLC X-box Asn-459 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, GABA receptor beta subunits, GABA receptor gamma-2 subunits (By similarity). Interacts with Ins(1,4,5)P3, Ins(1,4,5,6)P4, GABARAP, 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. Acts as an inhibitor of PPP1C.
Phosphorylation of Thr-94 resulted in dissociation of PPP1C from PRIP1 (By similarity). In vitro, phosphorylated by the catalytic subunit of PKA.
Also promotes endoribonucleolytic cleavage of some transcripts by promoting recruitment of the ribonuclease P/MRP complex (PubMed:10400702). Acts by bridging YTHDF2 and the ribonuclease P/MRP complex (By similarity). RIDA/HRSP12 binds to N6-methyladenosine (m6A)-containing mRNAs containing a 5'-GGUUC-3' motif: cooperative binding of RIDA/HRSP12 and YTHDF2 to such transcripts lead to recruitment of the ribonuclease P/MRP complex and subsequent endoribonucleolytic cleavage (By similarity).
Catalyzes the hydrolytic deamination of enamine/imine intermediates that form during the course of normal metabolism. May facilitate the release of ammonia from these potentially toxic reactive metabolites, reducing their impact on cellular components. It may act on enamine/imine intermediates formed by several types of pyridoxal-5'-phosphate-dependent dehydratases including L-threonine dehydratase.
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 (By similarity). Interacts with EML3 (phosphorylated form) (By similarity).
Belongs to the rod/cone cGMP-PDE gamma subunit family.
Participates in processes of transmission and amplification of the visual signal. cGMP-PDEs are the effector molecules in G-protein-mediated phototransduction in vertebrate rods and cones.
Belongs to the universal ribosomal protein uL16 family.
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 (By similarity).
Belongs to the protein-tyrosine phosphatase family. Receptor class 8 subfamily.
Detected in pancreas islets (PubMed:7657822, PubMed:10457160). Detected in pancreas alpha, beta and delta cells, and in chromaffin cells in the adrenal medulla (PubMed:8641276). Detected in amygdala, hypothalamus, autonomous nerve fibers and ganglia, especially at synaptic contacts (PubMed:8641276). Detected in pituitary (at protein level) (PubMed:8641276, PubMed:10457160). Detected in brain, specifically in cerebral cortex, diencephalon and brain stem (PubMed:7887886).
Does not possess catalytic activity due to replacement of highly conserved residues in tyrosine-protein phosphatase domain.
Homodimer; shown for the unprocessed protein (proICA512) in the endoplasmic reticulum and resolved during protein maturation as ICA512-TMF seems to be predominantly monomeric in secretory granules; however, ICA512-CCF interacts with ICA512-TMF disrupting the ICA512-TMF:SNTB2 complex. The isolated lumenal RESP18 homology domain has been shown to form disulfide-linked homooligomers. Interacts (via cytoplasmic domain) with phosphorylated SNTB2; this protects PTPRN against cleavage by CAPN1 to produce ICA512-CCF. Dephosphorylation of SNTB2 upon insulin stimulation disrupts the interaction and results in PTPRN cleavage. Interacts with SNX19. ICA512-CCF interacts with PIAS4; in the nucleus. Interacts with STAT5B (phosphorylated); down-regulated by ICA512-CCF sumoylation; ICA512-CCF prevents STAT5B dephosphorylation; ICA512-CCF mediates interaction of STAT5B with PIAS4. Interacts (via RESP18 homology domain) with insulin and proinsulin. Interacts with PTPRN2, PTPRA and PTPRE.
ICA512-CCF translocated to the nucleus promotes expression of insulin and other granule-related genes; the function implicates binding to and regulating activity of STAT5B probably by preventing its dephosphorylation and potentially by inducing its sumoylation by recruiting PIAS4 (By similarity). Enhances pancreatic beta-cell proliferation by converging with signaling by STAT5B and STAT3 (PubMed:18178618). ICA512-CCF located in the cytoplasm regulates dynamics and exocytosis of insulin secretory granules (SGs) by dimerizing with ICA512-TMF and displacing SNTB2 thus enhancing SGs mobility and exocytosis (By similarity).
ICA512-TMF regulates dynamics and exocytosis of insulin secretory granules (SGs); binding of ICA512-TMF to SNTB2/beta-2-syntrophin is proposed to restrain SGs mobility and exocytosis by tethering them to the actin cytoskeleton depending on UTRN; the function is inhibited by cytoplasmic ICA512-CFF dimerizing with ICA512-TMF and displacing SNTB2 (By similarity).
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). Required to maintain normal levels of renin expression and renin release. Seems to lack intrinsic enzyme activity.
Subject to proteolytic cleavage at multiple sites (PubMed:7568143). Subject to cleavage on a pair of basic residues (By similarity). Following exocytosis of secretory granules in pancreatic beta-cells ICA512-TMF located in the plasma-membrane is cleaved by mu-type calpain CPN1 to yield ICA512-CCF (PubMed:15596545).
Sumoylated at two sites including Lys-758. Sumoylation decreases interaction with STAT5.
The RESP18 homology domain is sufficient for targeting proICA512 to secretory granules.
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 RP2; interaction is direct and stimulated with the activated GTP-bound form of ARL3. Interacts with SYS1. Interacts with ARL2BP; the GTP-bound form interacts with ARL2BP. Microtubule-associated protein. Does not interact with TBCC (By similarity). Interacts with RP2. Interacts with PDE6D; the interaction occurs specifically with the GTP-bound form of ARL3. 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 (By similarity).
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). Required for normal cytokinesis and cilia signaling. 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. Targets NPHP3 to the ciliary membrane by releasing myristoylated NPHP3 from UNC119B cargo adapter into the cilium (By similarity). Required for PKD1:PKD2 complex targeting from the trans-Golgi network to the cilium (By similarity).
May be involved in retinal laminar formation. Promotes epithelial to mesenchymal transition (By similarity).
Discovered as DNA-binding protein in the serum of lupus-prone mice.
Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunits GNAI1, GNAI2 and GNAI3 with higher affinity for GNAI1 and GNAI3 than for GNAI2 (PubMed:10639138, PubMed:21653697). Preferentially interacts with inactive rather than active GNAI3 (PubMed:21653697). Interaction with GNAI3 is inhibited when NUCB1 binds calcium, probably due to a conformational change which renders the GBA motif inaccessible (PubMed:21653697).
Major calcium-binding protein of the Golgi which may have a role in calcium homeostasis (PubMed:7890746). Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates alpha subunits of guanine nucleotide-binding proteins (G proteins) (PubMed:21653697).
Minor constituent of the mineralized matrix of bone. Detected in calvaria, rib cartilage, liver, kidney, spleen, brain, lung, skeletal and heart muscle with highest expression in calvaria and approximately half the amount in kidney, liver and brain.
The EF-hand domains are unfolded in the absence of Ca(2+) and fold upon Ca(2+) addition.
Binds to the SECIS element in the 3'-UTR of some mRNAs encoding selenoproteins. Binding is stimulated by SELB.
Autoubiquitinated. Ubiquitinated by SH3RF2, leading to proteasome-mediated degradation.
Has E3 ubiquitin-protein ligase activity. In the absence of an external substrate, it can catalyze self-ubiquitination. Stimulates ubiquitination of potassium channel KCNJ1, enhancing it's dynamin-dependent and clathrin-independent endocytosis (By similarity). 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 (PubMed:12514131). 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 HERP1. Interacts with RAC1; in a GTP-dependent manner (By similarity). 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. 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:16230351, PubMed:16571722). 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 (By similarity). Interacts with SH3RF2 (PubMed:22128169).
Phosphorylated at Ser-305 by AKT1 and AKT2. When phosphorylated, it has reduced ability to bind Rac.
The RING finger domain is required for ubiquitin ligase activity and autoubiquitination.
A protein kinase activity has been reported kinase activity however PROSITE, Pfam do not detect a protein kinase domain. Its enzyme activity is therefore unsure.
May participate in the nuclear signaling of EGFR and MAPK1/ERK2.
Acyltransferase which transfers the acyl group to the N-terminus of glycine. Can conjugate a multitude of substrates to form a variety of N-acylglycines (By similarity).
Specifically expressed in kidney and liver. Up-regulated in the regenerating liver as well as in hepatocellular carcinoma.
May be a negative regulator of NF-kappa-B and p53-mediated gene transcription.
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 (By similarity). Homodimer; disulfide-linked (By similarity). Occurs in both reduced and oxidized monomeric form (By similarity). Oxidative conditions increase homodimerization (By similarity). Interacts with CANX (By similarity). Interacts with ATP2A2 (By similarity).
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.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 4 subfamily.
Dephosphorylates a range of proteins, and thereby regulates cellular signaling cascades.
Expressed in the brain, preadipocytes and pancreatic islet cells.
Is a receptor for the SMIM20 derived peptides Phoenixin-14 and Phoenixin-20 (PubMed:27440717). It mediates the Phoenixin-14 and Phoenixin-20 augmentation of gonadotropin-releasing hormone (GNRH) signaling in the hypothalamus and pituitary gland (PubMed:27440717). In the ovary, it mediates the effects of Phoenixin-14 and Phoenixin-20 induced granulosa cell proliferation during follicular growth (By similarity).
Expressed in liver and kidney. It is the major glucose-6-phosphatase expressed in the small intestine.
Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. May form with the glucose-6-phosphate transporter (SLC37A4/G6PT) a ubiquitously expressed complex responsible for glucose production through glycogenolysis and gluconeogenesis. Probably required for normal neutrophil function (By similarity).
Serine protease. Has a preference for substrates with an Arg instead of a Lys residue in position P1.
Interacts with AFG3L2. Interacts with SPG7. Interacts with SMDT1/EMRE (via the N-terminal transit peptide); interaction is direct and takes place before maturation of SMDT1/EMRE.
Promotes sorting of SMDT1/EMRE in mitochondria by ensuring its maturation. 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).
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.
Brain (at protein level). Expressed in fetal and adult brain.
E3 ubiquitin-protein ligase which ubiquitinates itself in cooperation with an E2 enzyme UBE2D2/UBC4 and serves as a targeting signal for proteasomal degradation. May play a role in regulation of neuronal functions (By similarity). May act as a regulator of synaptic vesicle exocytosis by controlling the availability of SNAP25 for the SNARE complex formation.
The coiled coil domain mediates the interaction with the N-terminal t-SNARE domain of SNAP25.
Seems to be involved in pore-forming activity and may contribute to the unspecific permeability of the peroxisomal membrane.
Component of splicing factor SF3A which is composed of three subunits; SF3A3/SAP61, SF3A2/SAP62 and SF3A1/SAP114. SF3A1 functions as scaffold that interacts directly with both SF3A2 and SF3A3. 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). Identified in the spliceosome 'E' complex, a precursor of the spliceosome 'A' complex. Identified in the spliceosome 'A' and 'B' complexes. Identified in the spliceosome 'C' complex. Interacts with HTATSF1.
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. Involved in pre-mRNA splicing as a component of pre-catalytic spliceosome 'B' complexes, including the Bact complex. Interacts directly with the duplex formed by U2 snRNA and the intron.
Belongs to the protein phosphatase inhibitor 1 family.
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 (By similarity). Promotes cell adhesion by mediating homophilic interactions via its extracellular N-terminal adhesion motif (N-NAM) (PubMed:19595672). Involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells (By similarity). 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 (By similarity). Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS (By similarity). Acts as a mediator of both programmed and necrotic cell death (By similarity). 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 (By similarity). Plays a role in nerve regeneration by promoting maturation of Schwann cells (By similarity). 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. Acts as an anti-inflammatory mediator by promoting monocyte recruitment, thereby ameliorating atherosclerosis.
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.
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 PSMC3 and few additional components. Interacts with PAAF1.
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. PSMC3 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.
Endonuclease that mediates miRNA decay of both protein-free and AGO2-loaded miRNAs (By similarity). As part of its function in miRNA decay, regulates mRNAs involved in G1-to-S phase transition (By similarity). Functions as a bridging factor between STAT6 and the basal transcription factor (By similarity). Plays a role in PIM1 regulation of MYB activity (By similarity). Functions as a transcriptional coactivator for STAT5 (By similarity).
Forms a ternary complex with STAT6 and POLR2A (By similarity). Associates with the RNA-induced silencing complex (RISC). Interacts with the RISC components AGO2, FMR1 and TNRC6A (PubMed:24882364). Interacts with GTF2E1 and GTF2E2 (By similarity). Interacts with PIM1 (By similarity). Interacts with STAT5 (By similarity). Interacts with SYT11 (via C2 2 domain); the interaction with SYT11 is direct (PubMed:24882364).
Interacts with TRIM63 (By similarity). Binds to actin and tropomyosin. Interacts with STK4/MST1 (By similarity).
Phosphorylated at Ser-23 and Ser-24 by PRKD1; phosphorylation reduces myofilament calcium sensitivity. Phosphorylated preferentially at Thr-32. Phosphorylation by STK4/MST1 alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylated at Ser-43 and Ser-45 by PRKCE; phosphorylation increases myocardium contractile dysfunction (By similarity).
Accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulating their cell-surface expression and cyclic nucleotide dependence.
Belongs to the peroxisomal targeting signal receptor family.
Forms an obligate 4:4 complex with HCN2 (By similarity). Interacts with RAB8B (PubMed:11278749). Interacts with HCN3 (By similarity).
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. Heterodimer; efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TWIST1 and TWIST2. Forms a heterodimer with NEUROD1; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element. Forms a heterodimer with TCF15; the heterodimer binds E-box element. Forms a heterodimer with MYOG; heterodimerization enhances MYOG DNA-binding and transcriptional activities. Forms a heterodimer with ATOH8; repress transcription of TCF3 and TCF3-NEUROG3 dimer-induced transactivation of E box-dependent promoters. Component of a nuclear TAL-1 complex composed at least of CBFA2T3, LDB1, TAL1 and TCF3. Interacts with NEUROD2 (By similarity). Interacts with EP300 (By similarity). Interacts with PTF1A, TGFB1I1 (By similarity). Interacts with UBE2I (PubMed:9013644). Interacts with BHLHA9 (By similarity). Interacts with ASB2; the interaction is mediated by SKP2 and targets TCF3 for Notch-induced proteasomal degradation (By similarity). Interacts with transcription factor ASCL5/AmeloD (By similarity).
Interacts with RALGAPA1 (By similarity). Interacts with FIGLA (By similarity).
Phosphorylated following NGF stimulation.
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 (By similarity). Binds to the consensus sequence CAC/GCTGT/C present, in the chymotrypsin, insulin, AP-4, and several other gene enhancer motifs (PubMed:2200736).
Plays a role in neuronal plasticity and the proteolytic action may subserve structural reorganizations associated with learning and memory operations.
Has a role in transport between endoplasmic reticulum and Golgi.
Belongs to the sodium channel auxiliary subunit SCN3B (TC 8.A.17) family.
Expressed broadly in neurons in the central and peripheral nervous systems, but not in glia and most non-neuronal cells. Weak detection in lung and adrenal gland.
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. Beta-1 or beta-3 subunits associate with NFASC. Associates with SCN10A.
Expressed in hepatocytes. Also expressed in granule cells of the hippocampus and the cerebellum.
Homodimer; can bind DNA as homodimer. 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 NR2C2AP; the interaction represses selective NR2C2-mediated transcriptional activity. 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. Interacts (MAPK-mediated phosphorylated form) with NRIP1; the interaction promotes repression of NR2C2-mediated activity. Interacts with NLRP10. Interacts (via ligand-binding region) with transcriptional corepressor JAZF1; the interaction promotes NR2C2-mediated transcriptional repression.
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. Activates transcriptional activity of LHCG and is antagonist of PPARA-mediated transactivation. 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).
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).
Interacts with calcineurin. Interacts with YWHAH, in a phosphorylation-dependent manner.
Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. May function as background potassium channel that sets the resting membrane potential. Channel activity is directly activated by calcium signal. Activated by the G(q)-protein coupled receptor pathway. The calcium signal robustly activates the channel via calcineurin, whereas the anchoring of 14-3-3/YWHAH interferes with the return of the current to the resting state after activation. Inhibited also by arachidonic acid and other naturally occurring unsaturated free fatty acids. Channel activity is also enhanced by volatile anesthetics, such as isoflurane. Appears to be the primary target of hydroxy-alpha-sanshool, an ingredient of Schezuan pepper. May be involved in the somatosensory function with special respect to pain sensation (By similarity).
Phosphorylation of Ser-275 is required for the binding of 14-3-3eta/YWHAH. Calcineurin-mediated dephosphorylation of Ser-287 enhances channel activity (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.
Heterohexamer (By similarity). Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8D and/or LRRC8E) to form a heterohexamer (Probable). Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E (By similarity). 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:28833202). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (By similarity). Plays a redundant role in the efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (By similarity). The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (By similarity). 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:28833202).
The cytoplasmic N-terminus preceding the first transmembrane (residues 1-22) regulates volume-regulated anion channel (VRAC) conductance, ion permeability and inactivation gating.
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 the basement membrane heparan sulfate proteoglycan perlecan and triple helical collagens type I and type II.
May anchor basement membranes to the underlying connective tissue.
The basic N-terminal Arg/Pro-rich region binds heparin and heparan sulfate. Binds collagens type I and type II through its leucine-rich repeat domain (By similarity).
Belongs to the peptidase C19 family. USP12/USP46 subfamily.
Detected in lung and spleen, and at lower levels in brain, kidney, testis and liver.
Deubiquitinating enzyme that plays a role in behavior, possibly by regulating GABA action. May act by mediating the deubiquitination of GAD1/GAD67 (By similarity). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity. Not involved in deubiquitination of monoubiquitinated FANCD2 (By similarity).
Interacts with WDR48. Interacts with WDR20.
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. Mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. Involved in internalization of P2RY1, P2RY4, P2RY6 and P2RY11 and ATP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 and subsequent recycling or degradation. Involved in ubiquitination of IGF1R. 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) and MAPK10 (JNK3). ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for the AKT1 pathway. 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). Increases ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Involved in CCR7-mediated ERK1/2 signaling involving ligand CCL19. Is involved in type-1A angiotensin II receptor/AGTR1-mediated ERK activity. Is involved in type-1A angiotensin II receptor/AGTR1-mediated MAPK10 activity. Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. Involved in AGTR1-mediated chemotaxis. 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. Suppresses UV-induced NF-kappa-B-dependent activation by interacting with CHUK. The function is promoted by stimulation of ADRB2 and dephosphorylation of ARRB2. Involved in IL8-mediated granule release in neutrophils (By similarity). Involved in p53/TP53-mediated apoptosis by regulating MDM2 and reducing the MDM2-mediated degradation of p53/TP53. May serve as nuclear messenger for GPCRs. Upon stimulation of OR1D2, may be involved in regulation of gene expression during the early processes of fertilization. Also involved in regulation of receptors other than GPCRs. Involved in endocytosis of TGFBR2 and TGFBR3 and down-regulates TGF-beta signaling such as NF-kappa-B activation. Involved in endocytosis of low-density lipoprotein receptor/LDLR. Involved in endocytosis of smoothened homolog/Smo, which also requires GRK2. Involved in endocytosis of SLC9A5. Involved in endocytosis of ENG and subsequent TGF-beta-mediated ERK activation and migration of epithelial cells. 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. Involved in insulin resistance by acting as insulin-induced signaling scaffold for SRC, AKT1 and INSR. Involved in regulation of inhibitory signaling of natural killer cells by recruiting PTPN6 and PTPN11 to KIR2DL1. Involved in the internalization of the atypical chemokine receptor ACKR3 (By similarity). Acts as an adapter protein coupling FFAR4 receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis. During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of pro-inflammatory cytokine release and inhibition of inflammation.
Homooligomer; the self-association is mediated by InsP6-binding (Probable). Heterooligomer with ARRB1; the association is mediated by InsP6-binding. Interacts with ADRB2 and CHRM2. Interacts with PDE4A. Interacts with PDE4D. Interacts with MAPK10, MAPK1 and MAPK3. Interacts with DRD2. Interacts with FSHR. Interacts with CLTC. Interacts with HTR2C. Interacts with CCR5. Interacts with CXCR4. Interacts with SRC. Interacts with DUSP16; the interaction is interrupted by stimulation of AGTR1 and activation of MAPK10. Interacts with CHUK; the interaction is enhanced stimulation of ADRB2. Interacts with RELA. Interacts with MDM2; the interaction is enhanced by activation of GPCRs. Interacts with SLC9A5. Interacts with TRAF6. Interacts with IGF1R. Interacts with ENG. Interacts with KIR2DL1, KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with AP2B1. Interacts with C5AR1. Interacts with RAF1. Interacts with MAP2K1. Interacts with MAPK1. Interacts with MAPK10; the interaction enhances MAPK10 activation by MAP3K5. Interacts with MAP2K4; the interaction is enhanced by presence of MAP3K5 and MAPK10. Interacts with MAP3K5. Interacts with AKT1. Interacts with IKBKB and MAP3K14. Interacts with SMO (activated). Interacts with GSK3A and GSK3B. Associates with protein phosphatase 2A (PP2A). Interacts with CXCR4; the interaction is dependent on C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with GPR143. Interacts with HCK and CXCR1 (phosphorylated) (By similarity). Interacts with ACKR3 and ACKR4 (By similarity). Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (By similarity). Interacts (via NACHT and LRR domains) with NLRP3; this interaction is direct and inducible by omega-3 polyunsaturated fatty acids (PUFAs) (By similarity). Interacts with FFAR4 (via C-terminus); this interaction is stimulated by long-chain fatty acids (LCFAs) (By similarity).
Hydroxylation by PHD2 modulates the rate of internalization by slowing down recruitment to the plasma membrane and inhibiting subsequent co-internalization with class A receptors.
Phosphorylated at Thr-383 in the cytoplasm; probably dephosphorylated at the plasma membrane. The phosphorylation does not regulate internalization and recycling of ADRB2, interaction with clathrin or AP2B1 (By similarity).
Predominantly localized in neuronal tissues and in the spleen.
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. Stimulation of a class B GPCR promotes a sustained ubiquitination (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-3 (Flt4) receptor (By similarity).
Highly expressed in the spleen, kidney, lung, tongue, ovary and mammary gland.
Homodimer; non-covalent and antiparallel.
Indolinones; MAE87, MAE106 and MAZ51 inhibit VEGF-D induced activation of VEGFR-3.
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 (By similarity).
Expressed in brain and spinal cord (at protein level) (PubMed:18096700). In the embryonic brain cortex, expressed in neurons but not in astrocytes (at protein level) (PubMed:18096700).
Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity (By similarity). Enhances trafficking of the glutamate transporter SLC1A1/EAAC1 from the endoplasmic reticulum to the cell surface (PubMed:18096700). 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 SPAST (By similarity). Interacts with BACE1 (By similarity). Interacts (via first transmembrane domain) with ARL6IP5/GTRAP3-18 (PubMed:18096700). Interacts (via N-terminus) with SLC1A1/EAAC1; the interaction promotes cell surface expression of SLC1A1 (PubMed:18096700).
Belongs to the galactose-3-O-sulfotransferase family.
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.
Highest expression in muscle (both skeletal and cardiac) and brain.
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 (By similarity).
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 (By similarity).
Expressed in injured skeletal muscles and sciatic nerve (at protein level). Expressed in the pancreas. Expression increases during the acute phase of pancreatitis.
Up-regulated in injured skeletal muscles and peripheral nerve.
Homooligomer. Interacts (via the C-terminal region) with WT1. Interacts with THAP1. Interacts with AATF. Interacts with BACE1. Interacts with SPSB1 (via B30.2/SPRY domain); this interaction is direct and occurs in association with the Elongin BC complex. Interacts with SPSB2 (via B30.2/SPRY domain); this interaction occurs in association with the Elongin BC complex. Interacts with SPSB4 (via B30.2/SPRY domain); this interaction occurs in association with the Elongin BC complex. Component of a ternary complex composed of SQSTM1 and PRKCZ (By similarity). Interacts with actin (PubMed:15817164).
In ventral prostate following castration.
Preferentially phosphorylated at the Thr-155 by PKC in cancer cells.
Pro-apoptotic protein capable of selectively inducing apoptosis in cancer cells, sensitizing the cells to diverse apoptotic stimuli and causing regression of tumors in animal models. Induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-kappa-B transcriptional activity. Inhibits the transcriptional activation and augments the transcriptional repression mediated by WT1. Down-regulates the anti-apoptotic protein BCL2 via its interaction with WT1. Seems also to be a transcriptional repressor by itself. May be directly involved in regulating the amyloid precursor protein (APP) cleavage activity of BACE1 (By similarity).
The B30.2/SPRY domain-binding motif mediates recognition by proteins containing a B30.2/SPRY domain.
The SAC domain is a death-inducing domain selective for apoptosis induction in cancer cells. This domain is essential for nuclear entry, Fas activation, inhibition of NF-kappa-B activity and induction of apoptosis in cancer cells (By similarity).
The leucine-zipper domain is not essential for apoptosis, but is required for sensitization of cells to exogenous apoptotic insults and for interaction with its partners.
Expressed predominantly in neural tissues.
May act in concert with RAB3A in regulating aspects of synaptic vesicle membrane flow within the nerve terminal.
The GTP bound form of RAB15 interacts with REP15. Interacts (GTP-bound form) with MICAL1, MICAL3, MICALCL, EHBP1 and EHBP1L1.
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 (By similarity).
Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells (By similarity).
Detected at low levels in stomach, spleen, brain, large intestine and lung.
Down-regulated in actively dividing cells. Not detectable in suspension cultures. Accumulates only in cells that are attached to a solid substrate (in vitro).
Part of a complex that contains BOC, CDON, NEO1, cadherins and CTNNB1. Interacts with NTN3. Interacts with DHH, IHH and SHH (By similarity). Interacts with PTCH1. Interacts with GAS1.
Autophosphorylated. Phosphorylated at Thr-208 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-208 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-212 by GSK3-beta (GSK3B) inhibits the kinase activity. Phosphorylation by CaMK1 promotes activity and is required to promote neurite outgrowth. Phosphorylation at Thr-539 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity and promotes binding to 14-3-3 protein YWHAZ, leading to relocation from cell membrane to cytoplasm.
Homodimer (PubMed:16472737). Interacts (when phosphorylated at Thr-539) with YWHAZ (By similarity). Interacts with MTCL1; the interaction is direct and increases MARK2 microtubule-binding ability (By similarity). Interacts with PAK5; leading to inhibit the protein kinase activity (PubMed:16014608). Interacts with MAPT/TAU (By similarity). Interacts with YWHAB, YWHAG and YWHAQ (By similarity).
Inhibited by hymenialdisine (By similarity). Activated by phosphorylation on Thr-208 by STK11/LKB1 and TAOK1. Inhibited by phosphorylation at Ser-212 or Thr-539. Inhibited by PAK5; inhibition is independent of the kinase activity of PAK5.
Serine/threonine-protein kinase. Involved in cell polarity and microtubule dynamics regulation. Phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4 and RAB11FIP2. Phosphorylates the microtubule-associated protein MAPT/TAU. Plays a key role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Regulates epithelial cell polarity by phosphorylating RAB11FIP2. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B and 14-3-3 and inhibiting microtubule-dependent accumulation of KIF13B. Also required for neurite outgrowth and establishment of neuronal polarity. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Modulates the developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery. Essential for the asymmetric development of membrane domains of polarized epithelial cells.
The KA1 domain mediates binding to phospholipids and targeting to membranes.
Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5).
Was first identified because of its ability to stimulate Na(+)-dependent phosphate cotransport.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.4/KCNA4 sub-subfamily.
Detected in brain (at protein level) (PubMed:8361540, PubMed:9334400). Heart and brain.
Homotetramer and heterotetramer of potassium channel proteins (PubMed:10896669). Interacts with KCNAB1 and KCNAB2 (PubMed:9334400). Binds PDZ domains of DLG1, DLG2 and DLG4. Interacts with SIGMAR1 (PubMed:11988171). Part of a complex containing KCNA1, KCNAB1 and LGI1 (PubMed:16504945). Detected in a complex with KCNA1 (PubMed:2348860, PubMed:10896669). Interacts with KCNA2 (PubMed:8361540, PubMed:10896669, PubMed:12632190). Interacts (via cytoplasmic N-terminal domain) with KCNRG (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. 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:2348860, PubMed:8495559, PubMed:10896669). 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:2384173). Likewise, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:2348860).
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. PP2A can modulate the activity of phosphorylase B kinase, casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase.
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. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Interacts with TBCD. Interacts with CTTNBP2NL. Interacts with PTPA.
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 (By similarity).
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 (By similarity).
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 (PubMed:15870114).
Nervous system. Strongly expressed in brain, where it is predominant in neurons from cerebral cortex and hippocampus. Also present in mast cells (at protein level).
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).
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.
Regulatory subunit of serine/threonine-protein phosphatase 4. May play a role in regulation of cell division in renal glomeruli. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3 (By similarity).
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complex PPP4C-PPP4R1. Interacts with HDAC3 (By similarity).
Up-regulated in anti-Thy1 glomerulonephritis.
Belongs to the Mrp/NBP35 ATP-binding proteins family. NUBP1/NBP35 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. Implicated in the regulation of centrosome duplication. Negatively regulates cilium formation and structure.
Heterotetramer of 2 NUBP1 and 2 NUBP2 chains. Interacts with KIFC1. Interacts with the BBS/CCT complex subunit CCT1.
Interacts with KATNA1. This interaction enhances the microtubule binding and severing activity of KATNA1 and also targets this activity to the centrosome. This interaction is weakly competed by KATNBL1 which has a lower affinity for it. Interacts with ASPM; the katanin complex formation KATNA1:KATNB1 is required for the association of ASPM. Interacts with dynein, microtubules, NDEL1 and PAFAH1B1. Interacts with KATNAL1; this interaction is weakly competed by KATNBL1 which has a lower affinity for it. Interacts with CAMSAP2 and CAMSAP3; leading to regulate the length of CAMSAP-decorated microtubule stretches.
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.
Belongs to the cyclin family. Cyclin Y subfamily.
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 (By similarity).
Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (By similarity). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (By similarity). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (By similarity). Interacts with histone H2AX this requires phosphorylation of H2AX on 'Ser-139' (By similarity). Interacts with HJURP, INTS3, KPNA2 and TERF2 (By similarity). Interacts with RBBP8; the interaction links the role of the MRN complex in DNA double-strand break sensing to resection (By similarity). Interacts with SP100; recruits NBN to PML bodies (By similarity). Interacts with ATF2 (By similarity). Interacts with MTOR, MAPKAP1 isoform 2 and RICTOR; indicative for an association with the mTORC2 complex (By similarity). Interacts with MRNIP (By similarity). Interacts with UFL1; promoting UFL1 recruitment to double-strand breaks following DNA damage (By similarity). Interacts with CYREN (via XLF motif) (By similarity).
Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance.
Present at approximately equal levels in the heart at fetal day 17, at relatively constant levels at postnatal days 10, 17 and 21 and at slightly lower levels in the adult heart. Barely detectable in the brain. Not detected in kidney, very low levels in liver and skeletal muscle and moderate levels in heart, lung and brain (at protein level).
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.
May be involved in the energy metabolism of the mature sperm.
Specifically expressed in late haploid male germ cells.
Expressed in the eye, thyroid, prostate, kidney and liver. Abundantly expressed in the CNS, including hippocampus, olfactory bulb, cortex, cerebellum and white matter.
Homohexamer (By similarity). Forms homomeric or PANX1/PANX2-heteromeric intercellular channels on coexpression in paired Xenopus oocytes.
S-nitrosylation inhibits channel currents and ATP release.
Structural component of the gap junctions and the hemichannels. May play a role as a Ca(2+)-leak channel to regulate ER Ca(2+) homeostasis (By similarity).
A scaffold protein that directs CASP3 to certain substrates and facilitates their ordered degradation during apoptosis. May also play a role in mediating CASP3 cleavage of KRT18. Regulates 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. Inhibits DNA transcription in vitro (By similarity).
Exists predominantly in a mono- or diubiquitinated form.
First detected in 20-day-old animals. Reaches a peak at 30 days.
Interacts with CASP8, CASP10, KRT8, KRT18, CASP3 and FADD. Homodimerizes and heterodimerizes with DEDD2 (By similarity).
Widely expressed with highest levels in testis. Within the testis, highly expressed in germ cells but not expressed in Sertoli cells.
Belongs to the SINA (Seven in absentia) family.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
The RING-type zinc finger domain is essential for ubiquitin ligase activity.
The SBD domain (substrate-binding domain) mediates the interaction with substrate proteins. It is related to the TRAF family.
Functions as a regulator of the biosynthesis of TSH in the anterior pituitary gland and as a neurotransmitter/ neuromodulator in the central and peripheral nervous systems.
Belongs to the chromogranin/secretogranin protein family.
Probable transcription factor involved in muscle spindle development.
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. Essential for proper kinetochore microtubule attachments.
Forms heterodimers with BAR domain-containing sorting nexins SNX1 and SNX2; does not homodimerize. 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. Interacts with SNX1, SNX2, VPS26A, VPS29, VPS35, DCTN1, DOCK1, MIB1, PIP5K1C. Interacts with HGS; increased by PIP5K1C kinase activity and by PtdIns(3P) and/or PtdIns(3,4)P2 (By similarity).
Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol lipids. 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). Does not have in vitro vesicle-to-membrane remodeling activity. Involved in retrograde transport of lysosomal enzyme receptor IGF2R. May function as link between endosomal transport vesicles and dynactin. Plays a role in the internalization of EGFR after EGF stimulation. Involved in EGFR endosomal sorting and degradation; the function involves PIP5K1C and is retromer-independent. Together with PIP5K1C facilitates HGS interaction with ubiquitinated EGFR, which initiates EGFR sorting to intraluminal vesicles (ILVs) of the multivesicular body for subsequent lysosomal degradation. Involved in E-cadherin sorting and degradation; inhibits PIP5K1C-mediated E-cadherin degradation. Plays a role in macropinocytosis (By similarity).
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 (By similarity).
The PX domain mediates interaction with membranes enriched in phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol 4,5-bisphosphate.
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.
Controls osteoclast survival and size (By similarity). As a dimer with JUN, activates LIF transcription (By similarity). Activates CEBPB transcription in PGE2-activated osteoblasts (PubMed:15299028).
Expressed in the brain cortex. Expressed at night in pineal gland (at protein level). Also expressed in osteoblasts (at protein level).
Heterodimer (By similarity). Interacts with the BAF multiprotein chromatin-remodeling complex subunits SMARCB1 and SMARCD1 (By similarity). Interacts with ARID1A and JUN (By similarity).
In the pineal gland, exhibits night/day variations with a 4-fold increased expression at night (at protein level). Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway. Nocturnally elevated expression is also observed in the brain cortex. In osteoblasts, up-regulated by PGE2 (at protein level).
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 (By similarity).
Predominantly expressed in limbic regions of the brain such as the lateral septum, the entorhinal cortex, the hypothalamic ventromedial nucleus and several amygdaloid nuclei. Also detectable in lung, kidney and heart.
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 (By similarity).
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class IV subfamily.
Present in femoral head and rib cartilage, as well as in tendon. Detected in bone marrow.
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).
Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs).
Interacts (active GTP-bound form) with RASSF7 (By similarity). Interacts (active GTP-bound form preferentially) with RGS14.
Palmitoylated by the ZDHHC9-GOLGA7 complex. Depalmitoylated by ABHD17A, ABHD17B and ABHD17C. A continuous cycle of de- and re-palmitoylation regulates rapid exchange between plasma membrane and Golgi.
Phosphorylation at Ser-89 by STK19 enhances NRAS-association with its downstream effectors.
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes.
Interacts with SQSTM1. Binds DNA as a dimer; homodimer or heterodimer with NR2F6. Interacts with NCOA1, NCOA2, NCOA3 and PPARGC1A. Interacts with ZFPM2 (By similarity).
Ligand-activated transcription factor. Activated by high concentrations of 9-cis-retinoic acid and all-trans-retinoic acid, but not by dexamethasone, cortisol or progesterone (in vitro). Regulation of the apolipoprotein A-I gene transcription. Binds to DNA site A. May be required to establish ovary identity during early gonad development.
May be involved in fusion of retrograde transport vesicles derived from an endocytic compartment with the Golgi complex.
Proteolytic processing into mature chains is required for histone eviction during spermatogenesis. Transition proteins (TNP1 and TNP2) are required for processing.
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.
Belongs to the ANT/ATPSC lysine N-methyltransferase family.
Contains an atypical, non-cleavable mitochondrial targeting sequence responsible for its localization to mitochondria.
Mitochondrial protein-lysine N-methyltransferase that trimethylates ATP synthase subunit C, ATP5MC1 and ATP5MC2. Trimethylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration (Probable). Promotes chronic pain. 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 (By similarity).
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 (By similarity).
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 (By similarity).
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.
Was originally thought to be located in the peroxisome (By similarity). However, was later shown to be cytosolic (PubMed:11725955).
Plays a regulatory role in the organization of neuroendocrine signals accessing the anterior pituitary gland. Stimulates water drinking and food intake. May play a role in the hypothalamic response to stress. When injected into the lateral cerebroventricle, it elevates prolactin (PRL) and corticosterone and lowers growth hormone (GH) release.
Interacts with PORCN (By similarity). Interacts with PKD1 (By similarity).
Ligand for members of the frizzled family of seven transmembrane receptors. Plays an important role in the embryonic development of the urogenital tract and the lung. Required for normal mesenchyme to epithelium transition during embryonic kidney development. Required for the formation of early epithelial renal vesicles during kidney development. Required for normal formation of the Mullerian duct in females, and normal levels of oocytes in the ovaries. Required for normal down-regulation of 3 beta-hydroxysteroid dehydrogenase in the ovary. Required for normal lung development and for normal patterning of trachael cartilage rings.
Palmitoleoylation is required for efficient binding to frizzled receptors. Depalmitoleoylation leads to Wnt signaling pathway inhibition.
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 (By similarity). This complex was also known under the names MINOS or MitOS complex (By similarity). 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 (By similarity). The MICOS and SAM complexes together with DNAJC11 are part of a large protein complex spanning both membranes termed the mitochondrial intermembrane space bridging (MIB) complex. Interacts with IMMT/MIC60. Interacts with CHCHD3/MIC19 (By similarity). Interacts with ARMC1 (By similarity).
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. Required for the assembly of TOMM40 into the TOM complex.
Acetylation, which is up-regulated by glucose and insulin and down-regulated by glucagon, inhibits the glycogen phosphorylase activity by promoting PPP1R3B-mediated recruitment of phosphatase PP1 and Ser-15 dephosphorylation.
Allosterically regulated through the non-covalent binding of metabolites, being activated by AMP and inhibited by ATP, ADP, and glucose-6-phosphate. The activity is also controlled by post-translational modifications including phosphorylation and acetylation.
Homodimer; enzymatically active (By similarity). Interacts with PPP1R3B; recruits the phosphatase PP1 which dephosphorylates and inactivates PYGL/glycogen phosphorylase (PubMed:7720853, PubMed:7498521, PubMed:9841883).
Phosphorylation at Ser-15 converts inactive phosphorylase b into active phosphorylase a. Dephosphorylation of Ser-15 by phosphatase PP1 inactivates the enzyme.
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. Enhances the enzymatic activity of SPC and facilitates the interactions between different components of the translocation site.
Interacts with ATP1B4. Interacts with TOR1A (ATP-bound). Interacts with TOR1B, TOR2A and TOR3A. Interacts with VIM.
Required for nuclear membrane integrity. Induces TOR1A and TOR1B ATPase activity and is required for their location on the nuclear membrane. Binds to A- and B-type lamins. Possible role in membrane attachment and assembly of the nuclear lamina.
Acetylation at Met-1 seems to be important for proper folding and native oligomeric structure.
Found only in brain (hippocampus, brainstem and cortex). Specifically expressed in neuronal cell bodies and synapses.
Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release (By similarity). Participates as a monomer in synaptic vesicle exocytosis by enhancing vesicle priming, fusion and dilation of exocytotic fusion pores (By similarity). Mechanistically, acts by increasing local Ca(2+) release from microdomains which is essential for the enhancement of ATP-induced exocytosis (By similarity). Acts also as a molecular chaperone in its multimeric membrane-bound state, assisting in the folding of synaptic fusion components called SNAREs (Soluble NSF Attachment Protein REceptors) at presynaptic plasma membrane in conjunction with cysteine string protein-alpha/DNAJC5 (By similarity). This chaperone activity is important to sustain normal SNARE-complex assembly during aging (By similarity). Also plays a role in the regulation of the dopamine neurotransmission by associating with the dopamine transporter (DAT1) and thereby modulating its activity (By similarity).
Phosphorylated, predominantly on serine residues. Phosphorylated on Tyr-125 upon osmotic stress.
Soluble monomer. Homotetramer. A dynamic intracellular population of tetramers and monomers coexists normally and the tetramer plays an essential role in maintaining homeostasis (By similarity). Interacts with UCHL1 (PubMed:12408865). Interacts with phospholipase D and histones. Interacts (via N-terminus) with synphilin-1/SNCAIP; this interaction promotes formation of SNCA inclusions in the cytoplasm. Interacts with CALM1. Interacts with STXBP1; this interaction controls SNCA self-replicating aggregation. Interacts with SNARE components VAMP2 and SNAP25; these interactions allows SNARE complex assembly and integrity (By similarity). Interacts with RPH3A and RAB3A (By similarity). Interacts with SERF1A; this interaction promotes the aggregation of SNCA (By similarity). Interacts with SEPTIN4 (By similarity).
Ubiquitinated. The predominant conjugate is the diubiquitinated form.
Homooligomer and heterooligomer (By similarity). Interacts with TRIM55 (PubMed:15802564). Interacts with titin/TTN (PubMed:15802564). Interacts with RNF29, USP8, MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAP, GABARAPL1 and GABARAPL2 (By similarity). Binds to ubiquitin and ubiquitinated proteins (By similarity). Interacts with SQSTM1 (PubMed:15802564). Interacts with TAX1BP1 (By similarity). Interacts with IRF3; this interaction mediates autophagic degradation of IRF3 (By similarity). 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. 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. Plays a role in the regulation of the innate immune response by modulating type I interferon production and targeting ubiquitinated IRF3 for autophagic degradation (By similarity). 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).
As part of the MLL1/MLL complex, involved in the methylation of histone H3 at 'Lys-4', particularly trimethylation. Histone H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. May play some role in histone H3 acetylation. In embryonic stem cells, may play a crucial role in retinoic acid-induced differentiation along the neural lineage, regulating gene induction and H3 'Lys-4' methylation at key developmental loci. May also play an indirect or direct role in endosomal transport (By similarity).
Homodimer. Core component of several methyltransferase-containing complexes including MLL1/MLL, MLL2/3 (also named ASCOM complex) and MLL4/WBP7. Each complex is at least composed of ASH2L, RBBP5, WDR5, DPY30, one or more specific histone methyltransferases (KMT2A/MLL1, KMT2D/MLL2, KMT2C/MLL3 and KMT2B/MLL4), and the facultative components MEN1, HCFC1, HCFC2, NCOA6, KDM6A, PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin (By similarity). Interacts with ASH2L; the interaction is direct (By similarity). Interacts with ARFGEF1. Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L/ASH2, CXXC1/CFP1, HCFC1 and DPY30 (By similarity).
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. Promotes splenocyte alloactivation (By similarity).
Plays a role in short-term synaptic plasticity in a subset of GABAergic neurons in the brain.
Induced in early phase of liver regeneration. Expression is maximally increased 6 hours after partial hepatectomy, both at the liver RNA level and at the plasma protein level.
Interacts with GPIHBP1 (By similarity). Interacts with SORL1; this interaction leads to APOA5 internalization and sorting either to lysosomes and degradation, or to the trans-Golgi network (By similarity).
Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL (By similarity). May also be associated with chylomicrons (By similarity). 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 (By similarity). Binds heparin (By similarity).
Belongs to the LAP (LRR and PDZ) protein family.
Belongs to the G-protein coupled receptor 1 family. Opsin subfamily.
Phosphorylated on some or all of the serine and threonine residues present in the C-terminal region.
Visual pigments are the light-absorbing molecules that mediate vision. They consist of an apoprotein, opsin, covalently linked to cis-retinal. May increase spectral sensitivity in dim light.
May play a role in carrying and orienting carbohydrate, as well as having a more specific role.
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 (By similarity).
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. Weakly interacts with CDKN1B. Interacts with ARHGEF28 and CDK16. Interacts with GAB2 (By similarity). Interacts with KCNK18 in a phosphorylation-dependent manner. Interacts with SAMSN1 (By similarity). Interacts with the 'Ser-241' phosphorylated form of PDPK1 (By similarity). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (By similarity). Interacts with SLITRK1 (By similarity). Interacts with MEFV (By similarity).
Phosphorylated on Ser-59 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.
Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala. Also shows low activity towards peptides with Ala or Ser at the P1 position. 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.
Expressed in the kidney, specifically in intercalated cells, but not in principal cells, of the distal convoluted tubule and cortical collecting duct (at protein level).
Homodimer. Interacts with TNFRSF1B/TNFR2 (activated) and TRAF2.
Belongs to the small GTPase superfamily. Rho family.
Interacts with CDC42EP1, CDC42EP2, CDC42EP3, CDC42EP4 and EXO70 in a GTP-dependent manner. Interacts with ARHGAP33/TCGAP and GOPC (By similarity). Interacts with 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).
May be post-translationally modified by both palmitoylation and polyisoprenylation.
Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. May play a role in CFTR trafficking to the plasma membrane. Causes the formation of thin, actin-rich surface projections called filopodia.
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.
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) (By similarity).
Belongs to the KCNMB (TC 8.A.14.1) family.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB4 subfamily.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB per KCNMA1 tetramer.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB4 per KCNMA1 tetramer. Interacts with FMR1 (via N-terminus).
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 (By similarity).
Phosphorylated. Phosphorylation modulates its effect on KCNMA1 activation kinetics (By similarity).
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. 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 (By similarity).
Resistance to charybdotoxin (CTX) toxin is mediated by the extracellular domain.
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 (By similarity). Interacts with HINT1 (By similarity). Interacts with GCNA (via SIM domains); this interaction allows the GCNA recruitment to DPCs sites (By similarity).
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 (By similarity).
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 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. Plays a role in the regulation of sumoylation status of SETX (By similarity).
Forms heterodimers with a number of antiapoptotic Bcl-2 proteins, including MCL1, BCL2, BCL2L1 isoform Bcl-X(L), BCL2A1/BFL-1, and BCL2L2/BCLW. Does not heterodimerize with proapoptotic proteins such as BAD, BOK or BAK (PubMed:9731710). Identified in a complex containing BCL2L11, DYNLL1 and BCL2L1 isoform Bcl-X(L); BH3 integrity is required for BCL2L1-binding. Interacts with YWHAZ. When phosphorylated, interacts with TRIM2; this interaction is associated with ubiquitination and degradation (PubMed:21478148). Interacts (via BH3) with MCL1; this interaction may sequester BCL2L11 and prevent its pro-apoptotic activity (PubMed:9731710). When phosphorylated, isoform BimEL interacts with USP27X; this interaction leads to BCL2L11 deubiquitination and stabilization (By similarity). Interacts with GIMAP5 (By similarity). Interacts with BCL2L10/BCL-B (By similarity).
Phosphorylation at Ser-65 by MAPK1/MAPK3 leads interaction with TRIM2 and ubiquitination, followed by proteasomal degradation. Deubiquitination catalyzed by USP27X stabilizes the protein.
Produced by alternative initiation at Met-104 of isoform BOD-L.
The BH3 motif is required for the interaction with Bcl-2 proteins and cytotoxicity.
Ubiquitination by TRIM2 following phosphorylation by MAPK1/MAPK3 leads to proteasomal degradation (PubMed:21478148). Conversely, deubiquitination catalyzed by USP27X stabilizes the protein (By similarity).
Ca(2+)-regulated transcription factor that is involved in several processes, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems. Involved in T-cell activation, stimulating the transcription of cytokine genes, including that of IL2 and IL4 (PubMed:12370307). Along with NFATC3, involved in embryonic heart development. Involved in mitochondrial energy metabolism required for cardiac morphogenesis and function. Transactivates many genes involved in heart physiology. Along with GATA4, binds to and activates NPPB/BNP promoter (PubMed:9568714). Activates NPPA/ANP/ANF and MYH7/beta-MHC transcription (PubMed:19026640). Binds to and transactivates AGTR2 gene promoter. 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. In cochlear nucleus neurons, may play a role in deafferentation-induced apoptosis during a 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). Plays a role in adipocyte differentiation. May be involved in myoblast differentiation into myotubes (By similarity). Binds the consensus DNA sequence 5'-GGAAAAT-3' (By similarity). In the presence of CREBBP, activates TNF transcription. Binds to PPARG gene promoter and regulates its activity (By similarity). 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 NFATC4, 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. Interacts with CREBBP; this interaction potentiates transcription activation (By similarity). Interacts with MAPK8/JNK1 and MAPK9/JNK2 (By similarity). Interacts with GATA4 (via the second Zn finger) (By similarity). Interacts (via N-terminus) with IRAK1 (via C-terminus). Interacts with RPS6KA3. Interacts with HOMER1, HOMER2 and HOMER3; this interaction competes with calcineurin/PPP3CA-binding and hence prevents NFATC4 dephosphorylation and activation (By similarity). Interacts with ESR1 and ESR2; this interaction decreases NFATC4 transcriptional activity. Interacts with MTOR and MAPK7/ERK5 (By similarity). 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 and MAPK9, and on Ser-289 and Ser-344 by RPS6KA3 (By similarity). Phosphorylated by GSK3B; this phosphorylation markedly increases NFATC4 ubiquitination (PubMed:19026640). Phosphorylation by MAPK8/JNK1, MAPK9/JNK2 and RPS6KA3 may stimulate NFATC4 transcriptional activity. Phosphorylation at Ser-168 and Ser-170 is stimulated by UV irradiation (By similarity).
Rel similarity domain (RSD) or Rel homology domain (RHD) allows DNA-binding and cooperative interactions with AP-1 factors.
Ubiquitinated, leading to degradation by the proteasome. Ubiquitination may be stimulated by GSK3B-dependent phosphorylation. Polyubiquitin linkage mainly occurs through 'Lys-48'.
Associates with GIRK1 or GIRK4 to form a G-protein-activated heteromultimer pore-forming unit. The resulting inward current is much larger (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.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ6 subfamily.
This potassium channel is controlled by G proteins. It may be involved in the regulation of insulin secretion by glucose and/or neurotransmitters. 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 or cesium.
Belongs to the trans-sulfuration enzymes family.
Catalyzes the last step in the trans-sulfuration pathway from L-methionine to L-cysteine in a pyridoxal-5'-phosphate (PLP)-dependent manner, which consists on cleaving the L,L-cystathionine molecule into L-cysteine, ammonia and 2-oxobutanoate (Probable) (PubMed:13525371). Part of the L-cysteine derived from the trans-sulfuration pathway is utilized for biosynthesis of the ubiquitous antioxidant glutathione. Besides its role in the conversion of L-cystathionine into L-cysteine, it utilizes L-cysteine and L-homocysteine as substrates (at much lower rates than L,L-cystathionine) to produce hydrogen sulfide (H2S). In vitro, it converts two L-cysteine molecules into lanthionine and H2S, and two L-homocysteine molecules to homolanthionine and H2S, which can be particularly relevant under conditions of severe hyperhomocysteinemia. Lanthionine and homolanthionine are structural homologs of L,L-cystathionine that differ by the absence or presence of an extra methylene group, respectively. Acts as a cysteine-protein sulfhydrase by mediating sulfhydration of target proteins: sulfhydration consists of converting -SH groups into -SSH on specific cysteine residues of target proteins such as GAPDH, PTPN1 and NF-kappa-B subunit RELA, thereby regulating their function. By generating the gasotransmitter H2S, it participates in a number of physiological processes such as vasodilation, bone protection, and inflammation (By similarity). Plays an essential role in myogenesis by contributing to the biogenesis of H2S in skeletal muscle tissue (By similarity). Can also accept homoserine as substrate (PubMed:13525371). Catalyzes the elimination of selenocystathionine (which can be derived from the diet) to yield selenocysteine, ammonia and 2-oxobutanoate (Probable).
Homotetramer (By similarity). Interacts with CALM in a calcium-dependent manner (By similarity).
Expression is restricted to the nervous system.
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.
E3 ubiquitin-protein ligase mediating 'Lys-63'-linked polyubiquitination of RRAGA in response to amino acid starvation. Thereby, regulates mTORC1 signaling and plays a role in the cellular response to amino acid availability. Also mediates 'Lys-48'-linked polyubiquitination of target proteins and their subsequent targeting to the proteasome for degradation. Induces apoptosis when overexpressed.
Interacts with RRAGA (inactive GDP-bound form); stimulated by amino acid starvation. Interacts with SEC16A.
Ubiquitinated. Autoubiquitinated in vitro, leading to its degradation by the proteasome.
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. Catalyzes the deconjugation of poly-SUMO2 and poly-SUMO3 chains. Has very low efficiency in processing full-length SUMO proteins to their mature forms (By similarity).
Required for gamma-tubulin complex recruitment to the centrosome.
May regulate the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone.
CASK and LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1 (PubMed:12040031). 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 (PubMed:15994232). Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity). Interacts with WHRN (PubMed:12641734). Interacts (via the PDZ, SH3 and guanylate kinase-like domains) with NRXN1 (via C-terminus) (PubMed:8786425, PubMed:25385611). Interacts with CASKIN1, APBA1, LIN7(A/B/C), and L27 domain of DLG1 and isoform 2 of DLG4 (PubMed:9753324, PubMed:12040031, PubMed:12151521, PubMed:11865057, PubMed:15048107). Interacts with FCHSD2 (PubMed:14627983). Interacts with KIRREL3 (By similarity). Interacts with TBR1 (PubMed:10749215). 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.
Expressed in the foot process layer of podocytes in the kidney glomerulus and in tubules (at protein level). Detected in brain and neurons.
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 (By similarity). Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking.ontributes 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.
Unlike other protein kinases, does not require a divalent cation such as magnesium for catalytic 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. In RNA Pol II, this subunit is present in 2-fold molar excess over the other subunits. 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. Interacts with URI1.
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.
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 (By similarity).
Receptor for TNFSF4/OX40L/GP34. Is a costimulatory molecule implicated in long-term T-cell immunity (By similarity).
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).
Belongs to the complex I subunit 1 family.
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 (By similarity).
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 (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, STAT3 and TRIP4 (By similarity). Interacts with RPS6KB1.
Protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation and cytokinesis. Phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, TRIP4, STAT3 and histones H1 and H3. Phosphorylates KIF11 to promote mitotic spindle formation. Involved in G2/M phase cell cycle arrest induced by DNA damage. Inhibition of activity results in apoptosis. May contribute to tumorigenesis by suppressing p53/TP53-induced cancer cell senescence (By similarity). Phosphorylates RPS6KB1 (PubMed:11516946). Phosphorylates EML4 at 'Ser-144', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression (By similarity).
Homodimer, and heterodimer with OIP5/MIS18B. Identified in a complex containing MIS18A, OIP5/MIS18B, MIS18BP1, RBBP7 and RBBP4.
Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. 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. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2 (By similarity). 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 (By similarity). 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. Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2. Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2.
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-822 but decreases phosphorylation of Ser-794. Phosphorylation at Thr-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding (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 NTRK1 and NTRK3, but does not form detectable complexes with NTRK2 (PubMed:17967490). Interacts with PPFIA1, PPFIA2 and PPFIA3 (By similarity).
Cell surface receptor that binds to glycosaminoglycans, including chondroitin sulfate proteoglycans and heparan sulfate proteoglycans. 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 (By similarity). Functions as tyrosine phosphatase (PubMed:8068021). 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. Down-regulates TLR9-mediated activation of NF-kappa-B, as well as production of TNF, interferon alpha and interferon beta (By similarity).
Detected in brain neocortex (at protein level) (PubMed:22519304). Detected in heart, testis and liver (PubMed:8068021). Detected at lower levels in skeletal muscle, brain, spleen and kidney (PubMed:8068021).
Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. Required for canonical autophagy (macroautophagy), non-canonical autophagy as well as for mitophagy. 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. 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. 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. In addition to the protease activity, also mediates delipidation of ATG8 family proteins. Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. 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). 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. 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.
Forms reversible intrachain disulfide bonds in response to oxidative stress. Forms interchain disulfide bonds, leading to formation of homooligomers in response to oxidation.
Inhibited by N-ethylmaleimide. 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. The cysteine protease activity compounds is inhibited by styrylquinoline compounds 4-28 and LV-320.
Interacts with PFKP; promoting phosphorylation of ATG4B at Ser-34 (By similarity). 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. Phosphorylation at Ser-316 by ULK1 inhibits autophagy by decreasing both proteolytic activation and delipidation activities. Phosphorylation at Ser-316 is dephosphorylated by protein phosphatase 2A (PP2A). Phosphorylation at Ser-34 by AKT2 promotes its hydrolase activity, leading to increased proteolytic activation and delipidation of ATG8 family proteins. 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).
S-nitrosylation 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. Required for proteolytic activation and delipidation of ATG8 proteins.
Ubiquitinated by RNF5, leading to its degradation by the proteasome.
Catalyzes the transport of 2-oxoglutarate (alpha-oxoglutarate) across the inner mitochondrial membrane in an electroneutral exchange for malate (PubMed:5083502, PubMed:3355813, PubMed:7703504). Can also exchange 2-oxoglutarate for other dicarboxylic acids such as malonate, succinate, maleate and oxaloacetate, although with lower affinity (PubMed:3355813, PubMed:7703504). Contributes to several metabolic processes, including the malate-aspartate shuttle, the oxoglutarate/isocitrate shuttle, in gluconeogenesis from lactate, and in nitrogen metabolism (PubMed:5083502, PubMed:3355813). Maintains mitochondrial fusion and fission events, and the organization and morphology of cristae (By similarity). Involved in the regulation of apoptosis (PubMed:16291728). Helps protect from cytotoxic-induced apoptosis by modulating glutathione levels in mitochondria (PubMed:16291728).
Expressed in brain, heart, intestine, kidney, liver, skeletal muscle. Highest levels in heart, liver, kidney and intestine. Also expressed in flagella of epididymal sperm. Expressed in lung tissue and pulmonary artery smooth muscle (at protein level) (PubMed:32173312).
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. The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner. Regulates mitochondrial respiration activity playing a role in cellular aging. The prohibitin complex plays a role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (By similarity). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (By similarity).
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. Interacts with STAT3 to affect IL17 secretion in T-helper Th17 cells.
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. Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation.
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. Plays a role in adipose tissue and glucose homeostasis in a sex-specific manner (By similarity) (PubMed:1996099). Contributes to pulmonary vascular remodeling by accelerating proliferation of pulmonary arterial smooth muscle cells (PubMed:32173312).
The mitochondrial prohibitin complex consists of two subunits (PHB1 and PHB2), assembled into a membrane-associated ring-shaped supercomplex of approximately 1 mDa. Interacts with STOML2. Interacts with MAP1LC3B (membrane-bound form LC3-II); the interaction requires PHB2 and takes place upon Parkin-mediated mitochondrial damage. Interacts with STAT3 (unphosphorylated or phosphorylated at 'Ser-727'). Interacts with CLPB (By similarity). Interacts with CD86 (via cytoplasmic domain); the interactions increases after priming with CD40 (By similarity).
Throughout gestation, highly expressed in brown fat, heart, liver, developing renal tubules and neurons, and detected at lower levels in tissues such as lung and exocrine pancreas.
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).
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. Interacts with PTPRJ. Interacts with DSG1. Interacts with DSC1 and DSC2. Interacts with PKP2 (By similarity).
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 (By similarity).
Most abundant in liver, kidney, lung, and testis. Present in all tissues tested.
Oxidizes the CoA-esters of 2-methyl-branched fatty acids.
Expression oscillates in a diurnal and melatonin-dependent fashion in the preoptic area (POA) region in the hypothalamus, with maximal expression attained during the dark phase of the light/dark cycle.
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.
Detected in brain where it is abundant in lamina V of the cerebral cortex. Also expressed within the hippocampus, mainly in pyramidal neurons in CA1 and CA3. Weakly expressed in the striatum and more robustly in amygdala and several thalamic nuclei. Also detected in several mesopontine nuclei (at protein level).
Expression increases gradually from 18 dpc through adulthood.
GTPase tethering membranes through formation of trans-homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis. May also regulate Golgi biogenesis. May regulate axonal development.
Monomer as apoprotein and in the GDP-bound form. Homodimer in the GTP-bound form. Homooligomer. Interacts (via N-terminal region) with MAP4K4 (via CNH regulatory domain). Interacts with SPAST; interaction is direct (By similarity). Interacts with REEP5, RTN3 and RTN4 (via the transmembrane region) (PubMed:19665976). Interacts with REEP1 (By similarity). Interacts with CPT1C (By similarity). Interacts with ARL6IP1 (PubMed:24262037). Interacts with ZFYVE27 (By similarity).
Belongs to the eIF-2B alpha/beta/delta subunits family.
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 bur is strongly enhanced in the presence of autoubiquitinated BRCA1 (By similarity).
The UBA domain specifically recognizes and binds 'Lys-6'-linked polyubiquitin chains.
Ubiquitin-binding protein that interacts with the BRCA1-BARD1 heterodimer, and regulates its activity. Specifically binds 'Lys-6'-linked polyubiquitin chains. Interaction with autoubiquitinated BRCA1, leads to inhibit the E3 ubiquitin-protein ligase activity of the BRCA1-BARD1 heterodimer. 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 (By similarity).
Acetylation at Lys-93 may increase chaperone activity.
Contributes to the transparency and refractive index of the lens (By similarity). Acts as a chaperone, preventing aggregation of various proteins under a wide range of stress conditions (PubMed:12118077). Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA (By similarity).
Heteropolymer composed of three CRYAA and one CRYAB subunits. Inter-subunit bridging via zinc ions enhances stability, which is crucial as there is no protein turn over in the lens. Can also form homodimers and homotetramers (dimers of dimers) which serve as the building blocks of homooligomers (By similarity). Within homooligomers, the zinc-binding motif is created from residues of 3 different molecules. His-123 and Glu-125 from one molecule are ligands of the zinc ion, and His-130 and His-177 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 (By similarity).
Highly expressed in eye lens. Also expressed in non-lenticular tissues such as brain, spleen, liver, lung, skin, small intestine and a several epithelial and fibroblast cell lines with highest levels in spleen.
Lenses of streptozotocin-induced diabetic rats show increased levels of C-terminal truncated forms.
May contribute to the transparency and refractive index of the lens. Has chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions.
Undergoes age-dependent proteolytical cleavage at the C-terminus. Cleavage by m-calpain produces specifically alpha-crystallin A(1-162), cleavage by Capn3/Lp82 produces specifically alpha-crystallin A(1-168) which is the major truncated form during normal maturation and induced cataract formation.
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 (By similarity).
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.
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.
N-glycosylated. Some N-linked glycan are of the complex-type.
Protein of the plasma which is primarily expressed by liver.
The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.
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.
Abundant levels detected in the brain (PubMed:18539757). High expression in the heart (at protein level) (PubMed:18539757). No detectable expression in other peripheral tissues (PubMed:18539757).
Orphan G-protein coupled receptor. Seems to act through a G(i)/G(o) mediated pathway (By similarity). May be involved in ciliogenesis (By similarity).
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane 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. Interacts with RIC3; which is required for proper folding and assembly. Interacts with LYPD6. The heteropentamer alpha3-beta-2 interacts with alpha-conotoxins BuIA, MII, ImI, ImII, PnIA and GID (PubMed:15609996, PubMed:15929983, PubMed:16964981). The heteropentamer alpha-4-beta-2 interacts with the alpha-conotoxins PnIA, GID and MII (PubMed:15929983).
Belongs to the Mrp/NBP35 ATP-binding proteins family. NUBP2/CFD1 subfamily.
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. Interacts with KIFC1. Interacts with NUBP1.
Belongs to the arginase family. Agmatinase subfamily.
May have little or no activity due to the lack of several residues essential for manganese binding and catalytic activity.
Acetylation by KAT5 at Lys-134 is increased during mitosis, impairs RANGRF binding and enhances RCC1 binding. Acetylation at Lys-37 enhances the association with nuclear export components. Deacetylation of Lys-37 by SIRT7 regulates the nuclear export of NF-kappa-B subunit RELA/p65.
Belongs to the small GTPase superfamily. Ran family.
GTPase involved in nucleocytoplasmic transport, participating both to the import and the export from the nucleus of proteins and RNAs. Switches between a cytoplasmic GDP- and a nuclear GTP-bound state by nucleotide exchange and GTP hydrolysis. 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. 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. RAN (GTP-bound form) triggers microtubule assembly at mitotic chromosomes and is required for normal mitotic spindle assembly and chromosome segregation. Required for normal progress through mitosis. 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. Acts as a negative regulator of the kinase activity of VRK1 and VRK2. Enhances AR-mediated transactivation.
Mg(2+) interacts primarily with the phosphate groups of the bound guanine nucleotide.
Monomer. Interacts with RANGAP1, which promotes RAN-mediated GTP hydrolysis. Interacts with KPNB1. Interaction with KPNB1 inhibits RANGAP1-mediated stimulation of GTPase activity. Interacts with RCC1 which promotes the exchange of RAN-bound GDP by GTP. Interaction with KPNB1 inhibits RCC1-mediated exchange of RAN-bound GDP by GTP. Interacts (GTP-bound form) with TNPO1; the interaction is direct. Interacts (GTP-bound form) with TNPO3; the interaction is direct. Interacts with KPNB1 and with TNPO1; both inhibit RAN GTPase activity. Interacts (via C-terminus) with RANBP1, which alleviates the inhibition of RAN GTPase activity. Interacts with RANGRF, which promotes the release of bound guanine nucleotide. RANGRF and RCC1 compete for an overlapping binding site on RAN. Identified in a complex with KPNA2 and CSE1L; interaction with RANBP1 mediates dissociation of RAN from this complex. Interaction with both RANBP1 and KPNA2 promotes dissociation of the complex between RAN and KPNB1. Identified in a complex composed of RAN, RANGAP1 and RANBP1. Identified in a complex that contains TNPO1, RAN and RANBP1. Identified in a nuclear export complex with XPO1. Found in a nuclear export complex with RANBP3 and XPO1. Interacts with RANBP2/NUP358. 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. Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1 (By similarity). 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. Interacts with RANBP9 and RANBP10. Interacts in its GTP-bound form with BIRC5/survivin at S and M phases of the cell cycle. Interacts with TERT; the interaction requires hydrogen peroxide-mediated phosphorylation of TERT and transports TERT to the nucleus. Interacts with MAD2L2. Interacts with VRK1 and VRK3. Interacts with VRK2 (By similarity). Interacts with NEMP1 and KPNB1 (By similarity). Interacts (GDP-bound form) with NUTF2; regulates RAN nuclear import. Interacts with CAPG; mediates CAPG nuclear import. Interacts with NUP153. Interacts with the AR N-terminal poly-Gln region; the interaction with AR is inversely correlated with the poly-Gln length (By similarity). Interacts with MYCBP2, which promotes RAN-mediated GTP hydrolysis (By similarity). Interacts with EPG5 (By similarity).
Homodimer or heterodimer (Potential). But, in contrast to other members of this family, cannot be disulfide-linked.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. UDP-glucuronic acid decarboxylase subfamily.
Catalyzes the NAD-dependent decarboxylation of UDP-glucuronic acid to UDP-xylose (PubMed:11877387). Necessary for the biosynthesis of the core tetrasaccharide in glycosaminoglycan biosynthesis (PubMed:11877387).
Homodimer and homotetramer (By similarity). Interacts with AKT1 (PubMed:11877387).
Ubiquitous. Detected in heart, brain, spleen, lung, testis, liver, skeletal muscle and kidney.
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 nucleolin/NCL. 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 (By similarity). Isoform 1 and isoform 2 interact with RNF20 (By similarity). Isoform 2 interacts with HUWE1 (By similarity). Interacts with AKT1. Interacts with DNAJC21 (By similarity).
Isoform 2 is polyubiquitinated, leading to proteasomal degradation and phosphorylation by PKC/PRKCD enhances polyubiquitination.
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). Together with PTBP1 is required for the translation initiation on the foot-and-mouth disease virus (FMDV) IRES (By similarity). Regulates cell proliferation, differentiation, and survival. Isoform 1 suppresses apoptosis whereas isoform 2 promotes cell differentiation.
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.
Seems to have a role in zinc absorption and may function as an intracellular zinc transport protein.
The concentration in intestinal tissues undergoes an abrupt increase during the animal's transition from suckling to weaning.
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 (PubMed:18783430). The OGDHC complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2) while reducing NAD(+) to NADH (PubMed:18783430). The OGDHC complex is mainly active in the mitochondrion (PubMed:18783430). Involved in the inhibition of cell proliferation and in apoptosis (By similarity).
Belongs to the alpha-ketoglutarate dehydrogenase family.
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) (Probable). 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 (Probable).
The OGDHL-containing OGDHC complex is present in the brain, but not in the heart.
Acts as a neurotrophic factor in postnatal mature neurons enhancing neuronal survival (PubMed:31536960). Promotes cell proliferation and neurogenesis in undifferentiated neural progenitor cells at the embryonic stage and inhibits differentiation of astrocytes (By similarity). Its neurotrophic activity is exerted via MAPK1/ERK2, MAPK3/ERK1 and AKT1/AKT pathways (By similarity). Neurotrophic activity is enhanced by binding to heme (By similarity). Acts also as an anorexigenic neurotrophic factor that contributes to energy balance (By similarity).
The cytochrome b5 heme-binding domain was proven to bind heme, although it lacks the conserved iron-binding His residue at position 81.
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. Specifically cleaves N-terminal signal peptides that contain a hydrophobic alpha-helix (h-region) shorter than 18-20 amino acids.
Component of the signal peptidase complex paralog C (SPC-C) composed of a catalytic subunit SEC11C and three accessory subunits SPCS1, SPCS2 and SPCS3. Within the complex, interacts with SPCS2 and SPCS3. 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. This ensures the selectivity of the complex towards h-regions shorter than 18-20 amino acids.
May undergo processing at the N-terminus.
The C-terminal short (CTS) helix is essential for catalytic activity. 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.
Belongs to the G-protein coupled receptor 1 family. Endothelin receptor subfamily. EDNRB sub-subfamily.
Non-specific receptor for endothelin 1, 2, and 3. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Widely distributed in cell types of a variety of tissues.
Belongs to the complex I NDUFA2 subunit family.
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.
Belongs to the acetyltransferase family. NAA40 subfamily.
Interacts with alpha-tubulin. Interacts with SIRT2.
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.
Adenylyltransferase activity is specifically phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).
Associates with the cleavage and polyadenylation specificity factor (CPSF) complex. Interacts with CPSF1 and CPSF3; the interaction is direct. Interacts with PIP5K1A.
Belongs to the DNA polymerase type-B-like family.
Phosphorylated by CK1 in the proline-rich (Pro-rich) region.
Poly(A) polymerase that creates the 3'-poly(A) tail of specific pre-mRNAs. Localizes to nuclear speckles together with PIP5K1A and mediates polyadenylation of a select set of mRNAs, such as HMOX1. In addition to polyadenylation, it is also required for the 3'-end cleavage of pre-mRNAs: binds to the 3'UTR of targeted pre-mRNAs and promotes the recruitment and assembly of the CPSF complex on the 3'UTR of pre-mRNAs. In addition to adenylyltransferase activity, also has uridylyltransferase activity. However, the ATP ratio is higher than UTP in cells, suggesting that it functions primarily as a poly(A) polymerase. Acts as a specific terminal uridylyltransferase for U6 snRNA in vitro: responsible for a controlled elongation reaction that results in the restoration of the four 3'-terminal UMP-residues found in newly transcribed U6 snRNA. Not involved in replication-dependent histone mRNA degradation.
The RRM domain is required for terminal uridylyltransferase activity. Together with the zinc-finger domain, binds the 5'-area of U6 snRNA.
The proline-rich region is dispensable for terminal uridylyltransferase activity.
The zinc-finger domain is required for terminal uridylyltransferase activity. Together with the RRM domain, binds the 5'-area of U6 snRNA.
Expressed predominantly in the brain. Also detected, although at much lower levels, in the heart and the liver. Within the brain, expressed in the cerebral cortex, hippocampus, cerebellum and brainstem.
Interacts with CCP110 and CEP97. Interacts with ARMC9, TOGARAM1, CCDC66 and CSPP1.
Required for ciliogenesis and for structural integrity at the ciliary tip.
Heterodimer of a B chain and an A chain linked by two disulfide bonds.
Highly abundant expression is detected in neurons within the ventomedial dorsal tegmental nucleus and the laterally central gray alpha of the pons. Also detected at much lower levels within the hippocampus.
May play a role in neuropeptide signaling processes. Ligand for LGR7, relaxin-3 receptor-1 and relaxin-3 receptor-2 (By similarity).
Down-regulated in nerve growth factor-treated PC12 cells.
Expression is first detected at embryonic day 13.
Guanine nucleotide exchange factor (GEF) for RAP1A, RAP2A and MRAS/M-Ras-GTP. Its association with MRAS inhibits Rap1 activation (By similarity).
In the embryo, expressed in young neurons of the developing telencephalon, diencephalon and hindbrain. Not expressed in progenitor cells in the ventricular zone.
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. 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.
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. Contributes to the regulation of gene expression; functions as activator in the absence of oxidative stress. Down-regulates expression of target genes in response to oxidative stress. Overexpression protects cells against apoptosis in response to oxidative stress.
In response to oxidative stress, Cys-358 is reversibly oxidized to cysteine sulfenic acid. Oxidation of Cys-358 impairs formation of a ternary complex with TBP and DNA and down-regulates expression of target genes in response to oxidative stress.
Acetylated at Lys-218 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. In particular, AURKB-phosphorylated INCENP acts as an activator of AURKB. Positive feedback between HASPIN and AURKB contributes to CPC localization.
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. Associates with RACGAP1 during M phase. Interacts with CDCA1, EVI5, JTB, NDC80, PSMA3, SEPTIN1, SIRT2 and TACC1. Interacts with SPDYC; this interaction may be required for proper localization of active, Thr-235-phosphorylated AURKB form during prometaphase and metaphase. Interacts with p53/TP53. Interacts (via the middle kinase domain) with NOC2L (via the N- and C-terminus domains). Interacts with TTC28 (By similarity). Interacts with RNF2/RING1B (By similarity).
High level expression seen in the testis. It is also expressed in the spleen, lung and heart. Expressed in the G2/M phase of the cell cycle.
Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis (By similarity). 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 (By similarity). Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis (PubMed:9450992). Required for central/midzone spindle assembly and cleavage furrow formation (By similarity). 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 (By similarity). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP (By similarity). Phosphorylation of INCENP leads to increased AURKB activity (By similarity). 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 (By similarity). A positive feedback loop involving HASPIN and AURKB contributes to localization of CPC to centromeres (By similarity). 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) (By similarity). A positive feedback between HASPIN and AURKB contributes to CPC localization (By similarity). AURKB is also required for kinetochore localization of BUB1 and SGO1 (By similarity). Phosphorylation of p53/TP53 negatively regulates its transcriptional activity (By similarity). 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 (By similarity). Phosphorylates KRT5 during anaphase and telophase (By similarity).
The phosphorylation of Thr-235 requires the binding to INCENP and occurs by means of an autophosphorylation mechanism. Thr-235 phosphorylation is indispensable for the AURKB kinase activity.
Ubiquitinated by different BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complexes. Ubiquitinated by the BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex, ubiquitination leads to removal from mitotic chromosomes and is required for cytokinesis. 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. Ubiquitination of AURKB by BCR(KLHL21) E3 ubiquitin ligase complex may not lead to its degradation by the proteasome.
Component of a multimeric complex consisting of several cytoskeletal proteins, including actin, ezrin, alpha-actinin, gelsolin, and IQGAP1.
Detected in cochlea, in cochlear and vestibular hair cell bundles in the organ of Corti (at protein level).
Required for normal hearing. It is necessary for the formation of stereocilia in the inner ear and normal development of the organ of Corti. Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. May play a role in the regulation of transepithelial ion absorption and secretion. Is required for the development and/or maintenance of the proper glomerular endothelial cell and podocyte architecture. Plays a role in formation of the lens suture in the eye, which is important for normal optical properties of the lens.
Hardly reversible, non-competitive, and potent inhibitor of CPA1, CPA2 and CPA4. May play a role in inflammation (By similarity).
Interacts with INPP5D/SHIP1 (By similarity). Interacts with DOCK2 and EPOR. Interacts with phosphorylated CBLB and IRS4 (By similarity). Interacts with BCAR1/CAS and NEDD9/HEF1 (By similarity).
May mediate the transduction of intracellular signals.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar3-9 subfamily.
Divalent metal cations. Prefers Ca(2+) or Mg(2+).
Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs (PubMed:8428592, PubMed:15796714). Expressed by non-hematopoietic tissues and preferentially cleaves protein-free DNA (PubMed:15796714). Among other functions, seems to be involved in cell death by apoptosis (PubMed:8428592, PubMed:15796714). 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).
Belongs to the beta-microseminoprotein family.
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.
Highly expressed in heart, kidney, liver and spleen. Weakly expressed in lung and skeletal muscle.
Inhibited by zinc ions. Competitive inhibition of dGMP hydrolysis by GMP and 6-methylthio-GMP.
Up-regulated in response to c-Myc and by partial hepatectomy.
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.
Belongs to the universal ribosomal protein uL3 family.
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.
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 (By similarity). Interacts with SYNGAP1, CAMK2N2 and MPDZ (PubMed:9724800, 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 (PubMed:22579289). Interacts with CAMK2N1; this interaction requires CAMK2B activation by Ca(2+) (PubMed:11182241).
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:12873385, PubMed:15312654). 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. Participates in the modulation of skeletal muscle function in response to exercise (PubMed:17272343). 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 (PubMed:11972023). Phosphorylates reticulophagy regulator RETREG1 at 'Ser-134' under endoplasmic reticulum stress conditions which enhances RETREG1 oligomerization and its membrane scission and reticulophagy activity (By similarity).
The CAMK2 protein kinases contain a unique C-terminal subunit association domain responsible for oligomerization.
Belongs to the carotenoid oxygenase family.
Interacts with UBA5. Interacts with UFC1.
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. The so-called ufmylation, requires the UFM1-activating E1 enzyme UBA5, the UFM1-conjugating E2 enzyme UFC1, and the UFM1-ligase E3 enzyme UFL1. Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress. Ufmylation of TRIP4 regulates nuclear receptors-mediated transcription.
Choline-specific phosphodiesterase that hydrolyzes sphingomyelin (SM) releasing the ceramide and phosphocholine and therefore is involved in sphingomyelin digestion, ceramide formation, and fatty acid (FA) absorption in the gastrointestinal tract (PubMed:16255717, PubMed:15708357). Has also phospholipase C activity and can also cleave phosphocholine from palmitoyl lyso-phosphatidylcholine and platelet-activating factor (PAF) leading to its inactivation. Does not have nucleotide pyrophosphatase activity (PubMed:16255717). May promote cholesterol absorption by affecting the levels of sphingomyelin derived from either diet or endogenous sources, in the intestinal lumen (By similarity).
Detected in small intestine (at protein level) (PubMed:15205117). Highly expressed in the jejunum (PubMed:15708357).
N-glycosylated; required for activity and transport to the plasma membrane.
platelet-activating factor hydrolysis is inhibited by higher amount of sphingomyelin (PubMed:16255717). The hydrolysis of platelet-activating factor and sphingomyelin can be inhibited by the presence of sphingomyelin and platelet-activating factor respectively, the inhibition of platelet-activating factor hydrolysis by sphingomyelin being stronger (PubMed:16255717). PAF hydrolysis is dose-dependently increased by both taurocholate (TC) and taurodeoxycholate (TDC) (PubMed:16255717). Hydrolase activity against PAF is inhibited by EDTA and stimulated by 0.1-0.25 mM Zn2+ (PubMed:16255717).
May be involved in drug clearance in the placenta.
Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism.
Binds trophinin, tastin and cytokeratins.
Required for processing of 20S pre-rRNA precursor and biogenesis of 40S ribosomal subunits.
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 (By similarity). Has substantial activity toward aflatoxin B1-8,9-epoxide (By similarity).
Liver from adult female rats contains about 2-fold greater levels of YC1 than is found in liver from adult male rats.
Degraded along with the delivery of its substrates to autolysosomal compartments (at protein level).
Expressed in spleen and, to a lesser degree in the lung. Not expressed in thymus, testis, ovary, heart, brain, liver, kidney and muscle.
Homotrimer. Interacts (via the B box-type zinc finger) with PSTPIP1. 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 (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with NFKBIA and RELA. Interacts weakly with VASP and ACTR3. 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. Interacts with YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; the interaction is required for the down-regulation of pyrin pro-inflammatory activity (By similarity).
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, ATG16L1, 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 several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18-mediated inflammation. 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 (By similarity). 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. Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization (By similarity).
Lacks the B30.2/SPRY domain found in the human ortholog, thus may have divergent function(s).
The B box-type zinc finger interacts, possibly intramolecularly, with the pyrin domain; this may be an autoinhibitory mechanism released by PSTPIP1 binding.
Involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs.
Expressed at low levels throughout the embryo and is enriched in the developing brain and spinal cord.
Follitropin decreased expression while lutropin and prolactin stimulated expression.
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.
Ubiquitous and in the seminiferous tubules expressed in Sertoli cells but not in germ cells. Expression decreases in all tissues with increased age and is detectable only in brain cortex and lung.
Important for normal spermatogenesis and male fertility. Specifically required for progression to the post-meiotic stages of spermatocyte development. Seems to be necessary for normal expression levels of a number of testis-expressed gene transcripts, although its role in this process is unclear.
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 (By similarity).
Substrate-binding subunit of tRNA (adenine-N1-)-methyltransferase, which catalyzes the formation of N1-methyladenine at position 58 (m1A58) in initiator methionyl-tRNA.
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 (By similarity).
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).
Expressed in the left ventricle of embryonic heart and is postnatally up-regulated through to adulthood.
Predominantly expressed in heart and skeletal muscle, and expressed at lower levels in adrenal gland, brain, kidney, liver, and testis.
The actin-binding domain 1 (ABD1) is intrinsically disordered, and binds to F-actin with higher affinity than ABD2.
Up-regulated within 1 hour in the left ventricle following the application of pressure overload by aortic banding.
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.
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. Interacts with ACTG1.
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 ATG9A-containing vesicles, thereby enabling growth into autophagosomes.
Homotrimer; forms a homotrimer with a central pore that forms a path between the two membrane leaflets. Interacts (via cytoplasmic its C-terminus) with ATG2A. Interacts with SUPT20H. Interacts (via the tyrosine-based sorting signal motif) with AP4M1; promoting association with the AP-4 complex. Interacts with ARFIP1 and ARFIP2. Interacts with PI4K2A and PI4KB. Interacts with ATG4A; the interaction is direct and promotes ATG9A trafficking.
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. Also required to supply phosphatidylinositol 4-phosphate to the autophagosome initiation site by recruiting the phosphatidylinositol 4-kinase beta (PI4KB) in a process dependent on ARFIP2, but not ARFIP1 (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.
Homophilic cell adhesion molecule that promotes axonal growth. May play a role in nerve regeneration and in the formation and function of other tissues.
Autoubiquitinated. Autoubiquitination leads to proteasomal degradation and is necessary to control KLHL24 levels.
Forms homodimers. Interacts with GRIK2 (PubMed:17254796). Component of the BCR(KLHL24) E3 ubiquitin ligase complex, composed of CUL3, RBX1 and KLHL24. Interacts with CUL3. Interacts with KRT14 (By similarity).
In 3-week postnatal brain, prominent in the cortex and in the hippocampus. In the hippocampal formation, detectable in the CA1-CA3 pyramidal cells and in the granule cell layer of the dentate gyrus. In the cerebral cortex, expressed in all layers (I-VI) (at protein level). In 10 week old animals, tends to segregate in CA3 regions.
Necessary to maintain the balance between intermediate filament stability and degradation, a process that is essential for skin integrity (By similarity). As part of the BCR(KLHL24) E3 ubiquitin ligase complex, mediates ubiquitination of KRT14 and controls its levels during keratinocytes differentiation (By similarity). Specifically reduces kainate receptor-mediated currents in hippocampal neurons, most probably by modulating channel properties (PubMed:17254796).
Most abundant in lung, brain, intestine and kidney.
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.
Homooligomer and heterooligomer with other family members. Binds PAX5, LEF1, TCF7, TCF7L1 and TCF7L2. Interacts with ZNF703; TLE4 may mediate ZNF703 transcriptional repression. Interacts with SIX3 and SIX6. Interacts with PAX2 (By similarity).
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).
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. 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 (By similarity).
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 (By similarity). Interacts with VTA1 (By similarity).
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.
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.
Interacts with CPA1. Interacts with SERPINA1.
Belongs to the carnitine/choline acetyltransferase family.
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. Interacts with ATL1 (By similarity).
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 (By similarity). Interacts with TBC1D21 (By similarity).
Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.
May participate in trafficking events that are associated with myogenesis, such as myoblast fusion and/or GLUT4 trafficking.
Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies. The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner. In the complex, it mediates the microtubule-stimulated oligomerization. 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.
Component of the SKA1 complex, composed of SKA1, SKA2 and 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 with SKA1; the interaction is direct.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6.
Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (By similarity). The elongator complex catalyzes formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (By similarity). Involved in cell migration (By similarity).
The elongator complex was originally thought to play a role in transcription elongation. However, it is no longer thought to play a direct role in this process and its primary function is thought to be in tRNA modification.
F-actin-binding protein which plays a role in cross-linking actin to other cytoskeletal proteins and also binds to microtubules. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (By similarity). 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 (By similarity). May play role in delivery of transport vesicles containing GPI-linked proteins from the trans-Golgi network through its interaction with GOLGA4 (By similarity). 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).
Interacts with MAPRE1, CLASP1, CLASP2 and GOLGA4 (By similarity). Interacts with AXIN1 and LRP6 (PubMed:16815997). Found in a complex composed of MACF1, APC; AXIN1, CTNNB1 and GSK3B (PubMed:16815997). Interacts with CAMSAP3 (By similarity).
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.
'Chibby' is Japanese for 'small'; the gene was so named for the RNAi phenotype seen in flies.
Homodimer. Interacts with polycystin-2/PKD2 and GM130. Interacts with the C-terminal region of CTNNB1. Interacts (C-terminus) with TCIM (C-terminus), TCIM competes with CTNNB1 for the interaction with CBY1. Interacts with FAM92A; this interaction facilitates targeting of FAM92A to cilium basal body. Interacts with CIBAR2.
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.
Activates pre-mRNA splicing. May inhibit PP1 phosphatase activity (By similarity).
Interacts with PPP1CA, PPP1CB and PPP1CC. Interacts via the PGR motif with PQBP1 in the nucleus. Interacts with the WW domains of WBP4 (By similarity).
Activated by a monovalent cation that binds near, but not in, the active site. The most likely occupant of the site in vivo is potassium. Ion binding induces a conformational change that may alter substrate affinity.
Belongs to the carbohydrate kinase PfkB family. Ribokinase subfamily.
Belongs to the carbohydrate kinase pfkB family.
Catalyzes the phosphorylation of ribose at O-5 in a reaction requiring ATP and magnesium. The resulting D-ribose-5-phosphate can then be used either for sythesis of nucleotides, histidine, and tryptophan, or as a component of the pentose phosphate pathway.
Requires a divalent cation, most likely magnesium in vivo, as an electrophilic catalyst to aid phosphoryl group transfer. It is the chelate of the metal and the nucleotide that is the actual substrate.
Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man(9)GlcNAc(2) to produce Man(8)GlcNAc(2), but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man(5-6)GlcNAc(2) (By similarity).
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 (By similarity).
The transmembrane domain is necessary for interaction with KCNMA1.
Both, HMG box 1 and HMG box 2, show antimicrobial activity.
Interacts with POU2F2, POU2F1 and POU3F1. Component of the RAG complex composed of core components RAG1 and RAG2, and associated component HMGB1 or HMGB2. Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Directly interacts with SET. Interacts with LEF1.
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 (By similarity). 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. 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). Proposed to be involved in the innate immune response to nucleic acids by acting as a cytoplasmic promiscuous immunogenic DNA/RNA sensor which cooperates with subsequent discriminative sensing by specific pattern recognition receptors. In the extracellular compartment acts as a chemokine. Promotes proliferation and migration of endothelial cells implicating AGER/RAGE. Has antimicrobial activity in gastrointestinal epithelial tissues. Involved in inflammatory response to antigenic stimulus coupled with pro-inflammatory activity. May play a role in germ cell differentiation. Involved in modulation of neurogenesis probably by regulation of neural stem proliferation. 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).
Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1. Interacts directly with SKP1 and CUL1 (By similarity). Interacts (via C-terminus) with actin (via N-terminus) (By similarity).
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.
Expression is low at birth. Increases to adult levels after 5 weeks.
Highest expression in liver. Also expressed in heart, kidney and muscle.
On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2. Phosphorylation on either (or all of) Tyr-534, Tyr-566 and/or Tyr-627 is required for STAT5 activation. Phosphorylation on Tyr-333 would seem necessary for JAK2 activation.
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.
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, and activates the JAK2/STAT5 pathway.
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 ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.
Acts as a transcriptional regulator in adaptive response to low oxygen tension. Attenuates the ability of transcription factor HIF1A, EPAS1 and the HIF1A-ARNT complex to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis. May act as a tumor suppressor.
Expressed in the perivenous zone of the liver (PubMed:11237857). Expressed in all tissues examined during normoxia (PubMed:12824304). Expressed in brain and lung. Expressed in periportal and perivenous hepatocytes and in endothelial cells of the central vein (at protein level) (PubMed:11237857). Expressed in the perivenous zone of the liver (PubMed:11237857). Highest expression seen in the cerebral cortex, hippocampus, and lung. Low expression in myocardial tissue and liver (PubMed:12824304).
In normoxia, hydroxylated on Pro-487 in the oxygen-dependent degradation domain (ODD) by PHD. The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation.
Interacts with ARNT, BAD, BCL2L2, EPAS1, HIF1A, MCL1 and VHL.
Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.
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.
Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.
Phosphorylated at Ser-65 by PINK1 during mitophagy (PubMed:29475881). Phosphorylated ubiquitin specifically binds and activates parkin (PRKN), triggering mitophagy (By similarity). Phosphorylation does not affect E1-mediated E2 charging of ubiquitin but affects discharging of E2 enzymes to form polyubiquitin chains (By similarity). It also affects deubiquitination by deubiquitinase enzymes such as USP30 (By similarity).
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. Component of the probable ECS(LRRC41) complex with the substrate recognition component LRRC41. Component of the probable ECS(SOCS1) complex with the substrate recognition component SOCS1. Component of the probable ECS(WSB1) complex with the substrate recognition subunit WSB1. Component of the probable ECS(SOCS3) complex with the substrate recognition component SOCS3. Component of the probable ECS(SPSB1) complex with the substrate recognition component SPSB1. Component of the probable ECS(SPSB2) complex with the substrate recognition component SPSB2. Component of the probable ECS(SPSB4) complex with the substrate recognition component SPSB4. Component of the probable ECS(RAB40C) complex with the substrate recognition subunit RAB40C. Component of the probable ECS(KLHDC1) complex with the substrate recognition component KLHDC1. May also form complexes containing CUL5, elongin BC complex (ELOB and ELOC), RBX1 and ELOA. May also form complexes containing CUL5, Elongin BC (ELOB and ELOC), RBX1 and VHL. Interacts with RNF7/RBX2, LRRC41, SOCS3, SPSB1, SPSB2, SPSB4 and RAB40C. Interacts with ASB1, ASB2, ASB6, ASB7 and ASB12. Interacts (when neddylated) with ARIH2; leading to activate the E3 ligase activity of ARIH1. Interacts with NOS2 in the presence of SPSB1 or SPSB2 or SPSB4. Interacts with ERCC6; the interaction is induced by DNA damaging agents or inhibitors of RNA polymerase II elongation. Interacts with ELOA (via BC-box). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation.
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. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. ECS(SOCS1) seems to direct ubiquitination of JAK2. 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. As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A. May form a cell surface vasopressin receptor.
Neddylated; which enhances the ubiquitination activity of SCF and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN).
Expressed in the liver, brain, kidney, choroid plexus and weakly in the eye (PubMed:10224140, PubMed:11961115, PubMed:11861777). Moderately expressed (at protein level) in the brain capillary endothelial cells (BCEC) (PubMed:12684544).
Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:12660303, PubMed:12488248). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:12660303, PubMed:12488248). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:10224140, PubMed:11961115, PubMed:12684544). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule. May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (By similarity). 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 (By similarity). 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) (PubMed:11861777, PubMed:12660303, PubMed:15846470). May contribute to the release of cortisol in the adrenals (By similarity). 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 (PubMed:11961115, PubMed:15319347, PubMed:15389674). Regulates the CSF concentration of histamine H(2)-receptor antagonists cimetidine and ranitidine at the CP (PubMed:15319347). 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 uptake from brain of organic anions, such as E1S, PAH, and OTA (PubMed:10224140, PubMed:11961115). 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) (PubMed:11961115, PubMed:12684544, PubMed:15292460). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (PubMed:15292460).
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.
Detected in kidney, choroid plexus, testis, lung, stomach, large and small intestine, spleen, fat and parotid gland (PubMed:21778275,PubMed:34075817). In eye, expressed in cornea, ciliary epithelium, lens epithelium and lens fiber (PubMed:21778275).
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.
Homozygous knockout rats are born to expected Mendelian ratios and no obvious ocular phenotype is observed.
Interacts with isoform 2 of BSG; this interaction is required for its localization to the plasma membrane.
Belongs to the eukaryotic ribosomal protein eL14 family.
By DNA damage, glucocorticoid treatment, growth factor deprivation and p53.
Essential mediator of p53/TP53-dependent and p53/TP53-independent apoptosis. Promotes partial unfolding of BCL2L1 and dissociation of BCL2L1 from p53/TP53, releasing the bound p53/TP53 to induce apoptosis. Regulates ER stress-induced neuronal apoptosis.
Interacts with MCL1 and BCL2A1 (By similarity). Interacts (via BH3 domain) with BCL2 and BCL2L1/BCL-XL (By similarity). Interacts (via BH3 domain) with NOL3/ARC (via CARD domain); this interaction prevents BBC3 association with BCL2 and results in CASP8 activation (PubMed:17998337).
The BH3 motif is intrinsically disordered in the absence of a binding partner but folds upon binding (By similarity). Folds when bound to BCL2L1 (By similarity). Also folds when bound to MCL1 (By similarity).
Plays a role in U6 snRNP assembly and function. Binds to the 3' end of U6 snRNA.
Abundant and ubiquitous expression in neurons.
At 9 dpc expressed in extraembryonic mesodermal layers with its prospective blood islands. Expressed in blood islands at day 12 dpc. Expressed by the intraembryonic primary ectoderm including the primitive streak at day 9 dpc. Expressed in the fetal liver and in circulating cells at 17 dpc, the liver expression disappear around birth (at protein level).
Expressed by bone marrow cells and osteoblasts. Also expressed by ameloblasts in tooth enamel (at protein level). Expressed in enamel organ, ameloblasts, spleen, bone marrow cells and osteoblasts.
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) (By similarity).
AP-1 family transcription factor that controls the differentiation of lineage-specific cells in the immune system: specifically mediates the differentiation of T-helper 17 cells (Th17), follicular T-helper cells (TfH), CD8(+) dendritic cells and class-switch recombination (CSR) in B-cells. Acts via the formation of a heterodimer with JUNB that recognizes and binds DNA sequence 5'-TGA[CG]TCA-3'. The BATF-JUNB heterodimer also forms a complex with IRF4 (or IRF8) in immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-3'), an immune-specific regulatory element, followed by cooperative binding of BATF and IRF4 (or IRF8) and activation of genes. Controls differentiation of T-helper cells producing interleukin-17 (Th17 cells) by binding to Th17-associated gene promoters: regulates expression of the transcription factor RORC itself and RORC target genes such as IL17 (IL17A or IL17B). Also involved in differentiation of follicular T-helper cells (TfH) by directing expression of BCL6 and MAF. In B-cells, involved in class-switch recombination (CSR) by controlling the expression of both AICDA and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (I(H)-C(H)). Following infection, can participate in CD8(+) dendritic cell differentiation via interaction with IRF4 and IRF8 to mediate cooperative gene activation. Regulates effector CD8(+) T-cell differentiation by regulating expression of SIRT1. Following DNA damage, part of a differentiation checkpoint that limits self-renewal of hematopoietic stem cells (HSCs): up-regulated by STAT3, leading to differentiation of HSCs, thereby restricting self-renewal of HSCs (By similarity).
Heterodimer; mainly heterodimerizes with JUNB. The BATF-JUNB heterodimer interacts with IRF4 and IRF8. Interacts (via bZIP domain) with IRF4 and IRF8; the interaction is direct. Also forms heterodimers with JUN and JUND. Interacts with IFI35 (By similarity).
Phosphorylated on serine and threonine residues and at least one tyrosine residue. Phosphorylation at Ser-43 inhibit DNA binding activity and transforms it as a negative regulator of AP-1 mediated transcription (By similarity).
Belongs to the Mediator complex subunit 12 family.
Belongs to the complex I 20 kDa subunit family.
May form part of a complex of membrane proteins attached to acetylcholinesterase (AChE).
First detected at day 25 postpartum, the expression increases until day 35 and remains identical till adulthood.
May interact with ACTB and the syntaxin STX1A and/or STX1B.
Specifically expressed in testis by haploid germ cells.
Detected in brain cortex GABAergic neurons, in striatum and substantia nigra, and in the Purkinje cell layer in the cerebellum and hippocampus (at protein level) (PubMed:16819986). Expressed at high levels in brain and lung and lower levels in testis, heart, and spleen (PubMed:9168931).
Interacts with GNAI1, GNAI2 and GNAI3; the interactions are GDP-dependent.
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.
The active site cysteine and glutamate residues are not conserved in this protein. Its activity is therefore unsure.
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM8 sub-subfamily.
Expressed in dorsal root and trigeminal ganglia. Specifically expressed in a subset of sensory neurons, including cold-sensitive neurons in trigeminal neurons.
Interacts (via N-terminus and C-terminus domains) with TCAF1; the interaction stimulates TRPM8 channel activity. Interacts (via N-terminus and C-terminus domains) with TCAF2; the interaction inhibits TRPM8 channel activity (By similarity). Homotetramer.
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 agonists 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.
The coiled coil region is required for multimerization.
Autophosphorylates upon activation by EFNA5. Phosphorylation on Tyr-603 mediates interaction with NCK1. Dephosphorylated by PTPN1 (By similarity).
Down-regulated by IL1-beta in neonatal cardiac myocytes.
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 (phosphorylated) with PTPN1; dephosphorylates EPHA3 and may regulate its trafficking and function. Interacts (phosphorylated) with CRK; mediates EFNA5-EPHA3 signaling through RHOA GTPase activation. Interacts with NCK1 (via SH2 domain); mediates EFNA5-EPHA3 signaling (By similarity).
Most abundant in the heart, brain and lung.
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 (By similarity).
Expressed in spinal cord and brain at 19 dpc through adulthood.
Has been shown to act as a sodium/bicarbonate cotransporter in exchange for intracellular chloride (PubMed:10993873, PubMed:20566632). 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 (By similarity).
In the brain, detected in cerebral cortex, subcortex, cerebellum, hippocampus and medulla (at protein level) (PubMed:18061361). Expressed in neurons but not in astrocytes (at protein level) (PubMed:18061361). Isoforms starting with Met-Glu-Ile-Lys are found predominantly in the brain with lower levels in the eye while isoforms starting with Met-Cys-Asp-Leu are most abundant in the kidney with lower levels in the duodenum, jejunum and ileum (at protein level) (PubMed:23409100). In the kidney, isoforms starting with Met-Cys-Asp-Leu are primarily expressed in the cortex, the outer stripe of the outer medulla and the inner stripe of the outer medulla (ISOM) but are not detectable in the inner medulla (IM) while isoforms starting with Met-Glu-Ile-Lys are predominantly expressed in the ISOM and IM (PubMed:28280139). Expressed in the brain, in the hippocampus as well as in dentate gyrus, cortical layers, cerebellum, olfactory bulb and in the epithelial cells of the choroid plexus. Detected in pituitary, testis, kidney and ileum. Detected also in spleen and lung.
Mainly expressed in the jejenum (at protein level).
Sodium/bicarbonate cotransporter which mediates cotransport of sodium and bicarbonate in association with an efflux of intracellular chloride and is involved in NaCl absorption in the small intestine.
Sodium/bicarbonate cotransporter which plays an important role in regulating intracellular pH (PubMed:20566632, PubMed:23409100). Has been shown to act as a sodium/bicarbonate cotransporter in exchange for intracellular chloride (PubMed:10993873, PubMed:20566632). 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 (By similarity). 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 (PubMed:28280139).
The N-terminal cytoplasmic domain is likely to have a high level of intrinsic disorder.
EF-1 is composed of four subunits: alpha, beta, delta, and gamma.
Probably plays a role in anchoring the complex to other cellular components.
Component of a progesterone-binding protein complex. Binds progesterone. Has many reported cellular functions (heme homeostasis, interaction with CYPs). Required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan. Intracellular heme chaperone. Regulates heme synthesis via interactions with FECH and acts as a heme donor for at least some hemoproteins (By similarity). May be implicated in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) immunotoxicity (PubMed:9006096).
Expressed at high levels in lung, liver, kidney and brain, low in testis and spleen. Not expressed in heart and skeletal muscle.
Homodimer. Forms stable homodimer through hydrophobic heme-heme stacking interactions. Interacts with FECH; the interaction results in decreased FECH activity (By similarity). Interacts with EGFR, CYP1A1 and CYP3A4; the interactions require PGRMC1 homodimerization (By similarity).
The cytochrome b5 heme-binding domain lacks the conserved iron-binding His residues at positions 107 and 131.
Homooligomer; may form higher order homooligomers in the dimer to octamer range. Part of the core SMN complex that contains SMN1, GEMIN2/SIP1, DDX20/GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8 and STRAP/UNRIP. 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. Component of an import snRNP complex composed of KPNB1, RNUT1, SMN1 and ZNF259. Interacts with DDX20, FBL, NOLA1, RNUT1 and with several spliceosomal snRNP core Sm proteins, including SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE and ILF3. Interacts with GEMIN2; the interaction is direct. Interacts with GEMIN3; the interaction is direct. Interacts with GEMIN8; the interaction is direct. Interacts with SNRPB; the interaction is direct. Interacts (via Tudor domain) with SNRPD1 (via C-terminus); the interaction is direct. Interacts with SNRPD2; the interaction is direct. Interacts (via Tudor domain) with SNRPD3 (via C-terminus); the interaction is direct. Interacts with SNRPE; the interaction is direct. Interacts with OSTF1, LSM10, LSM11 and RPP20/POP7. Interacts (via C-terminal region) with ZPR1 (via C-terminal region). Interacts (via Tudor domain) with COIL. Interacts with SETX; recruits SETX to POLR2A. Interacts with POLR2A (via the C-terminal domain (CTD)). Interacts with PRMT5. Interacts with XRN2. Interacts (via C-terminus) with FMR1 (via C-terminus); the interaction is direct and occurs in a RNA-independent manner. Interacts with SYNCRIP. Interacts (via Tudor domain) with SF3B2 (methylated form) (By similarity). Interacts with WRAP53/TCAB1. Interacts (via Tudor domain) with ELAVL4 in an RNA-independent manner; the interaction is required for localization of ELAVL4 to RNA granules (PubMed:21389246). Interacts with FRG1 (By similarity).
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 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, SMN1 acts as a structural backbone and together with GEMIN2 it gathers the Sm complex subunits. Ensures the correct splicing of U12 intron-containing genes that may be important for normal motor and proprioceptive neurons development. 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. May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs).
Belongs to the AAA ATPase family. Katanin p60 subunit A1 subfamily. A-like 2 sub-subfamily.
Severs microtubules in vitro in an ATP-dependent manner. This activity may promote rapid reorganization of cellular microtubule arrays.
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 (By similarity).
Up-regulated in periinfarct ventricular myocardium.
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.
Detected in primitive ectoderm, mesoderm and ventral endoderm; down-regulated when organogenesis is completed.
Expressed in the central nervous system, in postmitotic cells of spinal cord, hindbrain, midbrain and forebrain. Expressed in epithelium during the development of non-neural tissues. Expressed in tooth development, specifically in mesenchymal cells differentiating into odontoblast in dental papilla, as well as in the developing eye and hair follicle.
Extensively O-glycosylated (By similarity). The carbohydrate structure may be regulated in a tissue-specific and developmental stage-specific manner.
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. 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).
Phosphatase that has high activity toward pyridoxal 5'-phosphate (PLP). Also active at much lower level toward pyrophosphate, phosphoethanolamine (PEA), phosphocholine (PCho), phospho-l-tyrosine, fructose-6-phosphate, p-nitrophenyl phosphate, and h-glycerophosphate.
May function as a calcium/proton transporter involved in calcium and in lysosomal pH homeostasis. Therefore, it may play an indirect role in protein glycosylation (By similarity).
Expressed in brain, including the cortex, hippocampus, cerebellum, and brainstem, as well as the spinal cord (at protein level).
Expression gradually increases from late embryonic (18 dpc) stage until adulthood.
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. 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 (By similarity). 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.
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.
Binds DNA as a homodimer. Can form a heterodimer with ESR1. Interacts with NCOA1, NCOA3, NCOA5 and NCOA6 coactivators, leading to a strong increase of transcription of target genes. Interacts with UBE1C and AKAP13. Interacts with DNTTIP2 (By similarity). Interacts with CCDC62 in the presence of estradiol/E2; this interaction seems to enhance the transcription of target genes. Interacts with PRMT2. Interacts with CCAR2 (via N-terminus) in a ligand-independent manner (By similarity). Interacts with DNAAF4. Interacts with RBM39, in the presence of estradiol (E2) (By similarity).
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
Expressed in prostate, ovary, lung, liver, kidney, fat, bone, brain, uterus and testis.
Lacks ligand binding affinity and suppresses ESR1/ER-alpha and ESR2 isoform 1/ER-beta1 mediated transcriptional activation and may act as a dominant negative regulator of estrogen action.
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner.
Phosphorylation at Ser-87 and Ser-105 recruits NCOA1.
Unable to bind DNA and activate transcription due to the truncation of the DNA binding domain.
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.
Belongs to the reduced folate carrier (RFC) transporter (TC 2.A.48) family.
High-affinity transporter for the intake of thiamine.
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. Interacts with POLN. Interacts with UHRF1 and UHRF2; these interactions promote FANCD2 activation.
Monoubiquitinated on Lys-561 during S phase and upon genotoxic stress by FANCL in complex with E2 ligases UBE2T or UBE2W. 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 (By similarity).
Phosphorylated on several sites including Ser-222 and Ser-1401 in response to genotoxic stress.
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 (By similarity). Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching (By similarity).
Identified in the spliceosome C complex.
Homooligomer and/or heterooligomer. Interacts (via A20-type domain) with IKBKG and RIPK1 and with TRAF6 (via AN1-type domain) (By similarity). 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.
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 (By similarity).
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).
NAD(H)-dependent dehydrogenase/reductase with a preference for cyclic substrates (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 (By similarity).
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.
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 (By similarity).
Belongs to the ERCC1/RAD10/SWI10 family.
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 (By similarity).
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. Activates transcription of specific genes in response to oxidative stress through interaction with NFE2L2.
Interacts with NFE2L2; involved in activation of the transcription (By similarity). May interact with PPARA (PubMed:12189208).
Expressed during embryogenesis and in adult reproductive tissue and skeletal muscle.
Highly expressed in placenta. Lower levels in testis, epididymis, ovary and skeletal muscle.
Transcription factor required for differentiation of embryonic stem cells (ESCs) into primordial germ cells.
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) and also to most of the 20 standard L-amino acids, but not to their D-enantiomers or other compounds. TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners. TAS1R3 is essential for the recognition and response to the disaccharide trehalose. Sequence differences within and between species can significantly influence the selectivity and specificity of taste responses (By similarity).
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 (By similarity). 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.
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 H2AZ1 forms a heterodimer with H2B. H2AZ1 interacts with INCENP. Interacts (via M6 cassette) with ANP32E; leading to removal of H2A.Z/H2AZ1 from the nucleosome. Interacts with VPS72 (via N-terminal domain); the interaction is enhanced by VPS72 phosphorylation which is promoted by ZNHIT1. Interacts with PWWP2A. Interacts with FH (when phosphorylated by PRKDC). Interacts with ZNHIT1; the interaction results in recruitment of H2AZ1 to the MYOG promoter region which is required for muscle-specific gene expression (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).
Positively regulates dimethylation of two adjacent adenosines in the loop of a conserved hairpin near the 3'-end of 18S rRNA.
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.
Interacts (via LRR repeats) with NTNG2. Interacts with DLG4. Found in a complex with NMDA receptors.
Mainly expressed in the brain. Expression is concentrated in the olfactory bulb, cortex, hippocampus and cerebellum in adult brain. Detected both embryonically and postnatally with stronger expression in postnatal stages.
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.
The last 4 C-terminal residues binds to the first 2 PDZ domains of DLG4.
Probable transcription factor involved in the control of specification of mesoderm and endoderm.
Interacts with ARRB2 (By similarity). Interacts with CHP1 and CHP2.
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).
Interacts with SERPINB1. Identified in a complex composed of ACTA1, COBL, GSN and TMSB4X (By similarity).
Originally found in thymus but it is widely distributed in many tissues.
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).
Seraspenide inhibits the entry of hematopoietic pluripotent stem cells into the S-phase.
Detected in liver and kidney (at protein level) (PubMed:19307449). Expressed in kidney and liver. Weakly expressed in lung. Does not seem to be expressed in brain, adipose tissue, or muscle.
Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds (PubMed:3739217, PubMed:7736906). Plays an important role in the metabolism of trimethylamine (TMA), via the production of trimethylamine N-oxide (TMAO) metabolite. TMA is generated by the action of gut microbiota using dietary precursors such as choline, choline containing compounds, betaine or L-carnitine. By regulating TMAO concentration, FMO3 directly impacts both platelet responsiveness and rate of thrombus formation.
Essential hepatic enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing compounds including drugs as well as dietary compounds. Plays an important role in the metabolism of trimethylamine (TMA), via the production of trimethylamine N-oxide (TMAO) metabolite. TMA is generated by the action of gut microbiota using dietary precursors such as choline, choline containing compounds, betaine or L-carnitine. By regulating TMAO concentration, FMO3 directly impacts both platelet responsiveness and rate of thrombus formation.
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 (By similarity).
Belongs to the complex I 23 kDa subunit family.
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 (By similarity).
Modulates cytoplasmic dynein binding to an organelle, and plays a role in prometaphase chromosome alignment and spindle organization during mitosis. Involved in anchoring microtubules to centrosomes. May play a role in synapse formation during brain development.
Subunit of dynactin, a multiprotein complex associated with dynein. Interacts with BICD2, CEP135, DYNAP, ECPAS and MAPRE1.
Interacts with ABL1, ENAH, STX1A, SNAP25, VAMP2, EPS8, SOS1, SOS2, GRB2, SPTA1, NCKAP1/NAP1, the first SH3 domain of NCK1 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. Component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 (NCKAP1l/HEM1 in hematopoietic cells) and WASF2/WAVE2. 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 (By similarity).
Low protein levels at birth that increase progressively at least until 14 days after birth.
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.
Widely expressed in brain, high levels detected in cortex, hippocampus and cerebellum (at protein level).
ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility. Seems to contact the pointed end of the daughter actin filament. 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. 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).
Belongs to the actin family. ARP2 subfamily.
Expression in increased by palmitate at protein level but not mRNA level (PubMed:21994399). Expression is down-regulated by microRNA miR-137 and miR-181c (at protein level) (PubMed:21994399).
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. Interacts with ORMDL3 (By similarity). Interacts with RTN4 (isoform B) (By similarity).
Phosphorylation at Tyr-164 inhibits activity and promotes cell survival.
Serine palmitoyltransferase (SPT). The heterodimer formed with SPTLC2 or SPTLC3 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-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA. The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference (By similarity). Required for adipocyte cell viability and metabolic homeostasis (By similarity).
Belongs to the PPP phosphatase family. PP-6 (PP-V) subfamily.
Catalytic subunit of protein phosphatase 6 (PP6). PP6 is a component of a signaling pathway regulating cell cycle progression in response to IL2 receptor stimulation. N-terminal domain restricts G1 to S phase progression in cancer cells, in part through control of cyclin D1. During mitosis, regulates spindle positioning. Down-regulates MAP3K7 kinase activation of the IL1 signaling pathway by dephosphorylation of MAP3K7. Participates also in the innate immune defense against viruses by desphosphorylating RIGI, an essential step that triggers RIG-I-mediated signaling activation.
Highest levels found in spleen, brain and lung.
Protein phosphatase 6 (PP6) holoenzyme is proposed to be a heterotrimeric complex formed by the catalytic subunit, a SAPS domain-containing subunit (PP6R) and an ankyrin repeat-domain containing regulatory subunit (ARS). Interacts with subunits PPP6R1, PPP6R2 and PPP6R3. Interacts with subunit ANKRD28. Interacts with IGBP1. Interacts with MAP3K7. Interacts with NFKBIE. Interacts with TRIM14 and WRNIP1; these interactions positively regulate the RIG-I signaling pathway.
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.
Glomerular epithelium cell (podocyte). Expressed in cerebrum, cerebellum and hippocampus (at protein level). Expressed in the small intestine, lung, kidney and ovaries.
Has three main structural domains: an N-terminal FERM domain, a central alpha-helical domain and a C-terminal actin-binding domain.
Interacts with PODXL and SLC9A3R2. Found in a complex with EZR, PODXL and SLC9A3R2 (PubMed:11457882). Interacts with PALS1. Interacts with MCC, PLEKHG6, SCYL3/PACE1, SLC9A3R1 and TMEM8B. Interacts (when phosphorylated) with FES/FPS. Interacts with dimeric S100P, the interaction may be activating through unmasking of F-actin binding sites. Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin. Detected in a complex composed of at least EZR, AHNAK, PPL and PRX. Interacts with PDPN (via cytoplasmic domain); activates RHOA and promotes epithelial-mesenchymal transition. Interacts with SPN/CD43 cytoplasmic tail, CD44 and ICAM2 (By similarity).
Levels increase in the fetal gut epithelium between day 15 and day 20 of gestation and during the first week after birth.
Phosphorylated by tyrosine-protein kinases. Phosphorylation by ROCK2 suppresses the head-to-tail association of the N-terminal and C-terminal halves resulting in an opened conformation which is capable of actin and membrane-binding (By similarity).
Probably involved in connections of major cytoskeletal structures to the plasma membrane. In epithelial cells, required for the formation of microvilli and membrane ruffles on the apical pole. Along with PLEKHG6, required for normal macropinocytosis (By similarity).
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.
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) (By similarity).
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 (By similarity). Interacts with BUB1B (By similarity). The phosphorylated form interacts with APC/C (By similarity). Interacts with NINL (By similarity). May interact with MAD2L2 (By similarity). Interacts with CDK5RAP2 (By similarity). Interacts with SIRT2 (By similarity). Interacts with isoform 1 of NEK2 (By similarity). 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 (By similarity). Interacts (via the N-terminal substrate-binding domain) with FBXO5 (By similarity). Interacts with CCNF (By similarity).
Phosphorylated during mitosis (By similarity). Phosphorylated by BUB1 at Ser-41; Ser-72; Ser-92; Ser-153; Thr-157 and Ser-161 (By similarity). Phosphorylated by NEK2 (By similarity).
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 (By similarity). Interacts with NEK2 (By similarity).
Ubiquitinated and degraded by the proteasome during spindle assembly checkpoint. 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 (By similarity).
A cytochrome P450 monooxygenase involved in the metabolism of the pro-inflammatory lipid mediator leukotriene B4 (LTB4). Hydroxylates at the omega-1 and omega-2 positions LTB4. This oxidation step leads to LTB4 inactivation, which is postulated to be a crucial part of the resolution of inflammation. 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 developing brain and developing neurons.
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 (By similarity). Involved in the negative regulation of neurite outgrowth (PubMed:27866705).
In the brain, expression is high at embryonic day 18 and continually decreases through to postnatal day 60.
Expressed at highest levels in lung. Also detected in testis and heart. Very low expression, if any, in brain, liver, spleen, kidney and skeletal muscle.
Homotetramer; forms a two-fold symmetric tetramer in solution. Interacts with CUL3; interaction is direct and forms a 5:5 heterodecamer (By similarity). 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 (PubMed:15982757). Interacts with PCNA (By similarity).
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).
Component of the 60S subunit of the ribosome. Ribosomal protein L40 is essential for translation of a subset of cellular transcripts, and especially for cap-dependent translation of vesicular stomatitis virus mRNAs.
Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).
Expressed in females at day 35 with higher levels detected at day 56. Not detected in males of any age.
Isoform 1 is expressed in normal liver. Isoform 2 is expressed in the regenerating liver after partial hepatectomy and at very low levels in the normal lung, brain and testis.
Up-regulated by continuous exposure to growth hormone.
Involved in the modulation of neuronal aggregation (By similarity). May be involved in developmental events during the formation of the central nervous system (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:5871820). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:5871820).
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.
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 for the enzyme. MAP2K4 then phosphorylates Tyr-223 resulting in a further increase in Vmax. Inhibited by dual specificity phosphatases, such as DUSP1. Inhibited by HDAC9 (By similarity).
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 (By similarity).
Interacts with MAPK8IP1/JIP-1 and MAPK8IP3/JIP-3/JSAP1 (PubMed:21076496). Interacts with SPAG9/MAPK8IP4/JIP4 (By similarity). Interacts with HDAC9 and MAPKBP1 (By similarity). Interacts with ARRB2; the interaction enhances MAPK10 activation by MAP3K5 (By similarity). Interacts with SARM1 (By similarity). Interacts with JUND; interaction is inhibited in the presence of MEN1 (By similarity).
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 (By similarity). Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1 (By similarity).
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.
Interacts via its C-terminus with the first PDZ domain of USH1C.
Monomer. Part of a ternary complex containing KHSRP, PTBP1, PTBP2 and HNRPH1. Interacts with RAVER1 and SFPQ (By similarity).
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. 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. 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.
Binds to WAS within the N-terminal region, at a site distinct from the CDC42-binding site. Binds profilin and actin. Interacts with DBNL (By similarity). Binds to WASL. Interacts with DBNL. Interacts with FNBP1L (via the SH3 domain) (By similarity).
Isoforms were differentially expressed. One isoform was ubiquitously expressed, another was muscle-specific and another was expressed in the liver, heart and testis.
Plays a role in the reorganization of the actin cytoskeleton. Contributes with NCK1 and GRB2 in the recruitment and activation of WASL. Plays a role in the formation of cell ruffles (By similarity). May participate in regulating the subcellular localization of WASL, resulting in the disassembly of stress fibers in favor of filopodia formation.
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.
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. Binds preferrentially ferritin light chain (FTL) compared to heavy chain (FTH1).
Homodimer (By similarity). May form heterooligomers with other PACSINs (By similarity). Interacts (via NPF motifs) with EHD1 (via EH domain) (By similarity). Interacts with EHD3 (By similarity). Interacts (via the SH3 domain) with MICALL1 (By similarity). Interacts with RAC1 (By similarity). Interacts (via SH3 domain) with DNM1, SYN1, SYNJ1 and WASL (PubMed:10704453). Interacts with CAV1 (By similarity). Interacts with TRPV4 (By similarity).
Phosphorylated by casein kinase 2 (CK2) and protein kinase C (PKC). Phosphorylation by PKC probably decreases the membrane binding and tubulation capacities of PACSIN2, thereby modulating the lifetime of caveolae (By similarity).
Regulates the morphogenesis and endocytosis of caveolae (PubMed:22718246). Lipid-binding protein that is able to promote the tubulation of the phosphatidic acid-containing membranes it preferentially binds. Plays a role in intracellular vesicle-mediated transport. Involved in the endocytosis of cell-surface receptors like the EGF receptor, contributing to its internalization in the absence of EGF stimulus.
The F-BAR domain forms a coiled coil and mediates membrane-binding and membrane tubulation. In the autoinhibited conformation, interaction with the SH3 domain inhibits membrane tubulation mediated by the F-BAR domain (By similarity).
Widely expressed (at protein level). Isoforms 1/3 are predominantly expressed in heart and in PC-12 cells, a pheochromocytoma cell line (at protein level). Isoforms 2/4 are widely expressed with highest levels in muscle, testis and brain (at protein level).
Expressed during osteoblast differentiation and bone development. Detected in embryonic bone formation in calvariae and tibiae. Very low expression in neonate bone tissues. Expressed in kidney and brain.
Expressed in brain. Very low expression in adult bone tissues. Overexpression suppresses alkaline phosphatase induction by BMP7.
Interacts with RUNX2. Binds consensus element OSE2.
KRAB domain is not required for nuclear targeting or for DNA binding.
May function as a transcription repressor. Binds to 5'-CCACA-3' core sequence. Suppresses osteogenic effects of RUNX2. May be involved in osteoblastic differentiation. Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal (By similarity).
Zinc finger region is involved in nuclear targeting and DNA-binding.
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).
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-825 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.
Interacts with ZNF382 (PubMed:11154279). Interacts with SETX. 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 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 SMARCAD1. Interacts with, and sumoylates IRF7. Interacts with MAGEC2. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Interacts with AICDA. 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 (By similarity). Interacts with NR4A3; the interactions potentiates NR4A3 activity on NurRE promoter (By similarity). Interacts (unphosphorylated or phosphorylated form) with ZBTB1 (via BTB domain) (By similarity). Probably part of a corepressor complex containing ZNF304, TRIM28, SETDB1 and DNMT1. Interacts with ATRX. Forms a complex with ATRX, SETDB1 and ZNF274 (By similarity). Interacts with ZFP568; the interaction mediates ZFP568 transcriptional repression activity (By similarity). Interacts with RRP1B (By similarity). 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 (By similarity). Interacts with CYREN (via XLF motif) (By similarity). Interacts with TRIM17; this interaction prevents TRIM28 activity (By similarity). Interacts with ZNF746 (By similarity).
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). 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. Required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs). In ESCs, in collaboration with SETDB1, is also required for H3K9me3 and silencing of endogenous and introduced retroviruses in a DNA-methylation independent-pathway. Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing. The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc finger genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions.
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-555, Lys-780 and Lys-805 are the major sites of sumoylation. In response to Dox-induced DNA damage, enhanced phosphorylation on Ser-825 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.
Belongs to the universal ribosomal protein uL11 family.
Monomer. Interacts with pre-ribosome complex. May bind to RNA. Interacts with NOL8. Interacts with FTSJ3 (By similarity).
Required for proper 34S pre-rRNA processing and 60S ribosome subunit assembly.
By forskolin, thyrotropin and insulin. Down-regulated by the antithyroid drug methimazole.
Expressed in colon, duodenum, rectum and thyroid.
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.
Heterodimer with DUOXA2; disulfide-linked. Interacts with TXNDC11, TPO and CYBA.
In the N-terminal section; belongs to the peroxidase family.
The NADPH oxidase activity is calcium-dependent. Peroxidase activity is inhibited by aminobenzohydrazide (By similarity).
There is no evidence for the expression of the corresponding protein in vitro.
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. May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation.
Expressed in the liver as well as small intestine.
Homodimer. Part of the apolipoprotein B mRNA editing complex with A1CF. Interacts with SYNCRIP. Interacts with HNRPAB.
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:1400426). Interacts with LRP2/glycoprotein 330 (PubMed:1400426). Interacts with LRP1B; binding is followed by internalization and degradation. Interacts with LDLR (By similarity). Interacts with SORL1 (By similarity). Interacts with LRP1; this interaction is followed by rapid internalization (By similarity).
Molecular chaperone for LDL receptor-related proteins that may regulate their ligand binding activity along the secretory pathway.
Was originally thought to be Heymann nephritis antigen gp330.
Belongs to the metallo-dependent hydrolases superfamily. NagA family.
Binds 1 divalent metal cation per subunit.
Hydrolyzes the N-glycolyl group from N-glycolylglucosamine 6-phosphate (GlcNGc-6-P) in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway.
Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.
Homodimer; disulfide-linked, upon oxidation. 6 homodimers assemble to form a ring-like dodecamer. Interacts with NEK6. Interacts with LRRK2. Interacts with MAP3K13 (By similarity). Interacts with RPS6KC1 (via PX domain).
Phosphorylated by LRRK2; phosphorylation reduces perodixase activity.
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this typical 2-Cys peroxiredoxin, C(R) is provided by the other dimeric subunit to form an intersubunit disulfide. The disulfide is subsequently reduced by thioredoxin.
The enzyme can be inactivated by further oxidation of the cysteine sulfenic acid (C(P)-SOH) to sulphinic acid (C(P)-SO2H) and sulphonic acid (C(P)-SO3H) instead of its condensation to a disulfide bond.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides. Acts synergistically with MAP3K13 to regulate the activation of NF-kappa-B in the cytosol (By similarity). Required for the maintenance of physical strength (By similarity).
Belongs to the PRAME family. LRRC14 subfamily.
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. Interacts with CHUK.
Negatively regulates Toll-like receptor-mediated NF-kappa-B signaling by disrupting IKK core complex formation through interaction with IKBKB.
Auto-ubiquitinates in an E2-dependent manner leading to its own degradation (PubMed:23661642). Also polyubiquitinated by RNF41 for proteasomal degradation (By similarity).
Belongs to the RBR family. Parkin subfamily.
Forms an E3 ubiquitin ligase complex with UBE2L3 or UBE2L6. Mediates 'Lys-63'-linked polyubiquitination by associating with UBE2V1. Part of a SCF-like complex, consisting of PRKN, CUL1 and FBXW7. Interacts with SNCAIP. Binds to the C2A and C2B domains of SYT11. Interacts and regulates the turnover of SEPTIN5. Part of a complex, including STUB1, HSP70 and GPR37. The amount of STUB1 in the complex increases during ER stress. STUB1 promotes the dissociation of HSP70 from PRKN and GPR37, thus facilitating PRKN-mediated GPR37 ubiquitination. HSP70 transiently associates with unfolded GPR37 and inhibits the E3 activity of PRKN, whereas, STUB1 enhances the E3 activity of PRKN through promotion of dissociation of HSP70 from PRKN-GPR37 complexes. Interacts with PSMD4 and PACRG. Interacts with LRRK2. Interacts with RANBP2. Interacts with SUMO1 but not SUMO2, which promotes nuclear localization and autoubiquitination. Interacts (via first RING-type domain) with AIMP2 (via N-terminus). Interacts with PSMA7 and RNF41. Interacts with PINK1. Forms a complex with PINK1 and PARK7. Interacts with CHPF, the interaction with isoform 2 may facilitate PRKN transport into the mitochondria. Interacts with MFN2 (phosphorylated), promotes PRKN localization in dysfunctional depolarized mitochondria. Interacts with FBXO7; this promotes translocation to dysfunctional depolarized mitochondria. Interacts with ZNF746. Interacts with heat shock protein 70 family members, including HSPA1L, HSPA1A and HSPA8; interaction HSPA1L promotes translocation to damaged mitochondria. Interacts with BAG4 and, to a lesser extent, BAG5; interaction with BAG4 inhibits translocation to damaged mitochondria. Forms a complex with PRKN and PARK7. Interacts with AMBRA1 (By similarity).
Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Substrates include SYT11 and VDAC1. Other substrates are BCL2, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPTIN5, TOMM20, USP30, ZNF746, MIRO1 and AIMP2. Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation. Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Protects against mitochondrial dysfunction during cellular stress, by acting downstream of PINK1 to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components. 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. Activation and recruitment onto the outer membrane of damaged/dysfunctional mitochondria (OMM) requires PINK1-mediated phosphorylation of both PRKN and ubiquitin. After mitochondrial damage, functions with PINK1 to mediate the decision between mitophagy or preventing apoptosis by inducing either the poly- or monoubiquitination of VDAC1, respectively; polyubiquitination of VDAC1 promotes mitophagy, while monoubiquitination of VDAC1 decreases mitochondrial calcium influx which ultimately inhibits apoptosis. When cellular stress results in irreversible mitochondrial damage, promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1, MFN1 and USP30. Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains, leading to mitophagy. The PINK1-PRKN pathway also promotes fission of damaged mitochondria by PINK1-mediated phosphorylation which promotes the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2. This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes. Regulates motility of damaged mitochondria via the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma. Involved in mitochondrial biogenesis via the 'Lys-48'-linked polyubiquitination of transcriptional repressor ZNF746/PARIS which leads to its subsequent proteasomal degradation and allows activation of the transcription factor PPARGC1A. Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress. Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.
In the autoinhibited state the side chain of Phe-463 inserts into a hydrophobic groove in RING-0, occluding the ubiquitin acceptor site Cys-431, whereas the REP repressor element binds RING-1 and blocks its E2-binding site. Activation of PRKN requires 2 steps: (1) phosphorylation at Ser-65 by PINK1 and (2) binding to phosphorylated ubiquitin, leading to unlock repression of the catalytic Cys-431 by the RING-0 region via an allosteric mechanism and converting PRKN to its fully-active form. According to another report, phosphorylation at Ser-65 by PINK1 is not essential for activation and only binding to phosphorylated ubiquitin is essential to unlock repression.
Largely confined to neuronal elements, including fibers and neuropil. Highly expressed at the forebrain level, in pyramidal cells of layer V, in various cortical regions and cerebellum. Expressed in the nucleus of diagonal band of Broca, nucleus basalis, bed nucleus of the stria terminalis, and olfactory tubercle. Moderate expression is seen in most neurons of the subthalamic nucleus, heart, skeletal muscle and testis. Moderate expression was found in frontal cortex, parietal cortex, cerebellum, heart, skeletal muscle and testis.
Members of the RBR family are atypical E3 ligases. They interact with the E2 conjugating enzyme UBE2L3 and function like HECT-type E3 enzymes: they bind E2s via the first RING domain, but require an obligate trans-thiolation step during the ubiquitin transfer, requiring a conserved cysteine residue in the second RING domain.
Phosphorylated. Activation requires phosphorylation at Ser-65 by PINK1 and binding to PINK1 phosphorylated ubiquitin. Phosphorylation at Thr-175 by PINK1 and at Thr-217 is important for mitochondrial localization.
The RING-type 1 zinc finger domain is required to repress p53/TP53 transcription.
The ubiquitin-like domain binds the PSMD4 subunit of 26S proteasomes.
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.
Neuron-specific in the central and peripheral nervous system.
Cell surface proteoglycan that bears heparan sulfate. Regulates dendritic arbor morphogenesis (By similarity).
Interacts (via cytoplasmic domain) with SARM1. Forms a complex with SDCBP and PDCD6IP.
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. Involved in regulation of neuronal-specific transcription. May be involved in regulation of spermatogenesis (By similarity).
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).
Phosphorylation increases the actin-activated myosin ATPase activity and thereby regulates the contractile activity.
Binds itself as well as AMIGO1 and AMIGO3.
High level expression in cerebellum of newborn rats is down-regulated to 50% by postnatal day 14.
Highest levels in the lung. High levels in cerebellar granule neurons and Purkinje cells. Also in pyramidal cells between CA1 and CA3 regions of the hippocampus and granule cells of the dentate gyrus.
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.
Glycosylated. Glycosylation is required for plasma membrane localization and for its cleavage by BACE2.
Kidney; collecting ducts. Pancreas; beta cells of islets.
Monomer. Homodimer; dimerization prevents CLTRN cleavage by BACE2 (By similarity). Interacts with SLC6A18; this interaction regulates the trafficking of SLC6A18 to the cell membrane and its amino acid transporter activity. 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 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 (By similarity).
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 (By similarity).
The cleavage site containing the double Phe-Phe motif acts as negative regulator of shedding by BACE2.
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 (By similarity).
Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (By similarity). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and RICTOR within the TORC2 complex (By similarity).
Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-421'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. PRR5 plays an important role in regulation of PDGFRB expression and in modulation of platelet-derived growth factor signaling. May act as a tumor suppressor in breast cancer (By similarity).
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.
The protein is found both as a full-length peptide and in a cleaved version.
Binds cAMP-dependent protein kinase (PKA). Interacts with PRKCA; only the cytoplasmic form is capable of interacting with PRKCA.
Expressed highly in the heart, and moderately in brain, lung, liver, kidney and testis. Hardly detectable in spleen and skeletal muscle. In kidney, isoform Delta is expressed in the principal cells of the IMCD.
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 (By similarity). Isoform Delta may be involved in shuttling aquaporin-2 (AQP2) to the plasma membrane.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRA1 sub-subfamily.
Detected in spinal cord (at protein level) (PubMed:2483325, PubMed:6286620). Detected in spinal cord and brain stem (PubMed:3037383).
Glycine receptors are ligand-gated chloride channels. Channel opening is triggered by extracellular glycine (PubMed:1716350, PubMed:11981023, PubMed:2483325, PubMed:3037383). Channel opening is also triggered by taurine and beta-alanine (PubMed:1716350). Channel characteristics depend on the subunit composition; heteropentameric channels are activated by lower glycine levels and display faster desensitization. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents. Channel activity is potentiated by ethanol (By similarity). Potentiation of channel activity by intoxicating levels of ethanol contribute to the sedative effects of ethanol (By similarity).
Homopentamer (in vitro). Interacts with GLRB to form heteropentameric channels; this is probably the predominant form in vivo. Heteropentamer composed of two GLRA1 and three GLRB. Heteropentamer composed of three GLRA1 and two GLRB. Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different.
Inhibited by strychnine (PubMed:1716350, PubMed:2483325, PubMed:3037383). Inhibited by picrotoxin (PubMed:2483325).
The channel pore is formed by pentameric assembly of the second transmembrane domain from all five subunits. Channel opening is effected by an outward rotation of the transmembrane domains that increases the diameter of the pore.
Expressed in all tissues examined with highest levels in lung and kidney.
Homodimer and homotetramer via the coiled coil regions. Interacts tightly with GTP-bound but not GDP-bound CDC42 (By similarity). Interacts with TJP1; this interaction requires the presence of catalytically active CDC42 (PubMed:21240187). 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 (By similarity). Interacts with CPNE4 (via VWFA domain) (By similarity). Interacts with LURAP1 (PubMed:25107909). Interacts (via AGC-kinase C-terminal domain) with FAM89B/LRAP25 (via LRR repeat) (PubMed:25107909). 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:21240187, PubMed:21457715). In concert with MYO18A and LURAP1, is involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. Phosphorylates PPP1R12A (PubMed:18854160). 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).
Potassium channel displaying weak inward rectification in symmetrical K(+) solution.
Ubiquitous. In brain expression is rather low and restricted to the olfactory bulb and tubercle, to the ventromedial hypothalamic nucleus, lateral septal nucleus dorsal, lateral mammillary nucleus, lateral parabrachial nuclei, reticular nucleus and reunions nuclei.
Weakly sensitive to low extracellular pH. Activated by arachidonic acid; inhibited by halothane and Ba++.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.9/SCN11A subfamily.
Down-regulated after axotomy and up-regulated following hind paw inflammation. Down-regulated in vitro by electrical stimulation and by deprivation of NGF.
Expressed (at protein level) in myenteric sensory neurons. Expressed in small sensory neurons of the dorsal root ganglia (C-fiber neurons) and trigeminal ganglia.
Expressed in dorsal root ganglia at 17 dpc onwards.
The voltage-resistant sodium channel consists of an ion conducting pore forming alpha-subunit regulated by one or more auxiliary subunits SCN1B, SCN2B and SCN3B.
This protein 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. It is a tetrodotoxin-resistant sodium channel isoform. Also involved, with the contribution of the receptor tyrosine kinase NTRK2, in rapid BDNF-evoked neuronal depolarization (By similarity).
Acetylation by CLOCK reduces its binding to glucocorticoid response elements and its transcriptional activity.
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. The ligand-binding domain is required for correct chromosome segregation during mitosis although ligand binding is not required.
Has transcriptional activation and repression activity. Mediates glucocorticoid-induced apoptosis. Promotes accurate chromosome segregation during mitosis. May act as a tumor suppressor. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression.
Increased proteasome-mediated degradation in response to glucocorticoids.
Interacts with GRIP1 (By similarity). Heteromultimeric cytoplasmic complex with HSP90AA1, HSPA1A/HSPA1B, and FKBP5 or another immunophilin such as PPID, STIP1, or the immunophilin homolog PPP5C (PubMed:21730050). Upon ligand binding FKBP5 dissociates from the complex and FKBP4 takes its place, thereby linking the complex to dynein and mediating transport to the nucleus, where the complex dissociates (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (By similarity). Directly interacts with UNC45A (By similarity). Binds to DNA as a homodimer, and as heterodimer with NR3C2 or the retinoid X receptor (By similarity). Binds STAT5A and STAT5B homodimers and heterodimers (By similarity). Interacts with NRIP1, POU2F1, POU2F2 and TRIM28 (PubMed:10364267, PubMed:10480874). Interacts with several coactivator complexes, including the SMARCA4 complex, CREBBP/EP300, TADA2L (Ada complex) and p160 coactivators such as NCOA2 and NCOA6 (PubMed:9111344, PubMed:10866662). Interaction with BAG1 inhibits transactivation (By similarity). Interacts with HEXIM1 and TGFB1I1 (By similarity). Interacts with NCOA1 (PubMed:12917342). Interacts with NCOA3, SMARCA4, SMARCC1, SMARCD1, and SMARCE1 (PubMed:12917342, PubMed:12118039). Interacts with CLOCK, CRY1 and CRY2 in a ligand-dependent fashion (By similarity). Interacts with CIART (By similarity). Interacts with RWDD3 (PubMed:23508108). Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3 (PubMed:23508108). Interacts with NR4A3 (via nuclear receptor DNA-binding domain), represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE) (By similarity). Directly interacts with PNRC2 to attract and form a complex with UPF1 and DCP1A; the interaction leads to rapid mRNA degradation (By similarity). Interacts with GSK3B (By similarity). Interacts with FNIP1 and FNIP2 (By similarity). Interacts (via C-terminus) with HNRNPU (via C-terminus) (By similarity). Interacts with MCM3AP (By similarity). Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (By similarity).
Phosphorylated in the absence of hormone; becomes hyperphosphorylated in the presence of glucocorticoids. The Ser-224, Ser-246 and Ser-424-phosphorylated forms are mainly cytoplasmic, and the Ser-232-phosphorylated form is nuclear. Phosphorylation at Ser-232 increases transcriptional activity. Phosphorylation at Ser-224, Ser-246 and Ser-424 decreases signaling capacity. Phosphorylation at Ser-424 may protect from glucocorticoid-induced apoptosis. Phosphorylation at Ser-224 and Ser-232 is not required in regulation of chromosome segregation. May be dephosphorylated by PPP5C, attenuates NR3C1 action.
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:12917342). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (By similarity). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity).
Sumoylation at Lys-297 and Lys-313 negatively regulates its transcriptional activity. Sumoylation at Lys-721 positively regulates its transcriptional activity in the presence of RWDD3. Sumoylation at Lys-297 and Lys-313 is dispensable whereas sumoylation at Lys-721 is critical for the stimulatory effect of RWDD3 on its transcriptional activity. Heat shock increases sumoylation in a RWDD3-dependent manner.
Ubiquitinated; restricts glucocorticoid-mediated transcriptional signaling.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase type I family.
Expressed in cerebellar Purkinje cells (at protein level).
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:8626616). Plays a crucial role in the survival of cerebellar Purkinje cells (By similarity).
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. IF-2 subfamily.
One of the essential components for the initiation of protein synthesis. Protects formylmethionyl-tRNA from spontaneous hydrolysis and promotes its binding to the 30S ribosomal subunits. Also involved in the hydrolysis of GTP during the formation of the 70S ribosomal complex.
Expressed in 1-4% of neurons of the vomeronasal organ. Only one pheromone receptor gene may be expressed in a particular neuron. Not expressed in the main olfactory epithelium.
Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport pathways.
Expressed in the brain with expression in the cerebrum and the cerebellum.
Expressed in the spinal cord of newborn animals.
Homohexamer or homotetramer. Interacts with SRCIN1 (By similarity). Interacts with VAMP2; the interaction is inhibit by interaction of VAPM2 with SEPT8 (PubMed:19196426).
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.
Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly (By similarity). Promotes the progression of complex assembly after the association of Mt-Co1/Cox11 with Cox4I1 and Cox6c (By similarity). Chaperone-like assembly factor required to stabilize newly synthesized Mt-Co1/Cox1 and to prevent its premature turnover (By similarity).
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 (By similarity). Interacts with Coa3/Mitrac12 and Cox4i1 (By similarity). Directly interacts with newly synthesized Mt-Co1/Cox1 (By similarity).
Highly expressed in the hypothalamus, substantia nigra reticulata, Edinger-Westphal nucleus, and nucleus of the solitary tract/dorsal motor nucleus of the vagus, the spinal cord, and sensory ganglia (at protein level) (PubMed:22963497, PubMed:23912037). Also expressed in the heart, thymus, esophagus, stomach, spleen, lung, pituitary gland, kidney, jejunum, duodenum, ileum, cerebrum, pons, and colon (at protein level) (PubMed:22963497, PubMed:23912037, PubMed:28965207). Expressed in preadipocytes and apidocytes (at protein level) (PubMed:30251651). Expressed in pancreatic islet cells (at protein level) (PubMed:31422055).
Peptide involved in a broad spectrum of regulatory functions (PubMed:27440717, PubMed:28844870, PubMed:29364701, PubMed:28965207, PubMed:30609107). Is a ligand for GPR173 (PubMed:27440717). 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 (PubMed:22963497, PubMed:27440717). More specifically, it regulates the expression of transcription factors CEBPB and POU2F1/OCT1 through the cAMP-PKA signaling pathway, which subsequently regulate the expression of GNRHR and KISS1 (By similarity). Plays a protective role in memory retention through activation of GNRHR (By similarity). Regulates the secretion of AVP by hypothalamic neurons (PubMed:29364701). 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 increasing NUCB2 expression in neurons (PubMed:28844870, PubMed:30930149). In the ovary, it regulates follicular growth by stimulating granulosa cell proliferation by increasing the expression of GPR173, CREB1, CYP19A1, KITLG, FSHR, and LHCGR (By similarity). It also increases the production of estradiol (E2) (By similarity). In the heart, it regulates contractility and relaxation by activating the AKT1-NOS3 and MAPK1-MAPK3 signaling pathways (PubMed:28965207). It also plays a cardioprotective role during ischemia, where it activates the SAFE and RISK pathways (PubMed:28965207). Stimulates the proliferation and differentiation of preadipocytes (PubMed:30251651). In pancreatic islet cells, it induces proliferation of islet cells as well as the production of INS1 and INS2 through activation of the MAPK1-MAPK3 signaling pathways (PubMed:31422055).
Plays an important role in meiotic recombination and associated DNA double-strand break repair.
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) (By similarity).
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. 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)) (By similarity). Incorporation of the Rieske protein UQCRFS1 is the penultimate step in complex III assembly. Interacts with TTC19, which is involved in the clearance of UQCRFS1 fragments (By similarity).
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) (By similarity). 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 (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. 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 (By similarity).
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. 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.
The Rieske protein is a high potential 2Fe-2S protein.
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class III subfamily.
Cytosolic tripeptidyl-peptidase that releases N-terminal tripeptides from polypeptides and is a component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It plays an important role in intracellular amino acid homeostasis (By similarity). Stimulates adipogenesis (By similarity).
The limitation of proteolytic products to tripeptides is achieved by tailoring the size of the substrate-binding cleft: the two negatively charged residues Glu-305 and Glu-331 that are blocking position P4 limit the number of residues that can be accommodated in the binding cleft and thus create a molecular ruler. At the same time, they orient substrates so that the tripeptides are removed exclusively from the N-terminus (By similarity).
GTPase-activating protein for ADP ribosylation factor family members, including ARF1.
May form heterooligomers with GIT1 (Probable). Directly interacts with protein Piccolo/PCLO (PubMed:12473661). Interacts with PPFIA1 and PPFIA2 (PubMed:12629171). Interacts with ARHGEF7 (By similarity). Identified in a complex with ARHGEF6 and BIN2 (By similarity). Interacts with PAK3 (By similarity). Interacts with PXN/paxillin (By similarity). Interacts with TGFB1I1 (By similarity). Forms a complex with EFNB1 and GRB4/NCK2 (By similarity).
All isoforms are detected in kidney, and many are kidney specific. Isoforms 2 and 13 are also detected in liver. Isoforms 4 and 9/K4 are ubiquitous, but isoform 9/K13 is kidney specific. Isoforms 5 and 14 are detected in all tissues tested, with the exception of pancreas and spleen. Isoforms 11 and 15 are detected in kidney, pancreas and testis. Isoform 7 is detected in kidney, liver, testis and spleen.
Mediates the Na(+)-independent transport of organic anions such as methotrexate, taurocholate, folate and prostaglandin E2. May contribute to renal secretion and/or reabsorption of hydrophobic anionic compounds. Mediates renal clearance of methotrexate from the blood.
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.
Highest expression is detected in liver, followed by kidney and brain.
Interacts with DHCR24; this interaction regulates DHCR7 activity.
Phosphorylated on Tyr residues after EGF stimulation.
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 (By similarity).
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 (By similarity). May interact with ZNF540 (By similarity).
Expressed in postnatal central nervous system (CNS) germinal zones and, in early postnatal life, within numerous cells throughout the CNS. It is more highly localized to ventricular germinal zones.
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 (By similarity). Acts instructively to control the cell fate determination of CNS multipotent progenitor cells, resulting in astroglial induction and neuron/oligodendrocyte suppression.
Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with PSMA1 (By similarity). Interacts with HIF1AN (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. 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 EGF-like domains 10 and 11 are required for binding the ligands JAG1 and DLL1.
Heterodimer; heterodimerizes with the protein microsomal triglyceride transfer MTTP. Homodimer. Monomers and homotetramers may also occur. Interacts with P4HA2, forming a heterotetramer consisting of 2 alpha subunits (P4HA2) and 2 beta (P4HB), where P4HB plays the role of a structural subunit; this tetramer catalyzes the formation of 4-hydroxyproline in collagen (By similarity). Also constitutes the structural subunit of the microsomal triacylglycerol transfer protein MTTP in mammalian cells. Stabilizes both enzymes and retain them in the ER without contributing to the catalytic activity. Binds UBQLN1. Interacts with ERO1B. Interacts with ILDR2 (By similarity). Interacts with ERN1/IRE1A (via N-terminus); the interaction is enhanced by phosphorylation of P4HB by FAM20C in response to endoplasmic reticulum stress and results in attenuation of ERN1 activity (By similarity).
Phosphorylation of Ser-359 by FAM20C is induced by endoplasmic reticulum stress and results in a functional switch from oxidoreductase to molecular chaperone. It also promotes interaction with ERN1.
This multifunctional protein catalyzes the formation, breakage and rearrangement of disulfide bonds. At the cell surface, seems to act as a reductase that cleaves disulfide bonds of proteins attached to the cell. May therefore cause structural modifications of exofacial proteins. Inside the cell, seems to form/rearrange disulfide bonds of nascent proteins. At high concentrations and following phosphorylation by FAM20C, functions as a chaperone that inhibits aggregation of misfolded proteins. At low concentrations, facilitates aggregation (anti-chaperone activity). May be involved with other chaperones in the structural modification of the TG precursor in hormone biogenesis. Also acts as a structural subunit of various enzymes such as prolyl 4-hydroxylase and microsomal triacylglycerol transfer protein MTTP. Receptor for LGALS9; the interaction retains P4HB at the cell surface of Th2 T helper cells, increasing disulfide reductase activity at the plasma membrane, altering the plasma membrane redox state and enhancing cell migration.
Was originally (PubMed:8251535 and PubMed:3178809) thought to be identical to thyroxine deiodinase but this was later shown to be incorrect.
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.
E3 ubiquitin-protein ligase that mediates the ubiquitination of ATP6V0C and targets it to degradation via the ubiquitin-proteasome pathway. 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.
Silencing prevents ventricular remodeling in rats after myocardial ischemia-reperfusion injury by activating the mTOR signaling pathway.
The RING-type zinc finger domain is required for E3 ligase activity.
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.
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 CD163. Also component of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, the complex associating following UV irradiation (By similarity). Interacts with DYNLT2. 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 (By similarity).
Phosphorylated by alpha subunit. Also a component of a CK2-SPT16-SSRP1 complex composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B, the complex associating following UV irradiation (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 (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.
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 (By similarity).
Belongs to the metallo-dependent hydrolases superfamily. ACMSD family.
Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.
Liver and kidney. Very low levels detected in brain.
Monokine with inflammatory and chemokinetic properties.
Expressed in cardiomyocytes, cortical and hippocampal neurons.
Expressed in newborn and adult heart and brain tissues. Expression is not evident in prenatal days.
Interacts with TBP and the transcription factor IID (TFIID) complex, NR5A2, NR1H3 and PPARG. Interaction with TBP is regulated by phosphorylation. Binds NR5A1, ATF1 and FOS via their conserved basic region (By similarity). Interacts with JUN. 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.
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. Might function in endothelial cells differentiation, hormone-induced cardiomyocytes hypertrophy and lipid metabolism (By similarity).
Up-regulated upon cardiomyocytes hypertrophy.
Belongs to the glycosyl hydrolase 27 family.
Interacts with RHOQ and CDC42, in a GTP-dependent manner.
Probably involved in the organization of the actin cytoskeleton. Induced membrane extensions in fibroblasts (By similarity).
May play a specialized role in spermatogenesis.
Belongs to the SelWTH family. Selenoprotein W subfamily.
Higher levels are seen in the muscle and brain while lower levels are seen in the spleen and testis. Not detected in liver, heart, kidney, intestinal mucosa, intestinal muscle, lung, plasma or erythrocytes (at protein level).
In skeletal muscle, by dietary selenium.
Interacts with DPYSL2, PRDX1, YWHAB, YWHAG, HSP70 and HSP90.
Plays a role as a glutathione (GSH)-dependent antioxidant. May be involved in a redox-related process. May play a role in the myopathies of selenium deficiency.
A cytochrome P450 monooxygenase involved in muricholic acid (MCA) synthesis. Hydroxylates at the 6-beta position two major bile acids, chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) to form alpha-MCA and beta-MCA, respectively. May regulate NR1H4/farnesoid X receptor signaling, as taurine-conjugated MCAs are antagonists of NR1H4. 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).
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.
AP-1 family transcription factor that controls 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. 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).
Heterodimer; heterodimerizes with JUN family proteins. Interacts with JUN.
Present in almost all organs including spleen, small intestine, kidney, lung, liver and brain.
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.
Belongs to the LIMR family. LMBRD1 subfamily.
Interacts with ABCD4; this interaction induces the translocation of ABCD4 from the endoplasmic reticulum to the lysosome. Interacts with ABCD4 and MMACHC; this interaction ensures the transport of cobalamin from the lysosome to the cytoplasm (By similarity). 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. Targets ABCD4 transporter from the endoplasmic reticulum to the lysosome. Then forms a complex with lysosomal ABCD4 and cytoplasmic MMACHC to transport cobalamin across the lysosomal membrane (By similarity). 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).
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 (By similarity).
Belongs to the 5-formyltetrahydrofolate cyclo-ligase family.
Defects in Flcn may be involved in renal cell carcinoma.
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. Disassembly of the LFC complex upon amino acid restimulation liberates the GTPase-activating activity.
Interacts (via C-terminus) with FNIP1 or FNIP2 (via C-terminus). 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. Interaction with FNIP1 or FNIP2 mediates indirect interaction with the PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-activated protein kinase (AMPK). Interacts with HSP90AA1 in the presence of FNIP1. Interacts with HSP70, STUB1, CDC37, AHSA1, CCT2, STIP1, PTGES3 and PPP5C (By similarity). Interacts with GABARAP; interaction takes place in the presence of FNIP1 and/or FNIP2 (By similarity). Interacts with RILP; the interaction is direct and promotes association between RILP and RAB34 (By similarity). Interacts with KIF3A and KIF3B (By similarity). 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.
Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (By similarity). 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 (By similarity). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (By similarity). 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 (By similarity). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (By similarity). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (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). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (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 (By similarity). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (By similarity). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (By similarity).
Phosphorylation by ULK1 modulates the interaction with GABARAP and is required to regulate autophagy.
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 (By similarity). 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:8939997, PubMed:10640429). Plays a pivotal role in regulating available LCFA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation or triglyceride synthesis (PubMed:8939997, PubMed:10640429). Can also activate branched-chain fatty acids such as phytanic acid and pristanic acid (By similarity). May contribute to the synthesis of sphingosine-1-phosphate (By similarity). Does not activate C24 bile acids, cholate and chenodeoxycholate. 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. However, it is not critical for THCA activation and bile synthesis in vivo (By similarity).
Belongs to the eukaryotic ATPase B 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.
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. Found in a complex with GRIA1, GRIA2, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5.
Palmitoylated. Depalmitoylated upon glutamate stimulation. Cys-615 palmitoylation leads to Golgi retention and decreased cell surface expression. In contrast, Cys-841 palmitoylation does not affect cell surface expression but regulates stimulation-dependent endocytosis (By similarity).
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate (By similarity).
Probable mitochondrial acylpyruvase which is able to hydrolyze acetylpyruvate and fumarylpyruvate in vitro. Also has oxaloacetate decarboxylase activity.
Belongs to the sauvagine/corticotropin-releasing factor/urotensin I family.
Hormone regulating the release of corticotropin from pituitary gland (PubMed:6603620). Induces NLRP6 in intestinal epithelial cells, hence may influence gut microbiota profile (By similarity).
Interacts (via C-terminus) with CRFR1 (via N-terminal extracellular domain).
Expressed predominantly in fetal brain, in neurons but not glial cells. Mostly expressed in neuronal progenitor cells with reduced expression in differentiated cells. Less abundant in adult brain where expression is limited to cerebellum, olfactory bulb and hippocampus. Also found at lower levels in fetal and adult kidney, heart, lung and spleen.
Expression is highest in fetal brain at 16 dpc with decreased levels as development progresses. By postnatal day 3 detected in hippocampal pyrimidal neurons and cortical neurons.
RNA-binding protein with binding specificity for poly(C). May play an important role in neural development.
Hemopressin acts as an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:18077343). Hemopressin-binding efficiently blocks cannabinoid receptor CNR1 and subsequent signaling (PubMed:18077343).
In rats there are two non-allelic alpha chains and two non-allelic beta chains. The alpha-1 chain sequence is shown.
Belongs to the acetyltransferase family. ARD1 subfamily.
Component of the N-terminal acetyltransferase A (NatA) complex composed of NAA11 and NAA15. Interacts with HIF1A.
Displays alpha (N-terminal) acetyltransferase activity. Proposed alternative catalytic subunit of the N-terminal acetyltransferase A (NatA) complex.
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.
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 (By similarity). 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 (By similarity).
Acts as an 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 (By similarity).
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 (By similarity). Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK (By similarity).
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. Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. 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. Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity. 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. In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation. Acts as a tumor suppressor. 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. Does not seem to deacetylate PC. Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels. Down-regulates insulin secretion.
Belongs to the sirtuin family. Class II subfamily.
Interacts with GLUD1, IDE and SLC25A5. Interacts with DLAT and PDHX.
Expressed in neutrophils (at protein level) (PubMed:2543629). Highest expression in bone marrow and to a much lesser extent in small intestine (PubMed:7594610).
Host-defense peptide that has antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi (in vitro) (PubMed:2543629). Exhibits activity against E.coli, A.calcoaceticus, S,aureus and C.albicans (PubMed:2543629).
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. It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1.
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 (By similarity). At the COPII coat complex: interacts with SEC31A (PubMed:10788476). At the COPII coat complex: interacts with 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. The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine. The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids. Interacts with SEC16A (By similarity). Interacts with SEC16B (By similarity).
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. Required for the exit of adipsin (CFD/ADN), an adipocyte-secreted protein from the endoplasmic reticulum.
Belongs to the complex I 30 kDa subunit family.
Component of the PAT complex, an endoplasmic reticulum (ER)-resident membrane multiprotein complex that facilitates multi-pass membrane proteins insertion into membranes. 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. WDR83OS/Asterix is the substrate-interacting subunit of the PAT complex, whereas CCDC47 is required to maintain the stability of WDR83OS/Asterix. 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. Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis. Involved in the regulation of calcium ion homeostasis in the ER. Required for proper protein degradation via the ERAD (ER-associated degradation) pathway (By similarity). Has an essential role in the maintenance of ER organization during embryogenesis (By similarity).
The PAT complex includes WDR83OS/Asterix and CCDC47. 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 (By similarity). Interacts with VCP, HSPA5, DERL1, DERL2 and SELENOS (By similarity).
Monomer (By similarity). Homodimer; maybe disulfide-linked (By similarity). Homotrimer (By similarity). Interacts with ATL1 (PubMed:19665976). Interacts with ATL2 (By similarity). Interacts with ATL3 (By similarity). Interacts with CKAP4 (By similarity). Interacts with RTN4 (isoforms A and B) (By similarity). Interacts with ZFYVE27 (By similarity).
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.
2-oxoadipate dehydrogenase (E1a) component of the 2-oxoadipate dehydrogenase complex (OADHC). 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. 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). Can catalyze the decarboxylation of 2-oxoglutarate in vitro, but at a much lower rate than 2-oxoadipate. Responsible for the last step of L-lysine, L-hydroxylysine and L-tryptophan catabolism with the common product being 2-oxoadipate.
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.
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).
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. Binds ABL1 through the PTB domain and in a kinase-dependent manner. Does not interact with RasGAP (By similarity).
PTB domain mediates receptor interaction.
Degrades casein, gelatins of types I, III, IV, and V, and fibronectin. Activates procollagenase (By similarity).
Component of the TIM23 complex at least composed of TIMM23, some TIM17 (TIMM17A or TIMM17B) and TIMM50. The complex interacts with the TIMM44 component of the PAM complex. The complex also interacts with DNAJC15 (By similarity).
Addition of GM2A stimulates the hydrolysis of sulfated glycosphingolipid SM2 and the ganglioside GM2.
Belongs to the glycosyl hydrolase 20 family.
Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides. The isozyme B does not hydrolyze each of these substrates, however hydrolyzes efficiently neutral oligosaccharide. Only the isozyme A is responsible for the degradation of GM2 gangliosides in the presence of GM2A (By similarity). During fertilization is responsible, at least in part, for the zona block to polyspermy. Present in the cortical granules of non-activated oocytes, is exocytosed during the cortical reaction in response to oocyte activation and inactivates the sperm galactosyltransferase-binding site, accounting for the block in sperm binding to the zona pellucida (By similarity).
There are 3 forms of beta-hexosaminidase: hexosaminidase A is an heterodimer composed of one subunit alpha and one subunit beta (chain A and B); hexosaminidase B is an homodimer of two beta subunits (two chains A and B); hexosaminidase S is a homodimer of two alpha subunits (By similarity). The composition of the dimer (isozyme A versus isozyme S) has a significant effect on the substrate specificity of the alpha subunit active site (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. LI-cadherin may have a role in the morphological organization of liver and intestine.
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. Involved in Notch signaling by probably inducing JAG1 and JAG2. Activates RIPK4 transcription (By similarity). 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 (By similarity).
Binds DNA as a homotetramer. Isoform composition of the tetramer may determine transactivation activity. Interacts with HIPK2. Interacts with SSRP1, leading to stimulate coactivator activity. Interacts with WWP1. Interacts with PDS5A. Interacts (via activation domain) with NOC2L (By similarity).
Produced by alternative splicing of isoform 1.
Produced by alternative splicing of isoform 2.
Produced by alternative splicing of isoform 7.
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 (By similarity).
Widely expressed, notably in thymus, prostate, placenta, and skeletal muscle, although the precise isoform varies according to tissue type. Progenitor cell layers of skin, breast and prostate express high levels of DeltaN-type isoforms.
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.
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. Exerts a protective effect on the endothelial cell barrier function.
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.
Belongs to the Mediator complex subunit 21 family.
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).
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 termination codons UAA and UAG.
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 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. 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) (By similarity). Interacts with BRDT (PubMed:22215678). 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 (By similarity).
Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. 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 (By similarity).
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 (By similarity).
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 (By similarity).
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. May partially inactivate the current of KCNBMA. Two or more subunits of KCNMB3 are required to block the KCNMA1 tetramer (By similarity).
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.
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) (By similarity). The elongator complex catalyzes formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (By similarity). 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) (By similarity).
Homodimer; dimerization promotes ELP1 stability and elongator complex formation. Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6. Interacts preferentially with MAP3K14/NIK followed by IKK-alpha and IKK-beta.
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes including cartilage and bone formation (By similarity). Also plays an important role in the regulation of iron metabolism by acting as a ligand for hemojuvelin/HJV (By similarity). Initiates the canonical BMP signaling cascade by associating with type I receptor ACVR1 and type II receptor ACVR2B. In turn, ACVR1 propagates signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act as activators and repressors of transcription of target. Can also signal through non-canonical pathway such as TAZ-Hippo signaling cascade to modulate VEGF signaling by regulating VEGFR2 expression (By similarity).
Interacts with SOSTDC1 (By similarity). Interacts (when glycosylated) with type I receptor ACVR1. Interacts with type II receptor ACVR2B (By similarity). Interacts with Hemojuvelin/HJV (By similarity).
Secreted by the epididymal epithelium and then becomes associated with the sperm surface.
This protein is supposed to help spermatozoa undergo functional maturation while they move from the testis to the ductus deferens.
Two major variant protein D and E differ from each other by their carbohydrate side chains.
Belongs to the SMC family. SMC4 subfamily.
Mammary gland specific. Secreted in milk.
Sodium- and proton-independent thyroid hormones and aromatic acids transporter. Mediates both uptake and efflux of 3,5,3'-triiodothyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4) with high affinity, suggesting a role in the homeostasis of thyroid hormone levels (By similarity). Responsible for low affinity bidirectional transport of the aromatic amino acids, such as phenylalanine, tyrosine, tryptophan and L-3,4-dihydroxyphenylalanine (L-dopa) (PubMed:11278508). Plays an important role in homeostasis of aromatic amino acids (By similarity).
Strongly expressed in intestine, placenta and liver. In small intestine is detected in the basolateral membrane (at protein level).
Contributes to histone modification (By similarity). May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4' (By similarity). As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3 (By similarity). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (By similarity). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (By similarity). May regulate osteoblasts differentiation (By similarity). In association with RBBP5 and ASH2L, stimulates the histone methyltransferase activities of KMT2A, KMT2B, KMT2C, KMT2D, SETD1A and SETD1B (By similarity).
Interacts with PAXBP1; the interaction is direct and links a WDR5-containing histone methyltransferase complex to PAX7 and PAX3 (By similarity). Interacts with HCFC1 (By similarity). Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (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 (By similarity). Core component of several methyltransferase-containing complexes including MLL1/MLL, MLL2/3 (also named ASCOM complex) and MLL4/WBP7 (By similarity). Each complex is at least composed of ASH2L, RBBP5, WDR5, DPY30, one or more specific histone methyltransferases (KMT2A/MLL1, KMT2D/MLL2, KMT2C/MLL3 and KMT2B/MLL4), and the facultative components PAGR1, BAP18, CHD8, E2F6, HCFC1, HCFC2, HSP70, INO80C, KDM6A, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, MYST1/MOF, NCOA6, PAXIP1/PTIP, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9, TEX10 and alpha- and beta-tubulin (By similarity). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (By similarity). Interacts with KMT2A/MLL1 (via WIN motif) and RBBP5; the interaction is direct (By similarity). Component ofthe ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (By similarity). In the complex, it probably interacts directly with KAT2A, MBIP and KAT14 (By similarity). Interacts with histone H3 (By similarity). Interacts with SETD1A (via WIN motif) (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 (By similarity). Interacts with ZNF335 (By similarity). 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 (By similarity). Interacts with PER1 (PubMed:15860628). Interacts with KMT2B (via WIN motif), KMT2C (via WIN motif), KMT2D (via WIN motif) and SETD1B (via WIN motif) (By similarity).
Speen, lungs and liver non-parenchymal cells.
Inhibits the transcriptional activation activity of the cone-rod homeobox CRX (By similarity). May participate in the regulation of visual phototransduction or in the integration of photoreceptor metabolism.
Interacts with CRX (By similarity). Forms a complex with the beta and gamma subunits of the GTP-binding protein, transducin.
Light-induced changes in cyclic nucleotide levels modulate the phosphorylation of this protein by cAMP kinase.
Belongs to the major facilitator superfamily. SLC46A family.
Expressed almost exclusively in the small intestine: expressed at high 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:18174275). Expressed at low level in other tissues, including liver (PubMed:16143108, PubMed:18174275).
In contrast to human ortholog, not inhibited by myricetin.
Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (PubMed:18174275, PubMed:31792273). 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:18174275). Functions at acidic pH via alternate outward- and inward-open conformation states (By similarity). Protonation of residues in the outward open state primes the protein for transport (By similarity). 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 (By similarity). Also able to transport antifolate drugs, such as methotrexate and pemetrexed (PubMed:18174275). Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes (By similarity). Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine (By similarity). Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells (By similarity). Hence, participates in the trafficking of heme and increases intracellular iron content (By similarity).
Associated with nucleolar and cytoplasmic pre-60S particles (By similarity). At the end of biogenesis it dissociates from cytoplasmic pre-60S particles and is likely to be exchanged for its ribosomal homolog, RPL24 (By similarity).
Involved in the biogenesis of the 60S ribosomal subunit. Ensures the docking of GTPBP4/NOG1 to pre-60S particles (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. APG1/unc-51/ULK1 subfamily.
Serine/threonine-protein kinase involved in autophagy in response to starvation.
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.
Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor.
Expressed in retina, smooth muscle, skin, pancreas, skeletal muscle, heart, brain, lung, kidney and testis. Not found in cartilage, spleen and liver.
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). Interacts with tyrosine-based sorting signals on the cytoplasmic tail of cargo proteins such as APP, ATG9A, LAMP2 and NAGPA (By similarity). Interacts with the C-terminal domain of GRID2 (PubMed:14572453). Interacts with GRIA1 and GRIA2; the interaction is indirect via CACNG3. 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 (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 (By similarity). The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal (PubMed:14572453).
High levels in the olfactory bulb, the cerebral cortex, the granule and Purkinje cell layers of the cerebellar cortex and the CA3 region of the hippocampus. Low levels found in molecular layer of cerebellum.
GAP activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2).
GTPase-activating protein (GAP) for ADP ribosylation factor 1 (ARF1). Hydrolysis of ARF1-bound GTP may lead to dissociation of coatomer from Golgi-derived membranes to allow fusion with target membranes (By similarity).
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:17851531, PubMed:21399626, PubMed:7961907). Interacts with FNIP1 and FNIP2 (By similarity).
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. 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:14511394). 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 (By similarity). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (By similarity). 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:2369897, PubMed:9029219). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (By similarity). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (PubMed:11598104, PubMed:11069105, PubMed:12065600). 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:12740371, PubMed:11724780). 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 (By similarity). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (By similarity). In that process also activates WDR45/WIPI4. Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (By similarity). 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 (By similarity). 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 (PubMed:21204788). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:10025949, PubMed:17341212, PubMed:14709557).
Low expression in kidney, liver, lung, heart and brain.
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. There is some ambiguity for some phosphosites: Ser-360/Thr-368 and Ser-486/Thr-488. Dephosphorylated by PPM1A and PPM1B (By similarity).
Binds SFTPD and SPAR in a calcium-dependent manner (By similarity). Interacts with LGALS3.
Expressed in von Ebner glands (VEG) (at protein level), olfactory epithelium and the lateral nasal gland. Expressed in transit-amplifying ductular (oval) cells. Up-regulated at day 3 after hepatectomy. Expressed in newly formed bile ducts and in structures resembling intestinal epithelium.
Highly N- and O-glycosylated. The O-glycans are heavily sulfated (By similarity).
May play roles in mucosal defense system, cellular immune defense and epithelial differentiation (By similarity). 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. May function as a binding protein in saliva for the regulation of taste sensation. May play a role as an opsonin receptor for SFTPD and SPAR in macrophages tissues throughout the body, including epithelial cells lining the gastrointestinal tract (By similarity). Required for terminal differentiation of columnar epithelial cells during early embryogenesis. 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 (By similarity).
The SRCR domains mediate binding to bacteria.
Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
Homodimer (By similarity). 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) (By similarity). 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.
Interacts with ABCB9; this interaction strongly stabilizes ABCB9 and protects ABCB9 against lysosomal degradation. Interacts with FURIN.
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. Mechanistically, participates in cytotoxic granule movement to the cell surface and perforin trafficking to the lytic granule. In addition, protects NK-cells from degranulation-associated damage induced by their own cytotoxic granule content. Presents carbohydrate ligands to selectins. Also implicated in tumor cell metastasis (By similarity).
O- and N-glycosylated; some of the N-glycans attached to LAMP-1 are polylactosaminoglycans.
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.
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 (By similarity).
Dipeptidase that hydrolyzes leukotriene D4 (LTD4) into leukotriene E4 (LTE4) and cystinyl-bis-glycine.
Independently of its dipeptidase activity can also modulate macrophage inflammatory response by acting as a regulator of NF-kappa-B inflammatory signaling pathway.
Highly expressed in hippocampus, brain cortex, cerebellum and olfactory bulb. Detected at lower levels in midbrain, hindbrain and spinal cord. Detected retina and in spinal cord motor neurons.
Interacts with RAB3C, RAB10, RAB26 and RAB37 (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. Binds RAB3A, RAB3B and RAB3D that have been activated by GTP-binding. Binds UNC13A. Interacts with TSPOAP1 and RIMBP2. Interacts with PPFIA3 and PPFIA4. Interacts with ERC1.
Rab effector involved in exocytosis. 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. Plays a role in dendrite formation by melanocytes.
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).
Binds to the receptor tyrosine kinases EPHA2, EPHA3, EPHB1 and EPHB2. Interacts with EPHA8; activates EPHA8. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function (By similarity).
Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Induces compartmentalized signaling within a caveolae-like membrane microdomain when bound to the extracellular domain of its cognate receptor. This signaling event requires the activity of the Fyn tyrosine kinase. Activates the EPHA3 receptor to regulate cell-cell adhesion and cytoskeletal organization. With the receptor EPHA2 may regulate lens fiber cells shape and interactions and be important for lens transparency maintenance. May function actively to stimulate axon fasciculation. The interaction of EFNA5 with EPHA5 also mediates communication between pancreatic islet cells to regulate glucose-stimulated insulin secretion. Cognate/functional ligand for EPHA7, their interaction regulates brain development modulating cell-cell adhesion and repulsion (By similarity).
Expressed in brain, heart, placenta and lung.
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.
Regulates ADAM10 maturation and trafficking to the cell surface. Promotes ADAM10-mediated cleavage of CD44.
Belongs to the triosephosphate isomerase family.
It is also responsible for the non-negligible production of methylglyoxal a reactive cytotoxic side-product that modifies and can alter proteins, DNA and lipids.
Triosephosphate isomerase is an extremely efficient metabolic enzyme that catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde-3-phosphate (G3P) in glycolysis and gluconeogenesis.
Specifically methylates cytosine 38 in the anticodon loop of tRNA(Asp).
Activated by micromolar levels of Ca(2+) (PubMed:12502557).
Active at all calcium levels tested (PubMed:15040000). Activated by PKC (PubMed:15040000).
Belongs to the Ca(2+):cation antiporter (CaCA) (TC 2.A.19) family. SLC8 subfamily.
Detected in heart, brain cortex and hippocampus (at protein level) (PubMed:16914199). Cardiac sarcolemma or brain, and spleen. Expressed in all regions of the kidney, highest levels of expression in the distal convoluted tubule. Expressed throughout the CNS, in decreasing order of abundance in hippocampus, cortex, cerebellum, hypothalamus, midbrain and striatum. Expressed in numerous regions of the brain including multiple cortical layers, hippocampus, septal nuclei, thalamic nuclei, cerebellum, hypothalamus, olfactory bulb and brainstem. Also expressed in various regions of the spinal cord, ventricles and atria of the heart, lung, adrenals and kidney. Isoform 4 seems to be a predominant isoform in aorta, stomach, liver, and kidney.
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:8422940, PubMed:8454039, PubMed:10894800, PubMed:12502557). Contributes to Ca(2+) transport during excitation-contraction coupling in muscle. 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. SLC8A1 mediates the export of Ca(2+) from the cell during the next phase, so that cytoplasmic Ca(2+) levels rapidly return to baseline. Required for normal embryonic heart development and the onset of heart contractions (By similarity).
Only active at low calcium concentrations (PubMed:15040000). Activated by PKC (PubMed:15040000).
Only active at low calcium concentrations (PubMed:15040000). Not activated by PKC (PubMed:15040000).
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.
Calcium transport is down-regulated by Na(+) and stimulated by Ca(2+).
Detected in neocortex and hippocampus on pyramidal cells, astrocyte processes and dendrites (at protein level) (PubMed:16914199). Brain and 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 (PubMed:8021246, PubMed:9486131). Contributes to cellular Ca(2+) homeostasis in excitable cells (By similarity). 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). Plays a role in regulating urinary Ca(2+) and Na(+) excretion (By similarity).
'Ropporin' comes from the Japanese word 'oppo' which means 'tail'.
Homodimer. Interacts with AKAP3 (By similarity). May interact with SPA17 (By similarity). Interacts with RHPN1 (By similarity). 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.
Anterior pituitary, liver, brain, adrenal gland, kidney, testis and heart. Expression in the anterior pituitary is 3 fold higher in male as compared to female.
Farnesylated. Farnesylation is required for membrane targeting and for interaction with RABGGTB (By similarity).
In contrast to PTP4A1 and PTP4A3, does not interact with tubulin. Interacts with RABGGTB (By similarity).
Inhibited by sodium orthovanadate and pentamidine.
Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. Inhibits geranylgeranyl transferase type II activity by blocking the association between RABGGTA and RABGGTB (By similarity).
Belongs to the DEAD box helicase family. DDX21/DDX50 subfamily.
Induced by estrogens and suppressed by androgens. Expression is under the influence of pituitary growth hormone and thyroid hormone.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze sulfonation of hydroxysteroids and xenobiotics.
Can cross-link actin filaments into both network and bundle structures. May modulate changes in actin filament integrity and induce lamellipodia formation. May function as an adapter molecule that links other proteins, such as SRC and PKC to the actin cytoskeleton (By similarity).
Monomer and homomultimer. Interacts via its C-terminus with F-actin; probably involving AFAP1 multimers (By similarity). Interacts with activated SRC SH3-SH2 domains. Interacts via its PH 1 domain with PRKCA, PRKCB and PRKCI (By similarity).
Widely expressed with highest levels in brain.
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 (By similarity).
Specific cleavages in the N-terminal arm occur during lens maturation and give rise to several truncated forms.
The initiator methionine for isoform A1 is removed. The new N-terminal amino acid is then N-acetylated (By similarity).
Belongs to the histatin/statherin family.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1C subfamily.
Binding of intracellular calcium through the EF-hand motif inhibits the opening of the channel.
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1C) and ancillary beta, gamma and delta subunits (PubMed:15170217). The channel complex contains alpha, beta, gamma and delta subunits in a 1:1:1:1 ratio, i.e. it contains only one of each type of subunit. CACNA1C channel activity is modulated by ancillary subunits, such as CACNB1, CACNB2, CACNB3, CACNA2D1 and CACNA2D4 (By similarity). Interacts with the gamma subunits CACNG4, CACNG6, CACNG7 and CACNG8 (By similarity). Interacts with CACNB1 (By similarity). Interacts with CACNB2. Identified in a complex with CACNA2D4 and CACNB3 (By similarity). Interacts with CACNB3 (PubMed:24751537, PubMed:15170217). Interacts with CACNA2D1. Interacts with CACNA2D4. Interacts with CALM1. Interacts (via the N-terminus and the C-terminal C and IQ motifs) with CABP1; this inhibits Ca(2+)-dependent channel inactivation (PubMed:15140941). The binding via the C motif is calcium independent whereas the binding via IQ requires the presence of calcium and is mutually exclusive with calmodulin binding (PubMed:15140941). The binding to the cytoplasmic N-terminal domain is calcium independent but is essential for the channel modulation. Interacts (via C-terminal CDB motif) with CABP5; in a calcium-dependent manner. Interacts with CIB1; the interaction increases upon cardiomyocytes hypertrophy (By similarity). Interacts with STAC2 and STAC3; this inhibits channel inactivation (By similarity).
Detected in hippocampus and brain cortex, on neuronal cell bodies and dendrites, and in post-synaptic density in brain (at protein level) (PubMed:15140941). Isoforms 4 and 5 are expressed throughout the central nervous system, with highest levels in the olfactory bulb and cerebellum. Also expressed in heart, pituitary, adrenal gland, liver, kidney, and in a much lesser extent in testes and spleen.
Expressed from embryonic day 16 until the adult stage.
Inhibited by dihydropyridines (DHP), such as isradipine (By similarity). Inhibited by nifedipine (By similarity). Channel activity is regulated by Ca(2+) and calmodulin (PubMed:15140941). Binding of STAC1, STAC2 or STAC3 to a region that overlaps with the calmodulin binding site inhibits channel inactivation by Ca(2+) and calmodulin (By similarity). Binding of calmodulin or CABP1 at the same regulatory sites results in opposite effects on the channel function (PubMed:15140941). Shear stress and pressure increases calcium channel activity (By similarity).
Phosphorylation by PKA at Ser-1927 activates the channel (By similarity). Elevated levels of blood glucose lead to increased phosphorylation by PKA (By similarity). Is also phosphorylated in vitro by CaM-kinase II, PKC and CGPK (PubMed:8396138).
Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents (Probable) (PubMed:15140941, PubMed:15170217). Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm (By similarity). Plays an important role in excitation-contraction coupling in the heart (By similarity). Required for normal heart development and normal regulation of heart rhythm (By similarity). Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells (By similarity). Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (By similarity).
Interacts with GDI1, GDI2 and CHM; phosphorylation at Thr-80 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 Mycobacterium.
As part of the MCIA complex, involved in the assembly of the mitochondrial complex I (PubMed:22982022). Participates in constructing the membrane arm of complex I (By similarity).
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:22982022). Associates with the intermediate 370 kDa subcomplex of incompletely assembled complex I (By similarity). Interacts with TMEM70 (By similarity).
Reduction in respiration by about two-thirds, only when the electrons were fed into complex I via the NADH-linked substrates malate and glutamate in ADP-stimulated mitochondria.
Homomer assembled from elementary dimers (By similarity). Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin (By similarity). Interacts with BCAS3 (By similarity). Interacts with LGSN (By similarity). Interacts with SYNM (By similarity). Interacts (via rod region) with PLEC (via CH 1 domain) (By similarity). Interacts with STK33 (By similarity). Interacts with LARP6 (By similarity). Interacts with RAB8B (PubMed:12639940). Interacts with TOR1A; the interaction associates TOR1A with the cytoskeleton. Interacts with TOR1AIP1 (By similarity). Interacts with TOR1AIP1 (By similarity). Interacts with DIAPH1 (By similarity). Interacts with EPPK1; interaction is dependent of higher-order structure of intermediate filament (By similarity). Interacts with the non-receptor tyrosine kinase SRMS; the interaction leads to phosphorylation of VIM (By similarity). Interacts with NOD2 (By similarity). Interacts (via head region) with CORO1C (By similarity). Interacts with HDGF (By similarity). Interacts with PRKCE (via phorbol-ester/DAG-type 2 domain) (By similarity). Interacts with BFSP2 (By similarity). Interacts with PPL (By similarity). Interacts with PKP1 and PKP2 (By similarity).
Involved with LARP6 in the stabilization of type I collagen mRNAs for CO1A1 and CO1A2.
One of the most prominent phosphoproteins in various cells of mesenchymal origin (By similarity). Phosphorylation is enhanced during cell division, at which time vimentin filaments are significantly reorganized (By similarity). Phosphorylation by PKN1 inhibits the formation of filaments (By similarity). Filament disassembly during mitosis is promoted by phosphorylation at Ser-55 as well as by nestin (PubMed:12686602). Phosphorylated at Ser-56 by CDK5 during neutrophil secretion in the cytoplasm (By similarity). Phosphorylated by STK33 (By similarity). Phosphorylated on tyrosine residues by SRMS (By similarity).
The central alpha-helical coiled-coil IF rod domain mediates elementary homodimerization.
Vimentins are class-III intermediate filaments found in various non-epithelial cells, especially mesenchymal cells. Vimentin is attached to the nucleus, endoplasmic reticulum, and mitochondria, either laterally or terminally.
Activated by quisqualate > glutamate > ibotenate > trans-1- aminocyclopentyl-1,3-dicarboxylate.
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.
Interacts with RYR1, RYR2, ITPR1, SHANK1 and SHANK3. The PPXXF motif binds HOMER1, HOMER2 and HOMER3. Interacts with SIAH1 and TAMALIN. Interacts with NCDN. Interacts with NECAB2. Interacts with CAMK2A (By similarity).
Widely distributed in neuronal cells of the central nervous system.
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.
Expression coincides with the increasing numbers of round spermatids and decreases during the termination of the first spermatogenic cycle.
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 (By similarity). Interacts with HEATR2; probably involved in outer arm dynein assembly (By similarity).
Part of the dynein complex of respiratory cilia.
Expressed in kidney, adipose tissue, lung and heart, as well as at higher levels in brain.
Homodimer (By similarity). Interacts with both alpha- and beta-tubulin (PubMed:12966166).
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.
Homodimer (By similarity). Interacts with UBQLN4; leading to the export of UBQLN4 from the nucleus (By similarity).
Protease which deconjugates SUMO1, SUMO2 and SUMO3 from some substrate proteins. Has isopeptidase but not SUMO-processing activity. Desumoylates ZBTB46 (By similarity). Collaborates with UBQLN4 in the export of ubiquitinated proteins from the nucleus to the cytoplasm (By similarity).
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. PIM subfamily.
By membrane depolarization or forskolin.
Detected in various tissues, including brain.
Interacts with BAD. Interacts with PPP2CA; this interaction promotes dephosphorylation of PIM3, ubiquitination and proteasomal degradation. Interacts with SOCS6.
Phosphorylated. Interaction with PPP2CA promotes dephosphorylation (By similarity). Autophosphorylated (in vitro).
Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation.
Proto-oncogene with serine/threonine kinase activity that can prevent apoptosis and 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 and 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 (By similarity).
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.
Belongs to the major facilitator superfamily. Sodium/anion cotransporter family.
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).
Interacts with NOTCH2; this interaction increases MINAR1 stability. Interacts (via N-terminus) with DEPTOR (via PDZ domain); this interaction may stabilize DEPTOR protein by impairing its ubiquitination.
Intrinsically disordered protein which may negatively regulate mTOR signaling pathway by stabilizing the mTOR complex component DEPTOR (PubMed:30080879). Negatively regulates angiogenesis (By similarity). Negatively regulates cell growth (By similarity). Negatively regulates neurite outgrowth in hippocampal neurons (PubMed:30080879).
MINAR1 topology is a matter of debate, some authors think the N-terminus is extracellular, while preliminary experimental results suggest a cytosolic location.
Belongs to the GSK-3-binding protein family.
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.
Brain; in the CA1 region of hippocampus, the medial habenula, and raphe nuclei.
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. Probably involved in anxiety and depression.
Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication. Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B. Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.
Expressed in brain, heart, liver, lung, skeletal muscle, spleen and testis.
Interacts (phosphorylated by ATR) with RAD51. Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates CHEK1 through dephosphorylation. Interacts with TIMELESS; DNA damage-dependent. Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ. Interacts with CDK5RAP3; antagonizes CHEK1.
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 (By similarity).
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. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. 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. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. 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. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. 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. 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. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA (By similarity). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. 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. Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (By similarity). 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 (By similarity).
The autoinhibitory region (AIR) inhibits the activity of the kinase domain.
Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion. 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 (By similarity).
Interacts with TRPV5 and TRPV6 (By similarity). Interacts with YWHAZ/14-3-3 protein zeta.
May regulate epithelial calcium transport by inhibiting TRPV5 activity.
Predominantly expressed in testis. Expressed in brain at low levels.
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 (By similarity). 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 (By similarity).
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).
By pregnenolone-alpha-carbonitrile, dexamethasone, phenobarbital, and triacetyloleandomycin.
Catalyzes 16-beta- and 6-alpha-hydroxylations of testosterone.
Belongs to the metallo-dependent hydrolases superfamily. Adenosine and AMP deaminases family.
Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine (PubMed:19900420). 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. Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion. Enhances dendritic cell immunogenicity by affecting dendritic cell costimulatory molecule expression and cytokines and chemokines secretion. Enhances CD4+ T-cell differentiation and proliferation. Acts as a positive modulator of adenosine receptors ADORA1 and ADORA2A, by enhancing their ligand affinity via conformational change. Stimulates plasminogen activation. Plays a role in male fertility. Plays a protective role in early postimplantation embryonic development.
Detected in brain and liver (at protein level).
Interacts with DPP4 (via extracellular domain). Interacts with PLG (via Kringle 4 domain); the interaction stimulates PLG activation when in complex with DPP4.
Highly expressed in testis. Detected at lower levels in brain, astrocytes, heart and small intestine.
Interacts with STX17 (Probable). Interacts with the COG complex via COG4. Interacts with STX5A.
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.
Up-regulated in astrocytes upon reoxygenation after hypoxia.
Exhibits ester hydrolase activity on the substrate p-nitrophenyl acetate.
May be involved in induction of apoptosis in CD4(+) T-cells, but not CD8(+) T-cells or hepatocytes.
Autophosphorylated. Autophosphorylation is blocked by interaction with SUFU (By similarity).
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 (By similarity).
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.
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 oligomers with CBLN2, CBLN3 and CBLN4 prior to secretion. Once secreted, does not interact with other CBLN family members. Interacts with GRID1. 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 (By similarity). 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 (By similarity). Interacts with OTOL1 (By similarity).
Initially the cerebellin peptide was thought to present the biological active entity.
Localized in the Purkinje cells. Cerebellin is expressed in adrenal gland /adrenal cortex (at protein level). In the cerebellum, [des-Ser1]-cerebellin is more abundant than cerebellin. At lower levels also found in heart, kidney stomach and gastrointestinal tract.
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 (By similarity). 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 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. A conversion to [des-Ser1]-cerebellin by endopeptidases seems to be required for its autocrine-paracrine regulatory functions.
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.
Detected only in neural tissue. Expressed in the developing cerebellum and in primary granules neurons (at protein level).
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).
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:6122208) (By similarity). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases (PubMed:6122208). 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:6122208). Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4 (PubMed:6122208).
Detected in adult kidney and mammary gland, and in fetal liver.
N-glycosylated on both chains; contains sialic acid residues. It is not known if the sialic acid residues are present on N-linked or on O-linked glycans.
O-glycosylated; close to the membrane anchor on the heavy chain and on the light chain. The sugar moieties are localized to the stretch Thr-28 to Ser-30. Contains sialic acid residues. It is not known if the sialic acid residues are present on N-linked or on O-linked glycans.
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)) (By similarity). Interacts with BRAWNIN (By similarity). 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. 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 (By similarity). Seems to play an important role in the maintenance of proper mitochondrial function in nigral dopaminergic neurons (By similarity).
May be involved in the later stages of fibrous sheath biogenesis. Binds calcium (By similarity).
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.
Self-associates (via leucine-rich repeats), giving rise to homooligomers. Interacts with FGFR1. Interacts with FGFR2. Interacts (via extracellular domain) with ADGRL1/LPHN1 (By similarity). Interacts (via extracellular domain) with ADGRL3 (via olfactomedin-like domain) (PubMed:22405201). 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 (By similarity).
Adapter protein which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Essential for the efficient induction of IRF-dependent transcription following infection with Sendai virus (By similarity).
Homodimer (By similarity). May form a heterodimer with NAP1. Interacts with TKB1 and IKBKE (By similarity). Weakly interacts with DDX3X (By similarity).
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 (By similarity).
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.
Contains mostly 4-hydroxyproline. Prolines at the third position of the tripeptide repeating unit (G-X-P) are 4-hydroxylated in some or all of the chains.
Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces.
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 (By similarity). Part of a complex composed of CD9, CD81 and IGSF8 (By similarity). Also seems to interact with CD63, CD82 and CD151 (By similarity).
Limited proteolysis of myosin heavy chain produces 1 light meromyosin (LMM) and 1 heavy meromyosin (HMM). HMM can be further cleaved into 2 globular subfragments (S1) and 1 rod-shaped subfragment (S2).
Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2).
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-4 (MYO4).
The rodlike tail sequence is highly repetitive, showing cycles of a 28-residue repeat pattern composed of 4 heptapeptides, characteristic for alpha-helical coiled coils.
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.
Activated by cAMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening (By similarity).
Highly expressed in pyramidal and granule layer of the hippocampus, in thalamus anterior nucleus, in the supraoptic nucleus in hypothalamus, in cerebellum, and in trapezoid nuclei and superior olivary complex in the auditory system. Detected in a subset of elongated cells in taste buds.
Homotetramer. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits (By similarity).
Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih) (By similarity). May mediate responses to sour stimuli.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Widely expressed in brain and spinal cord.
Acts as a dimer forming a proton channel.
Expressed in a variety of organs, with predominant expression in the heart, lung and spleen.
UCP are mitochondrial transporter proteins that create proton leaks across the inner mitochondrial membrane, thus uncoupling oxidative phosphorylation from ATP synthesis. As a result, energy is dissipated in the form of heat (By similarity).
Belongs to the eukaryotic release factor 1 family. Pelota subfamily.
Cotranslational quality control factor involved in the No-Go Decay (NGD) pathway. In the presence of ABCE1 and HBS1L, is required for 48S complex formation from 80S ribosomes and dissociation of vacant 80S ribosomes. 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. 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.
The N-terminal domain has the RNA-binding Sm fold. It harbors the endoribonuclease activity.
Expressed in germ cells as well as in somatic cells of the testis (at protein level). Ubiquitous.
Plays a role in primary ciliogenesis by modulating actin polymerization.
Detected in spleen, mast cells and macrophages (at protein level).
Interacts with BIN1 and ARHGEF7 (via SH3 domain) (By similarity). Homodimer. Interacts with ARHGEF6 (via SH3 domain), SH3GL1, SH3GL2 and SH3GL3. Identified in a complex with ARHGEF6 and GIT2.
Promotes cell motility and migration, probably via its interaction with the cell membrane and with podosome proteins that mediate interaction with the cytoskeleton. Modulates membrane curvature and mediates membrane tubulation (By similarity). Plays a role in podosome formation. Inhibits phagocytosis.
The BAR domain mediates dimerization and interaction with membranes enriched in phosphatidylinositides.
By wound, in oral mucosa undergoing tooth extraction.
May be involved in wound healing pathway underlying the favorable early wound closure characteristics of oral mucosa. Accelerates the collagen gel contraction in vitro.
Acts as a ligand for galanin receptors GALR2 and GALR3 (By similarity). Intracerebroventricular administration of the peptide induces an increase in arterial blood pressure, a decrease in both heart rate and renal excretion and delayed natriuresis. Intraventricular administration of the peptide induces antinociceptive activity. Intraperitoneal administration of the peptide induces a reduction in food consumption and body weight. Inhibits long chain fatty acid uptake into adipocytes. Also induces contraction of muscarinic-like stomach smooth muscles (PubMed:24550067).
Intracerebroventricular administration of the peptide induces a decrease in heart rate, but no change in arterial pressure, and an increase in urine flow rate. Intraventricular administration of the peptide induces antinociceptive activity (PubMed:22038051).
Plays a role as a central modulator of cardiovascular and renal function and nociception. Also plays a role in energy metabolism and storage. Inhibits adrenocortical cell proliferation with minor stimulation on corticosteroid release (PubMed:20045034, PubMed:22038051).
Up-regulated by enucleation-induced adrenocortical regeneration (at protein level). Up-regulated by dexamethasone (DX) treatment. Down-regulated by adrenocorticotropic hormone (ACTH) treatment. Up-regulated by hypoxia in the carotid body.
Widely expressed; predominantly expressed in epithelial cells in the skin, respiratory, digestive, urinary and reproductive systems, retina, adrenal gland and various brain regions. In the adrenal gland, expressed in parenchymal cells of the cortex and in ganglionic cells and intermingled cortical cells of the medulla. Expressed in the type I glomic cells within the carotid body (at protein level). Widely expressed. Strongly expressed in esophagus, liver, pancreas, kidney, brain, hypothalamus, thyroid and ovary. Expressed in the zona glomerulosa (ZG) and zona fasciculata/reticularis (ZF/R) of the adrenal gland. Also expressed in stomach, lung, skeletal muscle, heart, uterus, spleen, adrenal gland and testis. Weakly expressed in small intestine, thymus, urinary bladder and adenohypophysis. In the brain, is expressed in the Barrington's nucleus, with lesser amount in the ventrolateral caudal periaqueductal gray (PAG) and in the mesopontine tegmentum.
Acts as an epigenetic regulator of myogenesis in cooperation with DPF3a (isoform 2 of DPF3/BAF45C) (By similarity). 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 (By similarity). 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 (By similarity). Preferentially binds to chromatin regions marked by H3K9me3, H3K27me3 and H3K36me2 (By similarity). Involved in cellular growth control, through the regulation of cyclin D1 expression (By similarity).
Expressed at highest levels in the spinal cord at embryonic day 9, expression remains high at postnatal day 7 (P7), become weak at P14 and is not detectable at two months (at protein level).
Expressed in the spinal cord (at protein level) (PubMed:26252862). Primarily restricted to neurons, astrocytes and oligodendrocytes and is particularly expressed in motor neurons of the anterior horn (at protein level) (PubMed:26252862). Significantly up-regulated in the injured spinal cord (at protein level) (PubMed:26252862).
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 (By similarity). Interacts with IWS1 (By similarity). Interacts with H2AX, POGZ, RBBP8 and CBX1 (By similarity). Interacts with histones H3K9me3, H3K27me3 and H3K36me2 (By similarity). Interacts with DPF3a (isoform 2 of DPF3/BAF45C). Interacts with SMARCA4/BRG1/BAF190A, SMARCC1/BAF155 and SMARCD1/BAF60A in a DPF3a-dependent manner (By similarity).
Interacts (via region A) with DDX6/RCK. Interacts (via region H and region C) with LSM1 and LSM4. Interacts (via region N) with DCP1A, DCP2, EDC3, EDC4 and XRN1. Interacts with the CCR4-NOT complex. Interacts with the Lsm-containing SMN-Sm protein complex. Interacts with EIF4ENIF1/4E-T.
RNA-binding protein involved in deadenylation-dependent decapping of mRNAs, leading to the degradation of mRNAs. Acts as a scaffold protein that connects deadenylation and decapping machinery. Required for cytoplasmic mRNA processing body (P-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.
Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump.
Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis. In aerobic conditions, required for intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. Necessary for endolysosomal acidification and lysosomal degradation (By similarity). May be involved in Golgi homeostasis (By similarity).
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. SOCE is a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Acts by interacting with STIM1, promoting STIM1 conformational switch. Involved in STIM1 relocalization to ER-PM junctions. Contributes to the maintenance and reorganization of store-dependent ER-PM junctions.
The GXXXG motif may mediate oligomerization. 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.
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. Hypusination is unique to mature eIF-5A factor and is essential for its function.
DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair. 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. 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. Also able to hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity (By similarity). 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. Interacts with NCL. Interacts (via FHA-like domain) with MDC1 (phosphorylated).
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.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA5 sub-subfamily.
Ligand-gated chloride channel subunit which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain. May be involved in GABA-A receptor assembly, and GABA-A receptor immobilization and accumulation by gephyrin at the synapse.
Belongs to the AB hydrolase superfamily. AB hydrolase 4 family.
ATP-dependent low-affinity peptide transporter which translocates a broad spectrum of peptides from the cytosol to the lysosomal lumen for degradation. Displays a broad peptide length specificity from 6-mer up to at least 59-mer peptides with an optimum of 23-mers. Binds and transports smaller and larger peptides with the same affinity. 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.
Belongs to the ABC transporter superfamily. ABCB family. MHC peptide exporter (TC 3.A.1.209) subfamily.
Divided into an N-terminal domain (TMD0) comprising four transmembrane helices and the following core domain (coreABCB9). TMD0 is required for lysosomal localization and LAMP1, LAMP2 and YIF1B interaction. The core domain is required for homodimerization and peptide transport activity.
Found in testis, particularly in the Sertoli cells of the seminiferous tubules. Also expressed in kidney, brain, heart, lung, spleen, thymus, intestine and testis. Higher expression detected in brain and testis than in thymus and intestine.
Homodimer (PubMed:18175933). Interacts (via TMD0 region) with LAMP1; this interaction strongly stabilizes ABCB9 and protects ABCB9 against lysosomal degradation. Interacts (via TMD0 region) with LAMP2 (isoform LAMP-2B). 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 (By similarity).
Highly expressed in heart, brain, spleen, lung, kidney and white adipose tissue. Detected at lower levels in skeletal muscle and liver.
Homodimer. Binds tankyrases 1 and 2 (By similarity).
Release of an N-terminal amino acid, cleave before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain (By similarity).
Belongs to the eukaryotic ribosomal protein eS12 family.
Belongs to the POU transcription factor family.
Activates macrophages and polarizes them into M1-like macrophages through the activation of the MAPK and NF-kappaB signaling pathway. Upon activation, up-regulates the expression of CD80, CD86, CD69 and MHC II on macrophages, and induces the release of pro-inflammatory cytokines such as TNF, IL1B, IL6, CCL2 and nitric oxide (By similarity). May play a role in inhibition of proliferation and migration (By similarity).
Component of the lateral elements of synaptonemal complexes (PubMed:8289794, PubMed:9933407). Homotetramer; the tetrameric helix bundles assemble end to end into long homopolimeric fibers (in vitro) (By similarity). Homooligomer that assembles into fibers; the fibers exhibit a transversal striation with a periodicity of about 20 nm (in vitro) (PubMed:9679134, PubMed:18391527). Interacts with SYCP2 (PubMed:10652260). Forms a complex with EWSR1, PRDM9, REC8 and SYCP1; complex formation is dependent of phosphorylated form of REC8 and requires PRDM9 bound to hotspot DNA; EWSR1 joins PRDM9 with the chromosomal axis through REC8 (By similarity).
Component of the synaptonemal complexes (SCS), formed between homologous chromosomes during meiotic prophase (PubMed:8289794, PubMed:9933407). Required for centromere pairing during meiosis in male germ cells. Required for normal meiosis during spermatogenesis and male fertility. Plays a lesser role in female fertility. Required for efficient phosphorylation of HORMAD1 and HORMAD2.
Composed of a long central coiled coil domain. The N-terminal and C-terminal regions interact with DNA.
Detected in spermatocytes and testis (at protein level) (PubMed:8289794, PubMed:9933407). Testis-specific (PubMed:8289794).
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 (By similarity).
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.
Prolyl 3-hydroxylase that catalyzes the post-translational formation of 3-hydroxyproline on collagens (PubMed:21757687). 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. Catalyzes hydroxylation of the first Pro in Gly-Pro-Hyp sequences where Hyp is 4-hydroxyproline. Has no activity on substrates that lack 4-hydroxyproline in the third position (By similarity).
Expressed specifically in the placenta. Highly expressed in invasive trophoblast cells lining the central placental vessel.
Highest levels are observed from day 11 until parturition, with peak levels also on day 13.
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.
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 (PubMed:29453251). 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 through the GPCR FPR2 (By similarity). Acts as a 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 (PubMed:29453251). Inhibits injury-induced cell proliferation and neointima formation in the femoral arteries (PubMed:29453251).
Expressed in the epididymal adipose tissue, in aortic adventitial fibroblasts and low expression in vascular smooth muscle cells (at protein level) (PubMed:29453251). Expressed in the central nervous system, highly expressed in the hypothalamic paraventricular nucleus (PubMed:29453251).
Repressed in adipocytes after stimulation with Tnfa, Il6 and Ins1 (PubMed:29453251). Specifically down-regulated in the hypothalamic paraventricular nucleus following water deprivation (PubMed:29453251).
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. 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 (By similarity). Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (PubMed:17404618). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7. May have a role in sialyl-lex-mediated transduction of apoptotic signals (By similarity). Involved in bone resorption (By similarity).
Expressed in testis, skeletal muscle, lung, liver, spleen, brain, heart, kidney and bone. Weakly expressed in monocytes (at protein level).
Interacts (via N- and C-terminus) with RAB7A (GTP-bound form). Simultaneously interacts with RAB7A and ARL8B; bringing about clustering and fusion of late endosomes and lysosomes. 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. PLEKHM1 and PLEKHM2 compete for interaction with ARL8B. Interacts with ARL8A; the interaction is weaker than with ARL8B. 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 (By similarity). Interacts with GABARAP, GABARAPL, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C (By similarity). 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). May interact with sialyl-lex-positive protein (By similarity).
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.
Calcium-regulated membrane-binding protein whose affinity for calcium is greatly enhanced by anionic phospholipids. It binds two calcium ions with high affinity. May be involved in heat-stress response. Inhibits PCSK9-enhanced LDLR degradation, probably reduces PCSK9 protein levels via a translational mechanism but also competes with LDLR for binding with PCSK9.
Heterotetramer containing 2 light chains of S100A10/p11 and 2 heavy chains of ANXA2/p36 (By similarity). Interacts with ATP1B1 (By similarity). Interacts with DYSF (By similarity). Interacts with COCH. Interacts (via repeat Annexin 1) with PCSK9 (via the C-terminal domain); the interaction inhibits the degradation of LDLR. Interacts with CEACAM1 (via the cytoplasmic domain); this interaction is regulated by phosphorylation of CEACAM1 (By similarity). Interacts with APPL2 and APPL1; targets APPL2 to endosomes and acting in parallel to RAB5A (By similarity). Interacts with S100A4 (By similarity). May interact with UBAP2 (By similarity).
It may cross-link plasma membrane phospholipids with actin and the cytoskeleton and be involved with exocytosis.
Belongs to the bZIP family. C/EBP subfamily.
Binds DNA as a homodimer and as a heterodimer. Can form stable heterodimers with CEBPA, CEBPB and CEBPD (PubMed:1884998). Interacts with GATA1 and SPI1 (By similarity). Interacts with SMARCD2 (By similarity).
Transcriptional activator. 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.
Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (PubMed:1556123, PubMed:9988735). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (By similarity). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (By similarity). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (By similarity). Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway (By similarity).
Monomer. Has a tendency to form higher mass oligomers.
Present primarily in testis (PubMed:1556123). Expressed in flagella of epididymal sperm (PubMed:19423663). Isoform Cytoplasmic: Highly expressed in testis (PubMed:14575705). Present in spermatogonia, spermatocyte and spermatid (at protein level) (PubMed:14575705).
Produced by alternative initiation at Met-28 of isoform Mitochondrial.
Required for male fertility by stabilizing the condensed chromatin in sperm nuclei.
Specifically able to suppress the production of leukotriene and prostaglandin in response to several stimuli by reducing fatty acid hydroperoxide (PubMed:9442035, PubMed:11010961).
Specifically required to prevent mitochondrial cell death by mediating reduction of cardiolipin hydroperoxide (PubMed:9988735, PubMed:10506188, PubMed:10998361). Also required for normal sperm development and male fertility (By similarity).
Magnesium-independent polyisoprenoid diphosphatase that catalyzes the sequential dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates. 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. May regulate the biosynthesis of cholesterol and related sterols by dephosphorylating presqualene and farnesyl diphosphate, two key intermediates in this biosynthetic pathway. 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. Has a lower activity towards phosphatidic acid (PA), but through phosphatidic acid dephosphorylation may participate in the biosynthesis of phospholipids and triacylglycerols. May also act on ceramide-1-P, lysophosphatidic acid (LPA) and sphing-4-enine 1-phosphate/sphingosine-1-phosphate.
Phosphorylation by PKC activates the phosphatase activity towards presqualene diphosphate.
Can form homomers (By similarity). Interacts (via N-terminus) with MAP6 (via C-terminus) (PubMed:24357581). Interacts (via C-terminus) with the vacuolar-type ATPase subunit ATP6AP1 (By similarity). Interacts (via N-terminus) with AP2M1 and CLTC (By similarity). Interacts with TMEM106C (By similarity).
Expressed in cortical neurons (at protein level).
In neurons, involved in the transport of late endosomes/lysosomes (PubMed:24357581). May be involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking (PubMed:24357581). May act as a molecular brake for retrograde transport of late endosomes/lysosomes, possibly via its interaction with MAP6 (PubMed:24357581). 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 particularly 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 (By similarity). Required for proper lysosomal acidification (By similarity).
Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking. May act as a molecular brake for retrograde transport of late endosomes/lysosomes, possibly via its interaction with MAP6 (PubMed:24357581). In neurons, may also play a role in the regulation of lysosomal size and responsiveness to stress (By similarity). Required for proper lysosomal acidification (By similarity).
Belongs to the complex I NDUFB7 subunit family.
Highly active in the 15-alpha-hydroxylation of testosterone.
Interacts with IL1RAP; the association is enhanced by IL36B indicative for an functional signaling complex and inhibited by IL36RN (By similarity).
Predominant expression in the lung and epididymis, with lower expression in cerebral cortex and testis. Expression in the brain is non-neuronal and associated with the cerebral vasculature. Not detected in any cell line tested.
Receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways. The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system. Seems to be involved in skin inflammatory response by induction of the IL-23/IL-17/IL-22 pathway. Receptor for the interleukin IL36G. Binding to the agonist leads to the activation of NF-kappa-B (By similarity).
Homodimer. Interacts with ARFGEF2/BIG2; both proteins are probably part of the same or very similar macromolecular complexes. Interacts with FKBP2. Interacts with MYO9B. Interacts with PRKAR1A and PRKAR2A. Interacts with PPP1CC. Interacts with NCL, FBL, NUP62 and U3 small nucleolar RNA. Interacts with DPY30. Interacts with PDE3A. Interacts with KANK1. Interacts with TBC1D22A and TBC1D22B.
Phosphorylated. In vitro phosphorylated by PKA reducing its GEF activity and dephosphorylated by phosphatase PP1 (By similarity).
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 (By similarity).
May be a regulator of keratinocyte proliferation or differentiation.
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. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.
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.
Expressed in heart only (at protein level).
Interacts with ZNF638 and TTN/titin. Interacts with E4F1. Interacts with GRB7. Interacts with SIRT1 and FOXO1. Interacts with CEFIP and calcineurin. Interacts with FOXK1.
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 (By similarity). Negatively regulates the calcineurin/NFAT signaling pathway in cardiomyocytes (PubMed:22851699).
The third LIM zinc-binding mediates interaction with E4F1.
Detected in brain, heart and lung (at protein level) (PubMed:31384490). Expressed in optic nerve sheath envelope(at protein level) (PubMed:29445566).
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 (By similarity).
Plays a role in cellular signaling via Rho-related GTP-binding proteins and activation of transcription factor SRF. Targets TJP1 to cell junctions (By similarity). In cortical neurons, may play a role in glutaminergic signal transduction through interaction with the NMDA receptor subunit GRIN1.
Homotetramer. Component of activated, catalytic and post-catalytic spliceosomes. 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 KNSTRN (By similarity). Interacts with PSMC5 (By similarity). Interacts (via N-terminus) with CDC5L (PubMed:16352598). Interacts with KHDC4 (By similarity). Interacts with USB1 (By similarity).
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. 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. Recruited to RNA polymerase II C-terminal domain (CTD) and the pre-mRNA, it may also couple the transcriptional and spliceosomal machineries. The XAB2 complex, which contains PRPF19, is also involved in pre-mRNA splicing, transcription and transcription-coupled repair. 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. May also play a role in DNA double-strand break (DSB) repair by recruiting the repair factor SETMAR to altered DNA. As part of the PSO4 complex may also be involved in the DNA interstrand cross-links/ICLs repair process. In addition, may also mediate 'Lys-48'-linked polyubiquitination of substrates and play a role in proteasomal degradation (By similarity). 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 (PubMed:16352598).
Ubiquitin-protein ligase which is mainly involved pre-mRNA splicing and DNA repair. Required for pre-mRNA splicing as component of the spliceosome.
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 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)) (By similarity). Interacts with AFG1L (By similarity). Interacts with RAB5IF (By similarity).
Expressed in the head of epididymal sperm but not in testicular sperm (at protein level).
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).
S-adenosyl-L-methionine-dependent methyltransferase that mediates mRNA cap1 2'-O-ribose methylation to the 5'-cap structure of mRNAs. Methylates the ribose of the first nucleotide of a m(7)GpppG-capped mRNA and small nuclear RNA (snRNA) to produce m(7)GpppRm (cap1). Displays a preference for cap0 transcripts. Cap1 modification is linked to higher levels of translation. May be involved in the interferon response pathway.
Brain-specific. High expression in the cerebellum, hippocampus, and cortex.
Calcium binding induces conformational changes in CALN1/CABP8. The calcium binding affinity is not regulated by magnesium.
Interacts with PI4KB. This binding competes with FREQ/NCS1 binding in a calcium-dependent manner.
Negatively regulates Golgi-to-plasma membrane trafficking by interacting with PI4KB and inhibiting its activity. May play a role in the physiology of neurons and is potentially important in memory and learning.
The C-terminal transmembrane domain (TMD) is necessary and sufficient for membrane targeting.
Probable calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes. Plays a role in dendrite formation by melanocytes.
Belongs to the secretoglobin family. Lipophilin subfamily.
Part of prostatein which is the major secretory glycoprotein of ventral prostate gland.
Prostatein is composed of three different peptides called C1, C2 and C3. These form covalent C1:C3 (F) and C2:C3 (S) heterodimers whose noncovalent association forms tetrameric (C1:C3/C3:C2) prostatein molecules.
The heterodimer can bind non-polar steroids, cholesterol and a group of small proline-rich peptides.
Was originally (Ref.4) thought to originate from mouse.
Belongs to the GTR/RAG GTP-binding protein family.
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade.
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 (By similarity).
Expressed abundantly in the adult brain and muscle.
Interacts with MORG1 (By similarity). Interacts with SGK1 (By similarity). Interacts with KSR1. Interacts with KSR1 and BRAF; the interaction with KSR1 mediates KSR1-BRAF dimerization. Interacts with GLS (By similarity).
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).
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.
Homodimer; mediated by the coiled coil domain. 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 (By similarity). 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.
Transcription coregulator that can have both coactivator and corepressor functions. 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 (By similarity).
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.
Highly expressed in skeletal muscle, lung and testes and also in the heart and thymus of both adult and neonatal rats.
Monomer. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with LIN7C, SCRIB, SYNJ2BP and SH3BP5. 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.
Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway (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 (By similarity).
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. Contributes to calcium sequestration involved in muscular excitation/contraction.
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.
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. 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. 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-196 is oxidated, leading to inactivation of channel activity.
Interacts with STIM1 and STIM2; this regulates channel activity (By similarity). 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+) (By similarity). Forms a complex with CRACR2A/EFCAB4B and STIM1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations (By similarity). Interacts with SLC35G1 (By similarity). Interacts with UBQLN1 (By similarity). 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 (By similarity). Interacts with EFHB; the interaction takes place upon Ca(2+)-store depletion (By similarity). Interacts (via N- and C-termini) with ATP2C2 (via N-terminus); this interaction regulates Ca(2+) influx at the plasma membrane.
N-glycosylated. N-glycosylation inhibits channel activity.
Oxidation at Cys-196 leads to inactivation of channel activity.
2 molecules of GDNFR-alpha are thought to form a complex with the disulfide-linked GDNF dimer and with 2 molecules of RET (PubMed:15044950). Interacts with RET (By similarity). Interacts with SORL1, either alone or in complex with GDNF. Interaction between SORL1 and GFRA1 leads to GFRA1 internalization, but not degradation (By similarity).
2 molecules of GDNFR-alpha are thought to form a complex with the disulfide-linked GDNF dimer and with 2 molecules of RET.
Expressed in liver, brain, kidney and cochlea.
Receptor for GDNF. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor.
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.
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.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids with implications in host antimicrobial defense, inflammatory response and tissue regeneration (By similarity). 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:3356705). 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. 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 (By similarity). 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. Independent of its catalytic activity, acts as a ligand for integrins. Binds to and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1. 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. Induces cell proliferation in an integrin-dependent manner (By similarity).
Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.
Proteolytic cleavage leads to an important conformation change. This reduces the affinity for steroids (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 (By similarity). Represses the splicing of MAPT/Tau exon 10.
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. Interacts with PACRG (By similarity). Interacts with DNAAF4 (By similarity). Interacts with DLEC1 (By similarity).
Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance. 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. The TRiC complex plays a role in the folding of actin and tubulin.
Defects in Cct4 are a cause of an early onset sensory neuropathy knowm as mutilated foot (mf). The main clinical features include ataxia, insensitivity to pain and foot ulceration. The pathological features include a severe reduction in the number of sensory ganglia and fibers.
5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint (By similarity). Possesses beta-lactamase activity, catalyzing the hydrolysis of penicillin G and nitrocefin (By similarity). Exhibits no activity towards other beta-lactam antibiotic classes including cephalosporins (cefotaxime) and carbapenems (imipenem) (By similarity).
Interacts with TERF2; the interaction is direct. Interacts with MUS81, MRE11 and FANCD2. Interacts with HSPA2, HSPA8 and HSPA14. Interacts with SPAG5 (By similarity).
The TBM domain mediates interaction with TERF2.
Ubiquitinated, leading to its degradation. Interaction with TERF2 protects it from ubiquitination (By similarity).
Expressed in muscle cells and in the liver.
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 (By similarity). 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.
Homodimer, heterodimer with PURA and heterotrimer with PURA and YBX1/Y-box protein 1.
Induced in the liver 48 hours after tetrachloromethane (CCL4) administration.
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).
Expressed at late stages of spermatogenesis, from late to maturing spermatids (at protein level).
Forms a channel that mediates water and glycerol transport across cell membranes at neutral pH (PubMed:9252401). The channel is also permeable to urea (PubMed:9252401). 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).
Homotetramer. Interacts (via N-terminus) with PLIN1.
Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the transient carboxylation of the biotin covalently attached to the C-terminal biotinyl-binding/biotin carboxyl carrier (BCC) domain.
Propionic acidemia due to recessively inherited deficiency of PCCase activity often causes life-threatening ketosis and acidosis.
The biotin cofactor is covalently attached to the C-terminal biotinyl-binding domain and is required for the catalytic activity. Biotinylation is catalyzed by HLCS.
The holoenzyme is a dodecamer composed of 6 PCCA/alpha subunits and 6 PCCB/beta subunits. Interacts (via the biotin carboxylation domain) with SIRT4. Interacts with SIRT3 and SIRT5.
This is one of the 2 subunits of the biotin-dependent propionyl-CoA carboxylase (PCC), a mitochondrial enzyme involved in the catabolism of odd chain fatty acids, branched-chain amino acids isoleucine, threonine, methionine, and valine and other metabolites. Propionyl-CoA carboxylase catalyzes the carboxylation of propionyl-CoA/propanoyl-CoA to D-methylmalonyl-CoA/(S)-methylmalonyl-CoA (By similarity). Within the holoenzyme, the alpha subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, while the beta subunit then transfers the carboxyl group from carboxylated biotin to propionyl-CoA (By similarity). Propionyl-CoA carboxylase also significantly acts on butyryl-CoA/butanoyl-CoA, which is converted to ethylmalonyl-CoA/(2S)-ethylmalonyl-CoA (By similarity). Other alternative minor substrates include (2E)-butenoyl-CoA/crotonoyl-CoA (By similarity).
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 are the cause of spontaneous male sterile mutant 'As'. Males are sterile and aspermic due to abnormal pairing and misalignments between homologous chromosomes, non-homologous partner switches, and autosynapsis of X chromosome cores in meiotic spermatocytes (PubMed:12764197).
Interacts with HSP72/HSPA2 and CLTC. Interacts with GAPDH; leading to inhibit GAPDH catalytic activity. Interacts (via TPR repeats) with HSP90 (By similarity).
Belongs to the Mediator complex subunit 23 family.
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.
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.
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. Ubiquitinated by the CRL2(APPBP2) complex, which recognizes the Arg-Xaa-Xaa-Gly sequence at the C-terminus, leading to its degradation.
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones (By similarity). Required for auditory function (By similarity). 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).
Despite its name, the rat TOMT protein does not contain a transmembrane region in contrast to primate orthologs.
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.
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 (By similarity).
Binds GTP but lacks intrinsic GTPase activity and is resistant to Rho-specific GTPase-activating proteins.
Binds ROCK1. Interacts with UBXD5 (By similarity).
Contributes to the regulation of axonal growth in the embryonic and adult central nervous system by inhibiting interactions between RTN4R and LINGO1. Inhibits RTN4R-mediated axon growth cone collapse (By similarity). May play an important role in regulating the production of neural crest cells by the neural tube (By similarity). May be required for normal responses to olfactory stimuli (By similarity).
Expressed in the brain (at protein level) (PubMed:7932877, PubMed:22632720). Expressed in the brain, predominantly in the cortex and hippocampus. In the pituitary only the two A-type and in the adrenal glands only the two B-type forms were detected (PubMed:7932877).
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 (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 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 (PubMed:22632720). Interacts with OLFM2 (By similarity).
In isoform 3 and isoform 4, the signal peptide is predicted to end in position 17.
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.
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). The cholesterol ester is then transported back to the liver. 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 (By similarity). Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines (PubMed:8820107, PubMed:14636062). 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) (By similarity). Also catalyzes the transfer of the acetate group from PAF to 1-hexadecanoyl-sn-glycero-3-phosphocholine forming lyso-PAF (By similarity). Catalyzes the esterification of (24S)-hydroxycholesterol (24(S)OH-C), also known as cerebrosterol to produce 24(S)OH-C monoesters (By similarity).
Detected in blood plasma (at protein level) (PubMed:8820107).
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:8999922). 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 (PubMed:11395520). Has no activity toward other glycerophospholipids including phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids or phosphatidylinositols, or glycerolipids such as triolein (PubMed:8999922).
Serine protease with trypsin- and chymotrypsin-like specificity. Also displays antibacterial activity against Gram-negative and Gram-positive bacteria independent of its protease activity. Prefers Phe and Tyr residues in the P1 position of substrates but also cleaves efficiently after Trp and Leu. Shows a preference for negatively charged amino acids in the P2' position and for aliphatic amino acids both upstream and downstream of the cleavage site. Required for recruitment and activation of platelets which is mediated by the F2RL3/PAR4 platelet receptor. Binds reversibly to and stimulates B cells and CD4(+) and CD8(+) T cells. Also binds reversibly to natural killer (NK) cells and enhances NK cell cytotoxicity through its protease activity. Cleaves complement C3 (By similarity). Cleaves vimentin (By similarity). Cleaves thrombin receptor F2R/PAR1. Cleaves the synovial mucin-type protein PRG4/lubricin. Cleaves and activates IL36G which promotes expression of chemokines CXCL1 and CXLC8 in keratinocytes. Cleaves IL33 into mature forms which have greater activity than the unprocessed form. Cleaves coagulation factor F8 to produce a partially activated form. Also cleaves and activates coagulation factor F10. Cleaves leukocyte cell surface protein SPN/CD43 to releases its extracellular domain and trigger its intramembrane proteolysis by gamma-secretase, releasing the CD43 cytoplasmic tail chain (CD43-ct) which translocates to the nucleus. During apoptosis, cleaves SMARCA2/BRM to produce a 160 kDa cleavage product which localizes to the cytosol. Cleaves MBP in B cell lysosomes at '88-Phe-|-Lys-89' and '112-Phe-|-Ser-113', degrading the major immunogenic MBP epitope and preventing the activation of MBP-specific autoreactive T cells. Cleaves annexin ANXA1 and antimicrobial peptide CAMP to produce peptides which act on neutrophil N-formyl peptide receptors to enhance the release of CXCL2. Acts as a ligand for the N-formyl peptide receptor FPR1, enhancing phagocyte chemotaxis. Has antibacterial activity against the Gram-negative bacteria N.gonorrhoeae and P.aeruginosa. Likely to act against N.gonorrhoeae by interacting with N.gonorrhoeae penA/PBP2. Exhibits potent antimicrobial activity against the Gram-positive bacterium L.monocytogenes. Has antibacterial activity against the Gram-positive bacterium S.aureus and degrades S.aureus biofilms, allowing polymorphonuclear leukocytes to penetrate the biofilm and phagocytose bacteria. Has antibacterial activity against M.tuberculosis (By similarity).
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-130, and between Cys-99 and Cys-104. Glutathione may be required to regulate its activity in the endoplasmic reticulum (By similarity).
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. Plays an important role in ER stress-induced, CHOP-dependent apoptosis by activating the inositol 1,4,5-trisphosphate receptor IP3R1.
Phosphorylated on Ser-144 by FAM20C in the Golgi which increases its enzymatic activity (By similarity). Phosphorylation is induced by lactation (By similarity). It is also induced by hypoxia and reductive stress (By similarity).
Predominantly monomer. May function both as a monomer and a homodimer. Interacts with PDILT. Interacts with ERP44; the interaction results in retention of ERO1A in the endoplasmic reticulum.
Stimulated by hypoxia; suggesting that it is regulated via the HIF-pathway. Increased expression in brain after global cerebral ischemia.
The Cys-94/Cys-99 and Cys-390/Cys-393 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-390/Cys-393. The regulatory Cys-99/Cys-104 disulfide bond stabilizes the other regulatory bond Cys-94/Cys-130 (By similarity).
Controls cell proliferation in a tissue-specific manner and is involved in morphogenesis. During embryonic development, exerts a role in the expansion of muscle progenitors. May play a role in the proper localization of asymmetric organs such as the heart and stomach (By similarity).
Phosphorylation at Thr-97 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1.
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.
Expressed predominantly in brain (at protein level). Highest expression in the dentate gyrus and lowest expression in the striatum. Concentrated on neuronal cell bodies and unevenly dispersed along neuritic projections in the nonmyelinated regions of the brain. Expressed in postmitotic-differentiating neurons of the developmental nervous system and neuronal structures associated with plasticity in the adult.
Expression first detected in developing brain at embryonic day 15; the level of expression increases throughout embryonic development and postnatally into adulthood.
Induced by neural activity and by the activity-regulated neurotrophins BDNF and NTF3.
Promotes neurite outgrowth and especially branching of neuritic processes in primary hippocampal and cortical cells.
Phosphorylated by ROCK, leading to activate the RacGAP activity.
Rho GTPase-activating protein involved in cell polarity, cell morphology and cytoskeletal organization. Acts as a GTPase activator for the Rac-type GTPase by converting it to an inactive GDP-bound state. Controls actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity. Able to suppress RAC1 and CDC42 activity in vitro. Overexpression induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. Isoform 2 is a vascular cell-specific GAP involved in modulation of angiogenesis (By similarity).
The coiled coil domain mediates the interaction with FLNA leading to its recruitment to lamellae.
Composed predominantly of six polypeptides ranging from 110 to 150 kDa and a minor 300 kDa polypeptide. The majority of N- and C-terminal cleavage products remain tightly, albeit non-covalently, associated. Interacts with POU2F1, CREB3, ZBTB17, EGR2, E2F4, CREBZF, SP1, GABP2, Sin3 HDAC complex (SIN3A, HDAC1, HDAC2, SUDS3), SAP30, SIN3B and FHL2. 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. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. Interacts directly with THAP3 (via its HBM). Interacts (via the Kelch-repeat domain) with THAP1 (via the HBM); the interaction recruits HCHC1 to the RRM1. 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. Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L, CXXC1, HCFC1 and DPY30. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1. 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. Within the complex interacts with ZNF335. Interacts with TET2 and TET3. Interacts with HCFC1R1 (By similarity). Interacts with THAP11 (By similarity). Interacts (via Kelch domain) with KMT2E/MLL5 isoform 3 (via HBM motif). Interacts with E2F1 (By similarity).
O-glycosylated. GlcNAcylation by OGT promotes proteolytic processing.
Proteolytically cleaved at one or several PPCE--THET sites within the HCF repeats. 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.
The HCF repeat is a highly specific proteolytic cleavage signal.
The kelch repeats fold into a 6-bladed kelch beta-propeller called the beta-propeller domain which mediates interaction with HCFC1R1.
Transcriptional coregulator (PubMed:24250814). Involved in control of the cell cycle (By similarity). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (By similarity). Coactivator for EGR2 and GABP2 (By similarity). 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 (By similarity). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (By similarity). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (By similarity). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (By similarity). 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 (PubMed:24250814). May negatively modulate transcriptional activity of FOXO3 (PubMed:21909281).
Ubiquitinated. Lys-1818 and Lys-1819 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.
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 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)) (By similarity). Interacts with RAB5IF (By similarity).
Antiapoptotic protein which protects cells uniquely from Fas-induced apoptosis. Regulates Fas-mediated apoptosis in neurons by interfering with caspase-8 activation. Plays a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development (By similarity).
Expressed at high levels on dendrites and to a lesser extent on the soma and axons of neurons in various regions of brain.
Low expression was detected in brain and spinal cord at birth, increasing with age to highest levels in postnatal days 60 (P60).
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:12199709, PubMed:12364335, PubMed:12419318). Has a broad spectrum of substrates such as apomucin-, MUC5AC-, MUC1- and MUC2-derived peptides (By similarity).
Heart, brain, spleen, liver, skeletal muscle and kidney.
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.
Belongs to the NADPH--cytochrome P450 reductase family.
In the C-terminal section; belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.
In the N-terminal section; belongs to the flavodoxin family.
This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.
Homodimer. Interacts (via C-terminus) with CCM2. Interacts (via C-terminus) with PXN. Interacts (via N-terminus) with STK25. Interacts (via N-terminus) with STK26. Interacts (via N-terminus) with STK24. Interacts with GOLGA2. Identified in a complex with KRIT1 and CCM2. Interacts with KDR/VEGFR2. Interaction with KDR/VEGFR2 is enhanced by stimulation with VEGFA. Interacts with RIPOR1 (via C-terminus); this interaction is required for the association of RIPOR1 with either STK24 and STK26 kinases and occurs in a Rho-independent manner.
Promotes cell proliferation. Modulates apoptotic pathways. Increases mitogen-activated protein kinase activity and STK26 activity. Important for cell migration, and for normal structure and assembly of the Golgi complex. Important for KDR/VEGFR2 signaling. Increases the stability of KDR/VEGFR2 and prevents its breakdown. Required for normal cardiovascular development. Required for normal angiogenesis, vasculogenesis and hematopoiesis during embryonic development.
Interacts with the cytoplasmic part of DCC (PubMed:10399920). Interacts with GNAI2 via its cytoplasmic part (By similarity). 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. Interacts (via extracellular domain) with FLRT2 and FLRT3 (via extracellular domain), but has higher affinity for FLRT3. Identified in a complex with FLRT3 and ADGRL3; does not interact with ADGRL3 by itself (By similarity).
Mainly expressed in regions of differentiating neurons. Expressed in the developing sensory ganglia that flank the spinal cord from E12, peaking at E14. Expressed in the roof plate region of the spinal cord from E14.
Palmitoylation is required for pro-apoptotic activity, but not for location at lipid rafts.
Phosphorylated on cytoplasmic tyrosine residues.
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. Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding.
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 (PubMed:10399920, PubMed:9126742). 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:11387206). Mediates apoptosis by activating DAPK1 (PubMed:18582460). In the absence of NTN1, activates DAPK1 by reducing its autoinhibitory phosphorylation at Ser-308 thereby increasing its catalytic activity (PubMed:15729359).
Plays an important role in cellular zinc homeostasis as a zinc transporter. Regulated in response to zinc availability (By similarity).
Cofactor involved in the regulation of various cellular mechanisms such as actin regulation, autophagy, chromatin regulation and DNA repair. In physiological conditions, interacts with cofactor JMY in the cytoplasm which prevents JMY's actin nucleation activity and ability to activate the Arp2/3 complex. Acts as a negative regulator of nutrient stress-induced autophagy by inhibiting JMY's interaction with MAP1LC3B, thereby preventing autophagosome formation (By similarity). Involves in tubulin autoregulation by promoting its degradation in response to excess soluble tubulin. To do so, associates with the active ribosome near the ribosome exit tunnel and with nascent tubulin polypeptides early during their translation, triggering tubulin mRNA-targeted degradation (By similarity). Following DNA damage, phosphorylated by DNA damage responsive protein kinases ATM and CHEK2, leading to its nuclear accumulation and stability. Nuclear TTC5/STRAP promotes the assembly of a stress-responsive p53/TP53 coactivator complex, which includes the coactivators JMY and p300, thereby increasing p53/TP53-dependent transcription and apoptosis. Also recruits arginine methyltransferase PRMT5 to p53/TP53 when DNA is damaged, allowing PRMT5 to methylate p53/TP53. In DNA stress conditions, also prevents p53/TP53 degradation by E3 ubiquitin ligase MDM2. Upon heat-shock stress, forms a chromatin-associated complex with heat-shock factor 1 HSF1 and p300/EP300 to stimulate heat-shock-responsive transcription, thereby increasing cell survival. Mitochondrial TTC5/STRAP interacts with ATP synthase subunit beta ATP5F1B which decreased ATP synthase activity and lowers mitochondrial ATP production, thereby regulating cellular respiration and mitochondrial-dependent apoptosis. Mitochondrial TTC5/STRAP also regulates p53/TP53-mediated apoptosis (By similarity).
Interacts with JMY and p300/EP300; the interaction occurs in the nucleus and augments the association between JMY and p300/EP300 in response to DNA damage. Interacts with PRMT5; the interaction is DNA damage-dependent and promotes PRMT5 interaction with p53/TP53 and subsequent methylation. Forms a complex with HSF1 and p300/EP300; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity, resulting in enhanced heat-shock-responsive transcription. Interacts with JMY; the interaction occurs in the cytoplasm and results in the inhibition of JYM's nucleation activity (By similarity). Interacts with ribosome-coding tubulin (via 60S subunit 28S rRNA and protein uL24/RPL26) and the N-terminal of nascent tubulin polypeptide (via alpha-tubulin MREC motif and beta-tubulin MREI motif); these interactions result in tubulin mRNA-targeted degradation (By similarity). Interacts with ATP5F1B; the interaction occurs in the mitochondria and results in ATP production decrease. Interacts with p53/TP53; the interaction occurs in the mitochondria and results in increased apoptosis (By similarity).
Phosphorylation by ATM kinase induces nuclear accumulation while interfering with nuclear export, and phosphorylation by CHEK2 kinase enhances nuclear stability.
The tetratricopep-repeat (TPR) motifs may function as protein interaction domains.
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.
Phosphorylation is regulated by binding of cGMP to the two allosteric sites. 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. Specifically regulates nitric-oxide-generated cGMP.
Binds DNA as a monomer. Binds TLE1. Interacts with FOXA1 and FOXA3 (By similarity). 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 (By similarity). Involved in regulation of fat metabolism. Acts synergistically with ONECUT1 to activate transcription of female-specific CYP2C12; the function is inhibited by growth hormone-activated STAT5B. Acts synergistically with HNF4A to activate transcription of APOA1.
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 (By similarity).
Interacts with FBLN1. Interacts with EGFR and ERBB4 (By similarity).
Most abundant in skeletal muscle, lung, spleen brain and heart.
Expressed in many tissues, including brain, spinal cord, kidney, liver, eye, adipose tissue, lung, epididymis, adrenal gland, pineal gland, skeletal muscle, heart, spleen, thymus, ovary, uterus, testis and epididymis.
Expression is detected at 3 weeks of postnatal development and persists up to adulthood (PubMed:27032685). Expressed in elongated spermatids but not detected in spermatogonia, spermatocytes, and round spermatids (PubMed:27032685).
Specifically expressed in testis (at protein level).
Produced by macrophages, IFN-alpha have antiviral activities. Interferon stimulates the production of two enzymes: a protein kinase and an oligoadenylate synthetase.
The antiviral activity of this interferon appears to be independent of glycosylation.
There appear to be at least 12 rat interferon-alpha-1 genes.
Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation. 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. Additionally, displays dehydratase activity, toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) producing 15-KETE and 15-HETE.
Expressed in bone marrow, spleen, lung, thymus, liver, uterus, and macrophages.
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.
Highly expressed in several brain areas, the intestine, liver and spleen. Detected in sympathetic stellate ganglion neurons.
Phosphorylation at Ser-360 requires GRK3.
Binds to the N-terminus of tropomyosin and to actin. Binds to TMBr3 as well as to other low molecular mass tropomyosins (TM5a or TM5), but not to high molecular mass tropomyosins (TM2 or TMBr1).
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).
During periods of oxidative stress, Sec-47 may react with a superoxide radical, irreversibly lose hydroselenide and be converted to dehydroalanine.
Homotetramer. Interacts with MIEN1 (By similarity).
Protects the hemoglobin in erythrocytes from oxidative breakdown. In platelets, plays a crucial role of glutathione peroxidase in the arachidonic acid metabolism.
Interacts with SHTN1; the interaction occurs in axonal growth cones (PubMed:18519736). Interacts with isoform 2 of BSG (By similarity).
Isoform 2 is predominantly found in the brain, while isoform 1 is found in the peripheral nervous system.
Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors. During brain development, critical in multiple processes, including neuronal migration, axonal growth and fasciculation, and synaptogenesis. In the mature brain, plays a role in the dynamics of neuronal structure and function, including synaptic plasticity.
Antibodies against SPAG1 interfere with fertilization.
May play a role in the cytoplasmic assembly of the ciliary dynein arms (By similarity). Binds GTP and has GTPase activity (By similarity). Plays a role in fertilization (PubMed:11517287).
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.
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:19027009) (By similarity). May participate in the establishment of the canalicular membrane integrity by ensuring asymmetric distribution of phospholipids in the canicular membrane. 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 (PubMed:19027009). Involved in the microvillus formation in polarized epithelial cells; the function seems to be independent from its flippase activity. Participates in correct apical membrane localization of CDC42, CFTR and SLC10A2 (By similarity). 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 (By similarity). Required for the preservation of cochlear hair cells in the inner ear. 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. The flippase ATP8B1:TMEM30A complex can form an intermediate phosphoenzyme in vitro. Also interacts with beta subunit TMEM30B.
Interacts with COPS5; regulates the phosphorylation of JUN and the transcriptional activity of AP-1. Interacts with RYBP; may prevent the ubiquitin-mediated proteasomal degradation of FANK1.
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.
High in striated muscle and adult heart.
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 (By similarity). LIM zinc-binding domain 1 mediates binding to MYOD1. LIM zinc-binding domain 2 mediates binding to SPTB (PubMed:9234731, PubMed:10751147).
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 (PubMed:7954791, PubMed:9234731). 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. The role in regulation of cytoskeleton dynamics by association with CFL2 is reported conflictingly. 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. In vitro can inhibit PKC/PRKCA activity. 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 (PubMed:16963613). Homooligomers preferentially form along the actin cytoskeleton (By similarity). Interacts with TCAP, ACTN2 and NRAP (By similarity). Interacts with LDHD, SPTB, MYOD1, MYOG, MYF6. Interacts with GLRX3 (via C-terminus); GLRX3 and calcineurin compete for interaction with CSRP3 (PubMed:9234731, PubMed:10751147, PubMed:12127981, PubMed:18258855). 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 (By similarity).
Choline-specific glycerophosphodiesterase that hydrolyzes glycerophosphocholine (GPC) and lysophosphatidylcholine (LPC) and contributes to supplying choline to the cells. 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.
Homodimer; disulfide-linked. Homotetramer.
Interacts with EPS15R and EPS15. Interacts with FCHO1 (By similarity).
Required for vesicle docking or fusion during acrosome biogenesis. May play a role in RNA trafficking or localization (By similarity).
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.
Cleavage of precursor form by SENP1, SENP2 or SENP5 is necessary for function.
Interacts with SAE2 and UBE2I. Covalently attached to a number of proteins. Interacts with USP25 (via ts SIM domain); the interaction sumoylates USP25 and inhibits its ubiquitin hydrolyzing activity. Interacts with BMAL1 (By similarity).
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. Plays a role in the regulation of sumoylation status of SETX (By similarity).
Has chymotrypsin-type protease activity and hypocalcemic activity.
Was originally thought to be elastase IV.
Heterodimer with RABGEF1. The heterodimer binds RAB4A and RAB5A that have been activated by GTP-binding. Interacts with TSC2 (By similarity). Interacts with GGA1 (via GAE domain), GGA2 (via GAE domain) and GGA3 (via GAE domain) (By similarity). Interacts with AP1G1 (via GAE domain) (By similarity). Interacts with AP1G2 (via GAE domain) (By similarity). Interacts with ECPAS (By similarity). 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 (PubMed:22841712).
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. Stimulates RABGEF1 mediated nucleotide exchange on RAB5A. Mediates the traffic of PKD1:PKD2 complex from the endoplasmic reticulum through the Golgi to the cilium.
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.
Expressed in brain, spleen, heart, liver and kidney.
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.
Belongs to the glycosyltransferase 47 family.
Interacts with FLNA. Interacts with the latency-associated peptides (LAP) of TGFB1 and TGFB2; the interaction results in a decrease in TGFB autoinduction.
May have roles in neural function. Ectopic expression promotes axonal regeneration. Augments also motility of gliomas (By similarity). May also have roles in cellular differentiation (By similarity). Induces differentiation of fibroblast into myofibroblast and myofibroblast ameboid migration (By similarity). 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 (By similarity).
Phosphorylated on Ser-59. Phosphorylation decreases stability and activity.
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.
In various regions of the central nervous system.
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. Interacts with RIC3; which is required for proper folding and assembly. Interacts with LYPD6. The heteropentamer alpha-4-beta-2 interacts with alpha-conotoxins PnIA, GID and MII (PubMed:15929983).
The nAChR composed of alpha-4 and beta-2 subunits does not bind the conotoxin BuIA.
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 GDI1.
Homodimers (By similarity). Interacts specifically with both prenylated Rab proteins (including RAB3A and RAB1), and VAMP2 (synaptobrevin-2), in an exclusive way. Interacts with NDRG1 (By similarity). Interacts with free GDI1 in the absence of Rab proteins. Also interacts with PCLO.
In contrast to the mouse ortholog, it does not interact with the Ras-like GTPases RAC1 and RHOA.
Homodimer. Interacts with DLG4; the interaction possibly being prevented by the association between NOS1 and CAPON (PubMed:23300088). Forms a ternary complex with CAPON and RASD1 (PubMed:11086993). Forms a ternary complex with CAPON and SYN1 (PubMed:11867766). Interacts with ZDHHC23 (PubMed:15105416). Interacts with NOSIP; which may impair its synaptic location (PubMed:15548660). Interacts with HTR4 (By similarity). Interacts with SLC6A4. Interacts with VAC14 (PubMed:17161399). Interacts (via N-terminal domain) with DLG4 (via N-terminal tandem pair of PDZ domains) (By similarity). Interacts with SLC6A4 (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).
Isoform N-NOS-1 is expressed in brain and colorectum. Found in the Auerbach's plexus of the enteric nervous system. Isoform PNNOS is expressed in the penis, urethra, prostate, and skeletal muscle, and coexists with the cerebellar nnos in the pelvic plexus, bladder and liver, and is detectable in the cerebellum.
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. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
Stimulated by calcium/calmodulin. Inhibited by n-Nos-inhibiting protein (PIN) which may prevent the dimerization of the protein (By similarity). 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 (By similarity). Mediates interaction with VAC14.
Ubiquitinated; mediated by STUB1/CHIP in the presence of Hsp70 and Hsp40 (in vitro).
May play a role in regulating vesicuar trafficking in cells.
Testis, kidney, skeletal muscle, liver, lung, brain, heart, pituitary gland, adrenal gland and ovary.
Belongs to the membrane magnesium transporter (TC 1.A.67) family.
Expressed in the proliferating cells of the coelomic epithelium of male and female gonads at 12 dpc. In female, expressed in the whole gonadal primordium at 13.5 dpc; in the surface epithelium and in the ovigerous cords at 15.5 dpc. In male, expressed at surface cells of the gonads at 13.5 dpc; in mesenchymal cells outside testicular cords at 18.5 dpc.
Belongs to the bacterial ribosomal protein bS18 family. Mitochondrion-specific ribosomal protein mS40 subfamily.
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. Regulates the release of 5-hydroxytryptamine in the brain, and thereby affects neural activity. May also play a role in regulating the release of other neurotransmitters. May play a role in vasoconstriction.
Homodimer. Heterodimer with HTR1B (By similarity).
Can form oligomers with SYN1 (By similarity). 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-426 by MAPK1/ERK2 and/or MAPK3/ERK1 may play a role in noradrenaline secretion by sympathetic neurons (By similarity). Phosphorylation at Ser-10 dissociates synapsins from synaptic vesicles.
Potent inhibitor of the complement membrane attack complex (MAC) action. Acts at or after the C5b-8 stage of MAC assembly.
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 IFT74; the interaction is direct: within the IFT complex B, IFT74 and IFT81 mediate the transport of tubulin within the cilium. Interacts with tubulin; the interaction is direct (By similarity). Interacts with IFT57 and TTC30B (By similarity). Interacts with RABL2/RABL2A; binding is equal in the presence of GTP or GDP. Interacts with IFT88 (By similarity). Interacts (via the IFT74/IFT81 heterodimer) with RABL2B (By similarity).
Component of the intraflagellar transport (IFT) complex B: together with IFT74, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. Binds tubulin via its CH (calponin-homology)-like region. Required for ciliogenesis. Required for proper regulation of SHH signaling (By similarity). Plays an important role during spermatogenesis by modulating the assembly and elongation of the sperm flagella (By similarity).
The CH (calponin-homology)-like region shows high similarity to a CH (calponin-homology) domain and mediated binding to the globular domain of tubulin.
Belongs to the small GTPase superfamily. RGK family.
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 (By similarity). Required for the translocation across the mitochondrial outer membrane of cytochrome P450 monooxygenases (PubMed:19401463).
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 TOMM40 (By similarity). Interacts with PPP2R2B.
The N-terminal domain (residues 1-60) is important for binding to the unfolded mature imported proteins. Residues (47-69) of the cytoplasmic domain interacts with TOMM20 while the C-terminal segment (residues 61-80) binds presequence of preproteins (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.
Interacts with BMP2. Interacts with low affinity with GDF5; positively regulates chondrocyte differentiation. Interacts with BMP4. Interacts with SCUBE3.
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.
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 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)) (By similarity). 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. Interacts with TMEM177 in a COX20-dependent manner (By similarity).
Belongs to the AB hydrolase superfamily. Epoxide hydrolase family.
Bifunctional enzyme (PubMed:8626766, PubMed:12574508). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:8626766). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (By similarity).
Bifunctional enzyme (PubMed:8626766, PubMed:12574508). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:8626766). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (PubMed:8626766). Also determines steady-state levels of physiological mediators (By similarity). 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 (By similarity).
Bifunctional enzyme (PubMed:8626766, PubMed:12574508). 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:12574508). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (By similarity).
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) (PubMed:21217101). Phosphatase activity is inhibited by dodecyl-phosphate, phospholipids such as phospho-lysophosphatidic acids and fatty acids such as palmitic acid and lauric acid (By similarity).
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 (By similarity).
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).
In the liver, by peroxisome proliferator (Clofibrate) treatment, via the peroxisome proliferator-activated receptors (PPARs) or fasting for 24 hours.
Acts as a transcriptional repressor. Plays a role as a transcriptional corepressor of the Notch-mediated signaling required for T-cell development. Also involved in the TNF and IL-1 induced NF-kappa-B activation. Associates with chromatin at the Notch-regulated SKP2 promoter (By similarity).
Component of the Notch corepressor complex. Interacts with CIR1 and HDAC3 (By similarity).
Heterotetramer of TRAP-alpha, TRAP-beta, TRAP-delta and TRAP-gamma.
TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins.
Component of the methylosome complex composed of PRMT5, WDR77 and CLNS1A (By similarity). Found in a complex composed of PRMT5, WDR77 and RIOK1 (By similarity). 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 (By similarity). Found in a complex wit the component of the methylosome, PRMT5, CLNS1A, WDR77, PRMT1 and ERH. Directly interacts with PRMT5, as well as with several Sm proteins, including SNRPB and SNRPD2 and, more weakly, SNRPD3 and SNRPE. 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. Interacts with CTDP1 and LSM11. Interacts with APEX1, AR and NKX3-1. Interacts with CHTOP. Interacts with FAM47E.
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. 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.
Component of the dolichol-phosphate mannose (DPM) synthase complex composed of DPM1, DPM2 and DPM3; in the complex interacts directly with DPM3 (PubMed:9724629). Component of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex composed at least by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY and DPM2. Interacts with PIGA, PIGC and PIGQ (By similarity).
Regulates the biosynthesis of dolichol phosphate-mannose (PubMed:9724629). Regulatory subunit of the dolichol-phosphate mannose (DPM) synthase complex; essential for the ER localization and stable expression of DPM1 (PubMed:9724629). 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. May act by regulating the GPI-GNT complex (By similarity).
Delipoylated at Lys-123 and Lys-249 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). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules. Interacts with PDK2 and PDK3. Interacts with SIRT4. Interacts with PDHB.
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. The E2 component of pyruvate dehydrogenase complex is the autoantigen for PBC.
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.
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. 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.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRB3 sub-subfamily.
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis.
White and brown adipose tissues, and digestive tract.
Belongs to the OHCU decarboxylase family.
Catalyzes the stereoselective decarboxylation of 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) to (S)-allantoin.
Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis (By similarity).
Isoform 1 is ubiquitously expressed. Expressed in epididymal adipose tissue, liver and skeletal muscle.
Phosphorylated on tyrosine residues in response to treatment with growth hormone (GH), IFN-gamma (IFNG), BDNF, PDGF and FGF. Phosphorylated on tyrosine residues by JAK2 and JAK1. Phosphorylated on multiple serine and threonine residues in response to treatment with NGF. Phosphorylated on serine residues.
Self-associates. Homopentamer. Forms a heteromultimeric complex with SH2B2. Interacts with SH2B2. Isoform 1 interacts via its SH2 domain with JAK2. Isoform 2 interacts via its SH2 domain and its N-terminus with JAK2; the SH2 domain is required for the major interaction with JAK2 phosphorylated on tyrosine residues; the N-terminus provides a low-affinity binding to JAK2 independent of JAK2 phosphorylation. Isoform 1 interacts via its SH2 domain with INSR; the interaction requires receptor activation. Isoform 1 interacts with IGF1R; the interaction requires receptor activation. Isoform 2 interacts via its SH2 domain with FGFR3. Isoform 2 interacts with RET; the interaction requires RET kinase activity. Isoform 2 interacts with RAC1. Isoform 2 interacts with PDGFRA and/or PDGFRB; the interaction requires receptor activation. Interacts with ISR1 and ISR2. Probably part of a complex consisting of INSR, ISR1 and SH2B1. Probably part of a ternary complex consisting of SH2B1, JAK2 and ISR1 or ISR2 (By similarity). May interact with FCER1G. Interacts (via SH2 domain) with NTRK1 (phosphorylated).
Brain. Expressed at high levels in the white matter and the oligodendroglial cells of the brain. Expressed at low levels in the liver.
First detected in significant amounts at postnatal day 2 (P2) and increases about twofold to a peak value at P17-P20 and declines significantly thereafter.
Restriction factor required to restrict infectivity of gammaretroviruses: acts by inhibiting early step of viral infection and impairing the ability of the viral particle to translocate its content to the cytoplasm (By similarity). Enhances the incorporation of serine into phosphatidylserine and sphingolipids. May play a role in providing serine molecules for the formation of myelin glycosphingolipids in oligodendrocytes.
Up-regulated during the differentiation of oligodendrocyte lineage cells and during brain development at the time of myelination. Down-regulated in the hippocampal CA fields and dentate gyrus by seizures.
Accessory potassium channel protein which modulates the activity of the pore-forming alpha subunit. Alters the functional properties of Kv1.4 but not Kv1.1 or Kv1.5.
Alteration of functional properties of alpha subunit is mediated through N-terminal domain of beta subunit.
Forms heteromultimeric complex with alpha subunits.
Predominantly expressed in brain. Strongest expression in olfactory bulb and thalamic nuclei. Not detected in heart, spleen, lung, liver, skeletal muscle, kidney and testis.
Stimulates the RNA helicase activity of EIF4A in the translation initiation complex. Binds weakly mRNA (By similarity).
Belongs to the glycosyltransferase 28 family.
May be involved in protein N-glycosylation, second step of the dolichol-linked oligosaccharide pathway.
Does not possess antizyme activity. Modulates PPP1CB activity through its interaction with PPP1R16A.
Interacts with ODC1 and thereby sterically blocks ODC homodimerization (By similarity). Interacts with AZIN2; this interaction disrupts the interaction between the antizyme and ODC1 (By similarity). Interacts with GGN (By similarity). Isoform 2 interacts with PPP1R16A; Modulates PPP1CB activity (PubMed:21712390).
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. 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).
Produced by alternative splicing. This form is not the result of ribosomal frameshift.
Produced by ribosomal frameshifting occurring between the codons for Ser-86 and Glu-87. An autoregulatory mechanism enables modulation of frameshifting according to the cellular concentration of polyamines.
PubMed:17040916 reports an event of trans-splicing that creates a hybrid 14-kDa protein whose N-terminal 105 amino acids are encoded by the rat Oaz3 gene, located on chromosome 2 and its C-terminal 33 amino acids by a novel gene located on chromosome 4. The nuclear pre-mRNA of Oaz3 gene has 5 adenosine residues whereas the nuclear trans-spliced RNA has 6 adenosine residues suggesting that an unknown nuclear process adds 1 adenosine affecting the reading frame. Moreover the hybrid 14-kDa protein is the result of ribosomal frameshift. The hybrid 14-KDa protein is present in the outer dense fibers and the fibrous sheath and expressed in lung.
Testis-specific. Isoform 2 is expressed in outer dense fibers, fibrous sheath and the connecting piece of sperm (PubMed:21712390).
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.
Can influence paracellular permeability. Appears to be involved in cell-cell interactions through adherens (By similarity).
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.
From 17 dpc to 18 dpc embryos, a very strong signal appeared and continued throughout the remaining prenatal days. The signal was strongest in the cerebral cortex (including the cingulate cortex, neocortex, and orbital and insular area), thalamus (anterior and intermediate thalamus), and weak in posterior thalamus and midbrain.
Homodimer; disulfide-linked (Probable). Heterodimer with either TENM1 or TENM3. May also form heterodimer with TENM4 (By similarity). 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. Mediates axon guidance and homophilic and heterophilic cell-cell adhesion. May function as a cellular signal transducer (By similarity). Acts as a ligand of the ADGRL1 receptor.
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. Overexpression induces metaphase arrest and chromosomal instability. Localizes to active rDNA loci and promotes the expression of rRNA genes. 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.
Homodimer; may form higher-order oligomers. Interacts with TCF7L2/TCF4; the interaction is direct. Interacts with HABP4 and SERBP1. Interacts with C11orf84/SPINDOC.
Phosphorylated during oocyte meiotic maturation.
The 3 tudor-like domains (also named Spin/Ssty repeats) specifically recognize and bind methylated histones. H3K4me3 and H3R8me2a are recognized by tudor-like domains 2 and 1, respectively.
Detected in the ureteric bud in embryonic kidney (at protein level).
Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development (By similarity). 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. Can also bind siderophores from M.tuberculosis (By similarity).
Monomer. Homodimer; disulfide-linked. Heterodimer; disulfide-linked with MMP9.
Belongs to the transglutaminase-like superfamily. PNGase family.
Component of a complex required to couple retrotranslocation, ubiquitination and deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Interacts with the proteasome components RAD23B and PSMC1. Interacts with directly with VCP. Interacts with DERL1, bringing it close to the endoplasmic reticulum membrane. Interacts with SAKS1 (By similarity).
Inhibited by Z-VAD-fmk, a well-known caspase inhibitor, which inhibits enzyme activity through covalent binding of the carbohydrate to the single Cys-306 residue.
Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl-glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high-mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins (By similarity).
The PUB domain mediates the interaction with VCP.
Belongs to the SLC41A transporter family.
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. According to PubMed:18817736, shows only specificity for GRIA2 and specifically to the form of GRIA2 for which a single amino acid in the pore region has been edited from a glutamine to an arginine residue. 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, CACNG3, CACNG4, CACNG7 and CACNG8. Interacts with GRIA1, GRIA2, GRIA3 and GRIA4.
Binds phospholipids; exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate. Stabilizes GTP-bound RAB7A on late endosomes/lysosomes and alters functional properties of late endocytic compartments via its interaction with RAB7A. Binds 25-hydroxycholesterol and cholesterol.
Interacts with VAPA (PubMed:16004875). Interacts with the GTP-bound form of RAB7A (By similarity). Interacts with OAS1B (By similarity). Interacts (via FFAT motif) with MOSPD2 (via MSP domain) (By similarity).
The FFAT motif is required for interaction with MOSPD2.
Deamidation of Asn-346 converts alpha-1 to alpha-3.
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 (By similarity). Interacts with RGS14 (By similarity). Interacts with RGS19 (By similarity).
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 (By similarity).
Histaminylated at Gln-205 residues by TGM2.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB2 subfamily.
Highly expressed in brain and heart. Also expressed in lung.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB2 per KCNMA1 tetramer (By similarity).
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 (By similarity).
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 (By similarity).
Forms protease inhibiting heterodimer with TMPRSS7.
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. 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 XPB, XPD, GTF2H1 and GTF2H3.
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.
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 (By similarity).
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). Helps to diversify peripheral B-cell functions by regulating Ca(2+) stores, antibody secretion, and integrin activation.
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. Interacts with HSP90B1 and PDIA3 in a calcium-dependent manner.
Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Does not catalyze the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate.
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).
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 large highly anionic extracellular domain allows to maintain open filtration pathways between neighboring podocyte foot processes. 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).
Glomerular epithelium cell (podocyte) (at protein level).
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 with SLC9A3R2. Interacts (via the C-terminal PDZ-binding motif DTHL) with SLC9A3R1 (via the PDZ domains); the interaction take place early in the secretory pathway and is necessary for its apical membrane sorting (By similarity). 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 SLC9A3R1 (via the PDZ domains); interaction is not detected in glomerular epithelium cells. Interacts (via the C-terminal PDZ-binding motif DTHL) with SLC9A3R2 (via the PDZ 1 domain); interaction is detected in glomerular epithelium cells. Interacts with EZR.
N- and O-linked glycosylated. Sialoglycoprotein (By similarity).
Binds RHOA, PPP1R12A/MBS and PPP1R12C/MBS85 through adjacent coiled coil domains. Interacts with MYZAP. Binds F-actin through its N-terminus (By similarity).
Targets myosin phosphatase to the actin cytoskeleton. Required for the regulation of the actin cytoskeleton by RhoA and ROCK1. Depletion leads to an increased number of stress fibers in smooth muscle cells through stabilization of actin fibers by phosphorylated myosin. Overexpression of MRIP as well as its F-actin-binding region leads to disassembly of stress fibers in neuronal cells (By similarity).
Belongs to the complex I 51 kDa subunit family.
Expressed in thyrocytes (at protein level).
Antiparallel disulfide-linked heterodimer of an alpha chain and a beta chain (PubMed:3415696). Self-associates and forms higher oligomers. Interacts with a broad range of misfolded proteins, including APP, APOC2 and LYZ. Slightly acidic pH promotes interaction with misfolded proteins. Forms high-molecular weight oligomers upon interaction with misfolded proteins. Interacts with APOA1, LRP2, CLUAP1 and PON1. Interacts with the complement complex. Interacts (via alpha chain) with XRCC6. Interacts with SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes. Interacts (via alpha chain) with BAX in stressed cells, where BAX undergoes a conformation change leading to association with the mitochondrial membrane. Does not interact with BAX in unstressed cells. Found in a complex with LTF, CLU, EPPIN and SEMG1. Interacts (immaturely glycosylated pre-secreted form) with HSPA5; this interaction promotes CLU stability and facilitates stress-induced CLU retrotranslocation from the secretory pathway to the mitochondria, thereby reducing stress-induced apoptosis by stabilizing mitochondrial membrane integrity. Interacts with BCL2L1; this interaction releases and activates BAX and promotes cell death. Interacts with TGFBR2 and ACVR1 (By similarity). Interacts (secreted form) with STMN3; this interaction may act as an important modulator during neuronal differentiation (PubMed:16038898). Interacts with VLDLR and LRP8 (By similarity).
Antiparallel disulfide-linked heterodimer of an alpha chain and a beta chain. Self-associates and forms higher oligomers.
Detected in Sertoli cells (at protein level). Detected in cultured Sertoli cells, testis, epididymis, liver and brain.
Expressed by cells undergoing programmed death as a result of the hormonal stimuli or a traumatic insult.
Extensively glycosylated with sulfated N-linked carbohydrates (PubMed:3651384). About 30% of the protein mass is comprised of complex N-linked carbohydrate. Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms. Core carbohydrates are essential for chaperone activity. Non-secreted forms are hypoglycosylated or unglycosylated (By similarity).
Functions as extracellular chaperone that prevents aggregation of non native proteins. Prevents stress-induced aggregation of blood plasma proteins.
Functions as extracellular chaperone that prevents aggregation of non native proteins. Prevents stress-induced aggregation of blood plasma proteins. Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro). Does not require ATP. Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70. Does not refold proteins by itself. Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation. When secreted, protects cells against apoptosis and against cytolysis by complement. Intracellular forms interact with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes and promote the ubiquitination and subsequent proteasomal degradation of target proteins. Promotes proteasomal degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional activity (By similarity). Following stress, promotes apoptosis (By similarity). Inhibits apoptosis when associated with the mitochondrial membrane by interference with BAX-dependent release of cytochrome c into the cytoplasm. Plays a role in the regulation of cell proliferation. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (By similarity). Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3 (PubMed:16038898). Plays a role in the clearance of immune complexes that arise during cell injury (By similarity).
Polyubiquitinated, leading to proteasomal degradation. Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation.
Proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen (PubMed:3415696, PubMed:3651384). Proteolytic cleavage is not necessary for its chaperone activity. All non-secreted forms are not proteolytically cleaved. Chaperone activity of uncleaved forms is dependent on a non-reducing envoronment (By similarity).
Detected at 10 dpc in the hindbrain and at 11 dpc in the forebrain. During the next 3 embryonic days the levels of RTN1-S increases and remains stable at 13 dpc in the hindbrain and at 14 dpc in the forebrain. The levels of RTN1-B does not change as significantly during development of the hindbrain.
Expressed predominantly in central and peripheral nervous system of newborn and adult rats. Low levels have been also detected in heart, adrenal gland and spleen. Expression of isoform RTN1-B is restricted to particular neuronal types.
Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.
Interacts with NDRG1. Interacts with BACE1. Interacts with TMEM33.
Interacts with UGCG; regulates the ceramide glucosyltransferase activity of UGCG.
Favors the reduction of estrogens and androgens. Uses preferentially NADH.
A tripeptide motif (NQE) within disintegrin-like domain could be involved in the binding to egg integrin receptor and thus could mediate sperm/egg binding.
Heterodimer with ADAM1/fertilin subunit alpha.
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 (By similarity).
The prodomain and the metalloprotease domain are cleaved during the epididymal maturation of the spermatozoa.
Binds DNA as a monomer or a homodimer (By similarity). Interacts with C1D, NR2E3, SP1 and ZNHIT1 (By similarity). Interacts with OPHN1 (via C-terminus) (PubMed:21874017). Interacts with PER2; the interaction associates PER2 to BMAL1 promoter region (By similarity). Interacts with CRY1 (By similarity). Interacts with CCAR2 (By similarity). Interacts with SIAH2 (By similarity). Interacts with FBXW7 and CDK1 (By similarity). Interacts with HUWE1 (By similarity). Interacts with NR0B2 (By similarity). Interacts with NFIL3 (By similarity). Interacts (via domain NR LBD) with HSP90AA1 and HSP90AB1 (By similarity).
In bladder smooth muscle cells, exhibits night/day variations with a peak time at circadian time (CT) 4-12 and a trough at CT16-24.
Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic localization.
Sumoylated by UBE2I, desumoylated by SENP1, and sumoylation is a prerequisite to its ubiquitination.
Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC1 and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator (By similarity). In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis (PubMed:22425774). In collaboration with SP1, activates GJA1 transcription in a heme-independent manner (By similarity). Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity). Represses the transcription of CES2 (By similarity). Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity). Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity). Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity). Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity). Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity).
Ubiquitinated, leading to its proteasomal degradation (By similarity). Ubiquitinated by the SCF(FBXW7) complex when phosphorylated by CDK1 leading to its proteasomal degradation (By similarity). Ubiquitinated by SIAH2; leading to its proteasomal degradation (By similarity). Rapidly ubiquitinated in response to inflammatory triggers and sumoylation is a prerequisite to its ubiquitination (By similarity).
Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily.
MK 571 inhibits sphingosine 1-phosphate and leukotriene C4 export.
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics. Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export. Hydrolyzes ATP with low efficiency (PubMed:15129170). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity).
Skeletal muscle, brain, heart, spleen, lung and kidney.
Belongs to the complex I NDUFA3 subunit family.
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. May play a role in controlling terminal differentiation events.
Skeletal muscle in late fetal and adult rats.
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.
Adapter protein able to interact with different proteins and involved in different biological processes. 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. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. 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. 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. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.
Homooligomer. Heterodimer with REV3L. 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. 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. Interacts with REV1. Interacts with ADAM9. Interacts with CHAMP1. Interacts with FZR1 (in complex with the anaphase promoting complex APC). May interact with CDC20. Interacts with RAN. Interacts with ELK1; the interaction is direct and recruits MAD2L2 to ELK1-specific promoters. May interact with the JNK kinases MAPK8 and/or MAPK9 to stimulate ELK1 phosphorylation and transcriptional activity upon DNA damage. Interacts with TCF7L2; prevents its binding to promoters and negatively modulates its transcriptional activity. Interacts with YY1AP1. Interacts with PRCC; the interaction is direct. Interacts with POGZ.
Interacts with PAFAH1B1 (PubMed:9601647). Interacts with PLK1 and DCDC1. Part of a complex containing PLK1, NUDC, dynein and dynactin (By similarity). Interacts with EML4 (via WD repeats) (By similarity).
Plays a role in neurogenesis and neuronal migration. Necessary for correct formation of mitotic spindles and chromosome separation during mitosis (By similarity). Necessary for cytokinesis and cell proliferation (By similarity).
Reversibly phosphorylated on serine residues during the M phase of the cell cycle. Phosphorylation on Ser-275 and Ser-327 is necessary for correct formation of mitotic spindles and chromosome separation during mitosis. Phosphorylated by PLK and other kinases (By similarity).
Ubiquitous. Detected in stomach, small intestine, spleen, liver, kidney, brain, heart and lung.
Up-regulated by prolactin in T-cell lymphoma. Maximum level of expression occurs at the G1/S phase transition of the cell cycle.
A missense mutation at Ser-309 is the cause of the autosomal dominant myokymia and seizures (ADMS) phenotype. Homozygous and heterozygous rats are born at the expected Mendelian rate. After 6 weeks, heterozygous rats begin to display muscle twitching, startle responses and spontaneous convulsive seizures; over 80% of the animals are dead after 30 weeks. After 16 weeks, they display lower body weight compared to wild-type. The rats exhibit severe periodic seizures with characteristic alterations in their cortical and hippocampal electroencephalogram, similar to rodent models of temporal lobe epilepsy. Homozygous rats display impaired development starting 14 days after birth, with reduced body weight, tremors, motor incoordination, spontaneous convulsive seizures; none survive past 18 days after birth.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.1/KCNA1 sub-subfamily.
Detected in hippocampus, in the middle third of the molecular layer of the dentate gyrus and in stratum radiatum and stratum oriens (PubMed:9334400). Detected in the mossy fiber zone in the hippocampus CA3 region, at or near axon terminals (PubMed:9334400). Detected in brain cortex, at basket cell terminals (PubMed:9334400). 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 (PubMed:11086297). Detected in juxtaparanodal regions adjacent to the nodes of Ranvier in myelinated axons in cerebellar white matter (PubMed:9334400). Detected in sensory neurons (PubMed:17855588). Detected in neurons from the medial nucleus of the trapezoid body (PubMed:12177193). Detected in basolateral amygdala (PubMed:16306173). Detected in the paraventricular nucleus of the hypothalamus (PubMed:17869444). Detected in the islet of Langerhans (at protein level) (PubMed:21483673). 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:10896669, PubMed:10884227). Channel activity is regulated by interaction with the beta subunits KCNAB1 and KCNAB2 (PubMed:9334400, PubMed:12114518). Identified in a complex with KCNA2 and KCNAB2 (PubMed:10896669, PubMed:11086297, PubMed:23318870, PubMed:10884227). Interacts (via C-terminus) with the PDZ domains of DLG1, DLG2 and DLG4. Interacts with LGI1 within a complex containing LGI1, KCNA4 and KCNAB1. Interacts (via cytoplasmic N-terminal domain) with KCNRG; this inhibits channel activity (By similarity). Interacts with ANK3; this inhibits channel activity (By similarity). Interacts (via N-terminus) with STX1A; this promotes channel inactivation (PubMed:12114518). Interacts (via N-terminus) with the heterodimer formed by GNB1 and GNG2; this promotes channel inactivation (PubMed:12114518). Can interact simultaneously with STX1A and the heterodimer formed by GNB1 and GNG2 (PubMed:12114518). Interacts with ADAM11 (By similarity).
Inhibited by 4-aminopyridine (4-AP) and by tetraethylammonium (TEA) (PubMed:2539643). Inhibited by kaliotoxin (KTX) (PubMed:23725331).
Palmitoylated on Cys-243; which may be required for membrane targeting.
Partially edited. RNA editing is at an average of 50% in the whole brain.
Phosphorylated on tyrosine residues. Phosphorylation increases in response to NRG1; this inhibits channel activity (By similarity). Phosphorylated by PKA (PubMed:8038169, PubMed:12681381). Phosphorylation at Ser-446 regulates channel activity by down-regulating expression at the cell membrane (By similarity).
The cytoplasmic N-terminus is important for tetramerization and for interaction with the beta subunits that promote rapid channel closure.
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 kidney. Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:12177193, PubMed:17855588, PubMed:22206926). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:23725331). The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:2539643). 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:2348860, PubMed:12177193, PubMed:10896669, PubMed:23725331). 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:10896669, PubMed:12114518). 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:2348860, PubMed:8038169, PubMed:12681381, PubMed:22206926, PubMed:23725331). In contrast, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation (PubMed:2348860). 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 (PubMed:12177193, PubMed:23318870). May function as down-stream effector for G protein-coupled receptors and inhibit GABAergic inputs to basolateral amygdala neurons (PubMed:16306173). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) release (PubMed:17869444). 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:22206926). 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 (By similarity).
Interacts with TJP1/ZO1. Interacts with VAPA. Interacts with CLDN1, CLDN6, CLDN9, CLDN11, CLDN12 and CLDN17. Interacts with PLSCR1. Interacts with LSR, ILDR1 and ILDR2.
May play a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier. May be involved in the organization of actin in endothelial cells.
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).
Expressed in heart, skeletal muscle and testis.
Inhibits cell growth by regulating the TOR signaling pathway upstream of the TSC1-TSC2 complex and downstream of AKT1.
Up-regulated in soleus muscle atrophied by disuse.
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. Binds to 40S and 60S ribosomal subunits and to 80S assembled ribosomes. Interacts in a cooperative manner with SLBP to the mature 3'-end of histone mRNAs. Found in a ternary complex with SLBP and the stem-loop structure of the 3'-end of histone mRNAs (By similarity).
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). Binds with high affinity to the 3' side of the stem-loop structure and to the downstream cleavage product (DCP) of histone pre-mRNAs. 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 (By similarity).
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.
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Associates with the BLOC-2 complex to facilitate the transport of TYRP1 independent of AP-3 function. Plays a role in synaptic vesicle trafficking and in neurotransmitter release. Plays a role in the regulation of cell surface exposure of DRD2. May play a role in actin cytoskeleton reorganization and neurite outgrowth. May modulate MAPK8 phosphorylation. Appears to promote neuronal transmission and viability through regulating the expression of SNAP25 and SYN1, modulating PI3-kinase-Akt signaling and influencing glutamatergic release. Regulates the expression of SYN1 through binding to its promoter. Modulates prefrontal cortical activity via the dopamine/D2 pathway.
Detected in hippocampus neurons (at protein level). Ubiquitously expressed. The highest expression is observed in testis, liver, kidney, brain, heart and lung. In the brain, found primarily in axon bundles and axon terminals, notably in the cerebellum and hippocampus. Expressed at lower levels in stomach, small intestine and skeletal muscle, where it is detected at the sarcolemma.
Interacts (via its coiled coil domain) with KXD1. Interacts with AP3B2, TRIM32, CMYA5, PI4K2 and RNF151. Interacts with the DNA-dependent protein kinase complex DNA-PK; the interaction phosphorylates DTNBP1 in vitro. Interacts directly in this complex with XRCC5 and XRCC6. Interacts with XPO1; the interaction exports DTNBP1 out of the nucleus (By similarity). Component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) composed of at least BLOC1S1, BLOC1S2, BLOC1S3, BLOC1S4, BLOC1S5, BLOC1S6, DTNBP1/BLOC1S7 and SNAPIN/BLOC1S8. Interacts directly in the complex with BLOC1S5, BLOC1S6 and SNAPIN/BLOC1S8. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos. This BLOC-1 complex also associates with the BLOC-2 complex in endosomes. Binds to DTNA and DTNB but may not be a physiological binding partner. Interacts with AP3M1.
Ubiquitinated by TRIM32. Ubiquitination leads to DTNBP1 degradation.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.2/KCNA2 sub-subfamily.
Detected in neurons in dorsal root ganglion (PubMed:24472174). Detected in hippocampus neurons (PubMed:21602278). Detected on neurons of the anteroventral cochlear nucleus (PubMed:12777451). Detected in renal arteries (PubMed:12632190). Detected in neurons of the medial nucleus of the trapezoid body (PubMed:12177193). Detected in neurons in the brain cortex (PubMed:14713306). Detected in axon tracts of the corpus callosum, specific terminal fields of the brain cortex neuropil, neurons in the medial entorhinal cortex, and in puncta representing mossy fiber terminals in the hippocampus mossy fiber tract; these puncta correspond to synapses made by dentate granule cells (PubMed:8361540). Detected in paranodal and juxtanodal zones in the central nervous system, including myelinated spinal cord (PubMed:11086297, PubMed:20089912). Detected in the juxtaparanodal region in optic nerve (PubMed:10624965). Detected at nerve terminal plexuses of basket cells in the cerebellum (at protein level) (PubMed:7477295, PubMed:20089912). Detected in brain (PubMed:2722779). Detected in heart atrium and ventricle (PubMed:1715584). Detected in renal arteries (PubMed:12632190).
Homotetramer and heterotetramer with other channel-forming alpha subunits, such as KCNA1, KCNA4, KCNA5, KCNA6 and KCNA7 (PubMed:8495559, PubMed:8361540, PubMed:10896669, PubMed:12777451, PubMed:12632190, PubMed:15618540, PubMed:11007484, PubMed:16002581, PubMed:18004376, PubMed:20534430). Channel activity is regulated by interaction with beta subunits, including KCNAB1 and KCNAB2 (PubMed:18003609, PubMed:19713757, PubMed:16002581, PubMed:18004376, PubMed:20534430, PubMed:20360102, PubMed:23705070). Identified in a complex with KCNA1 and KCNAB2 (PubMed:11086297, PubMed:23318870). Identified in a complex with KCNA5 and KCNAB1 (By similarity). Identified in a complex with KCNA4 and FYN (By similarity). Interacts (via C-terminus) with the PDZ domains of DLG1 and DLG2 (PubMed:7477295). Interacts with DLG4 (via PDZ domain) (PubMed:7477295, PubMed:20089912). Interacts with PTK2B (PubMed:11739373). Interacts (via C-terminus) with CTTN (PubMed:12151401). 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 (PubMed:9635436). Interacts with DRD2 (By similarity). Interacts with SIGMAR1; cocaine consumption leads to increased interaction (By similarity). Interacts with CNTNAP2 (PubMed:10624965). Interacts with ADAM22 (PubMed:20089912). Interacts with ADAM11 (By similarity).
Inhibited by 4-aminopyridine (4-AP), dendrotoxin (DTX) and charybdotoxin (CTX), but not by tetraethylammonium (TEA) (PubMed:2555158, PubMed:8495559, PubMed:18638484). Inhibited by tityustoxin-K alpha (TsTX-Kalpha), a toxin that is highly specific for KCNA2 (PubMed:8355670). Inhibited by maurotoxin (PubMed:24472174). Inhibited by kappaM conotoxins kappaM-RIIIJ and kappaM-RIIIK (By similarity).
N-glycosylated, with complex, sialylated N-glycans.
Phosphorylated on tyrosine residues; phosphorylation increases in response to ischemia (PubMed:14713306). Phosphorylated on tyrosine residues by activated PTK2B/PYK2 (PubMed:7544443). Phosphorylation on tyrosine residues suppresses ion channel activity (PubMed:7544443). Phosphorylated on tyrosine residues in response to CHRM1 activation; this abolishes interaction with CTTN (PubMed:12151401). This is probably due to endocytosis of the phosphorylated channel subunits. Phosphorylated on serine residues in response to increased cAMP levels; phosphorylation is apparently not catalyzed by PKA (PubMed:18003609).
The cytoplasmic N-terminus is important for tetramerization. Interactions between the different subunits modulate the gating characteristics (PubMed:11007484). Besides, the cytoplasmic N-terminal domain mediates interaction with RHOA and thus is required for RHOA-mediated endocytosis (PubMed:9635436).
Up-regulated in brain cortex in response to ischemia (at protein level) (PubMed:14713306). Down-regulated in dorsal root ganglion neurons after peripheral nerve injury (at protein level) (PubMed:24472174). Down-regulated in pulmonary artery myocytes in response to chronic moderate hypoxia.
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:12151401, PubMed:21602278, PubMed:24472174). 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:15618540, PubMed:20805574, PubMed:23725331). 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:18003609, PubMed:19713757). In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to a 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:1715584, PubMed:16770729, PubMed:17766348, PubMed:18003609, PubMed:18638484, PubMed:19713757, PubMed:20089912). In contrast, a heteromultimer formed by KCNA2 and KCNA4 shows rapid inactivation (PubMed:8495559). 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 (PubMed:23318870). KCNA2-containing channels play a presynaptic role and prevent hyperexcitability and aberrant action potential firing (PubMed:12777451). 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 (PubMed:16210348). 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 (PubMed:16306173). May contribute to the regulation of neurotransmitter release, such as gamma-aminobutyric acid (GABA) (PubMed:17869444). Contributes to the regulation of the axonal release of the neurotransmitter dopamine (PubMed:21647367). Reduced KCNA2 expression plays a role in the perception of neuropathic pain after peripheral nerve injury, but not acute pain (PubMed:24472174). Plays a role in the regulation of the time spent in non-rapid eye movement (NREM) sleep (By similarity).
Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain.
Consists of three domains; the N-terminal catalytic domain, the editing domain and the C-terminal C-Ala domain. The editing domain removes incorrectly charged amino acids, while the C-Ala domain, along with tRNA(Ala), serves as a bridge to cooperatively bring together the editing and aminoacylation centers thus stimulating deacylation of misacylated tRNAs.
Monomer. Interacts with ANKRD16; the interaction is direct.
Abundant expression in fetal tissues, immature brain, skin wound and atretic ovarian follicles.
Abundant in whole fetus but decreases rapidly after birth. In adults is highly expressed in the adrenal, present in the brain and uterus but undetectable in the heart.
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. 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. Upon switching to a membrane-bound conformation, helix VIII can support the recruitment of G proteins and beta-arrestins.
Receptor for angiotensin II, a vasoconstricting peptide (PubMed:8227011). Signals primarily via a non-canonical G-protein- and beta-arrestin independent pathways. Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation (By similarity).
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, contrary to other family members (By similarity).
Detected in seminiferous tubules (at protein level). Detected in spermatocytes and spermatids. Not detected in spermatogonium.
Expression coincides with the onset of meiosis. Detected in nearly all stages of spermiogenesis (at protein level).
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).
In the intracellular compartments, may function as a channel or small molecule transporter.
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. Interacts with VPS37A, VPS37B and VPS37C. Interacts with DMAP1. Interacts with ubiquitin (By similarity). Interacts with AATF (PubMed:14761944). Interacts with stathmin and GMCL (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. Interacts with HGS; the interaction mediates the association with the ESCRT-0 complex. Interacts with GGA1 and GGA3. Interacts (via UEV domain) with PDCD6IP/AIP1. Interacts with VPS28, SNF8 and VPS36. Self-associates. 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. Interacts with PDCD6. Interacts with LITAF. Interacts with MGRN1 (By similarity). Interacts with ARRDC1; recruits TSG101 to the plasma membrane (By similarity).
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. Required for the exosomal release of SDCBP, CD63 and syndecan (By similarity). It may also play a role in the extracellular release of microvesicles that differ from the exosomes (By similarity).
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 is required for the interaction of the complex with ubiquitin.
The coiled coil domain may interact with stathmin.
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:7993622). 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 (PubMed:29166604). Plays a role in dendrite formation by melanocytes (By similarity).
Up-regulated by potassium depolarization, calcium ionophore, ATP and forskolin in culture cells (PubMed:7892240). Up-regulated by kainate in the hippocampus and piriform cortex (PubMed:7892240).
Widely expressed (PubMed:7892240). Expressed in the brain (PubMed:7892240). Expressed in pituitary gland, cerebellum, cortex, hypothalamus and hippocampus (PubMed:7892240).
Belongs to the peptidase M28 family. M28B subfamily.
Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes (By similarity). 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). Positively regulates T and B cell proliferation through iron uptake (By similarity). Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway (By similarity). 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 (By similarity). When dietary levels of stearate (C18:0) are high, TFRC stearoylation inhibits activation of the JNK pathway and thus degradation of the mitofusin MFN2 (By similarity).
Homodimer; disulfide-linked. Binds one transferrin molecule per subunit. Interacts with SH3BP4 (By similarity). Interacts with STEAP3; facilitates TFRC endocytosis in erythroid precursor cells (By similarity).
In testis, expressed in Sertoli cells, peritubular myoid cells and in germinal cells. Highest levels in Sertoli cells.
N- and O-glycosylated, phosphorylated and palmitoylated.
Stearoylated by ZDHHC6 which inhibits TFRC-mediated activation of the JNK pathway and promotes mitochondrial fragmentation (By similarity). Stearoylation does not affect iron uptake (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 (By similarity).
Expressed in the brain, testis, kidney, heart, lung and liver.
Interacts with GRB2 and PIP5K1B. 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 (By similarity). Interacts with SLC1A2. Interacts with EIF4E, AGO1, AGO2, DCP2, DDX6, LATS1, LATS2, SAV1, EGLN2/PHD1 and EGLN3/PHD3. Interacts (via LIM domains) with VHL (By similarity). Interacts (via LIM domains) with SNAI1 (via SNAG domain), SNAI2/SLUG (via SNAG domain) and SCRT1 (via SNAG domain) (By similarity).
LIM region interacts with CTNNA1. The preLIM region binds directly actin filaments (By similarity).
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 (By similarity).
Phosphorylated by LATS2 during mitosis. Phosphorylated by AURKA (By similarity).
Forms a complex composed of PDGFRL, TNK2 and GRB2.
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). 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.
Induces activation of MAPK14/p38 cascade, when overexpressed. Induces apoptosis, when overexpressed.
Interacts with RELT, RELL1, OXSR1, PLSCR1 and TRAF2.
Binds to photoactivated, phosphorylated RHO and terminates RHO signaling via G-proteins by competing with G-proteins for the same binding site on RHO. May play a role in preventing light-dependent degeneration of retinal photoreceptor cells.
Monomer. Homodimer. Homotetramer. Interacts with RHO (via the phosphorylated C-terminus).
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.
Brain-specific. Restricted to the CA3 region of the hippocampus, entorhinal cortex, the antero-dorsal and antero-ventral thalamus and the inferior and superior colliculus.
Negatively regulates Golgi-to-plasma membrane trafficking by interacting with PI4KB and inhibiting its activity.
The calcium-binding affinity is not regulated by magnesium.
E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.
Homo- and heterodimer. Heterodimer (RING-type zinc finger) with BRCA1. Heterodimer (via ANK repeats and BRCT domains) with CSTF1/CSTF-50. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Interacts with UBXN1.
Processed during apoptosis. The homodimer is more susceptible to proteolytic cleavage than the BARD1/BRCA1 heterodimer.
Highly expressed in testis, cerebrum and cerebellum, and barely detectable in liver, heart, spleen and muscle. Also highly expressed in various tumor cells from hepatoma, glioblastoma and pheochromocytoma.
Homodimer. Interacts with IPO9; the interaction is direct. Associates with 20S and 26S proteasomes (By similarity). Interacts with SMARCD1; promoting SWI/SNF complex recruitment. Interacts with NFKBIZ (By similarity). Interacts with YWHAB (PubMed:18460465).
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 (By similarity). 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 (By similarity). 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. Also involved in adaptive immunity by promoting B-cell activation. Involved in brain development: required for the survival and proliferation of cerebral cortical progenitor cells. Involved in myogenesis: required for skeletal muscle formation and skeletal development, possibly by regulating expression of muscle differentiation factors. Also plays a role in facilitating interdigital tissue regression during limb development (By similarity).
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 (By similarity).
Detected at high levels in lung during the late fetal and postnatal period and at lower levels in adult.
Expressed constitutively by vascular endothelium. Detected in alveolar and serosal epithelial cells as well as in endothelial cells in one day old rat. In adult lung, detected in rare endothelial cells.
Homodimer. Interacts with NOSIP and NOSTRIN (By similarity). Interacts with HSP90AB1 (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).
Phosphorylation by AMPK at Ser-1176 in the presence of Ca(2+)-calmodulin (CaM) activates activity. In absence of Ca(2+)-calmodulin, AMPK also phosphorylates Thr-494, resulting in inhibition of activity.
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. 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 (By similarity).
Encoded on a bicistronic transcript that code for two proteins, SNRPN and SNURF.
Essential for female fertility. May play a role in the oocyte-to-embryo transition (By similarity).
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. Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity. Regulates the expression of DPPA4 and NANOG in the NT2 embryonic carcinoma cells.
Highly expressed in brain, cerebellum, heart and testis.
Interacts with BCORL1, forming heterodimers (By similarity). The PCGF1-BCORL1 heterodimeric complex interacts with the KDM2B-SKP1 heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (By similarity). Component of the repressive BCOR complex containing a Polycomb group subcomplex at least composed of RYBP, RING1 and RNF2/RING2 (By similarity). Specifically interacts with BCOR, RING1 and RNF2/RING2 (By similarity). Component of a PRC1-like complex (By similarity). Interacts with CBX6, CBX7 and CBX8 (By similarity). Interacts with DPPA4, NANOG, POU5F1 and RYBP (By similarity).
Interacts with GRIP1, GRIP2 and GRIA2. Forms a ternary complex with GRIP1 and GRIA2. Interacts with ITGA4 through its chondroitin sulfate glycosaminoglycan. Interacts with BCAR1, CDC42 and ACK1. Interacts with MMP16 (By similarity). Interacts with the first PDZ domain of MPDZ. Interacts with PRKCA. Interacts with LGALS3 and the integrin composed of ITGB1 and ITGA3. Binds TNC, laminin-1, COL5A1 and COL6A2. Interacts with PLG and angiostatin. Binds FGF2 and PDGFA.
Neural cells and also extraneural tissues, especially in the developing mesenchyme.
O-glycosylated; contains glycosaminoglycan chondroitin sulfate which are required for proper localization and function in stress fiber formation. 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.
The level of expression is highest on immature, proliferating cells and decreases as these cells differentiate.
Valuable marker for several incompletely differentiated precursor cells.
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. Interacts with NSMCE3.
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. Involved in maintenance of genome integrity, DNA damage response and DNA repair.
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. NSMCE3/MAGEG1 and NSMCE1 ubiquitin ligase are components of SMC5-SMC6 complex and may positively regulate homologous recombination-mediated DNA repair.
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. 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.
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.
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 (By similarity).
Heterodimer of a type I and a type II keratin. Heterodimer with type II keratin KRT5 leading to the formation of keratin intermediate filament (KIF) network. Interacts with KRT6A to form filaments.
Liver. Not found in the lung, kidney and prostate.
Belongs to the bacterial ribosomal protein bS18 family.
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 (By similarity).
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. Plays an important role in chromosome congression and in the recruitment of CENP-O complex (which comprises CENPO, CENPP, CENPQ and CENPU), CENPE and PLK1 to the kinetochores.
Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU.
Phosphorylation at Ser-52 is essential for CENPE recruitment to kinetochores and orderly chromosome congression.
Component of the tRNA-splicing ligase complex.
Belongs to the arylamine N-acetyltransferase family.
Interacts with AP5Z1, AP5B1, AP5S1 and SPG11. Interacts with TTC19 and KIF13A (By similarity).
Phosphatidylinositol 3-phosphate-binding protein required for the abcission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abcission. May also be required for efficient homologous recombination DNA double-strand break repair (By similarity).
The FYVE-type zinc finger mediates binding to phosphatidylinositol 3-phosphate and recruitment to the midbody during cytokinesis.
Expressed (at protein level) at a high level in kidney, lung and spleen; at a lower level in testis, liver, brain and heart. Expressed in kidney and retinal pigment epithelium derived cell line.
Forms a SNARE complex composed of VAMP8, SNAP29 and STX17 involved in fusion of autophagosome with lysosome (By similarity). Found in a number of SNARE complexes with NAPA, SNAP23, SNAP25, STX1A, STX4, STX7, STX8 and VTI1B (PubMed:10336434, PubMed:9614193, PubMed:11786915). Interacts with PICALM (By similarity). SNARE complex formation and binding by PICALM are mutually exclusive processes for VAMP8 (By similarity). Interacts with SBF2/MTMR13 (By similarity). Interacts with RAB21 (in GTP-bound form) in response to starvation; the interaction probably regulates VAMP8 endolysosomal trafficking (By similarity). Interacts with STX17; this interaction is increased in the absence of TMEM39A (By similarity). Interacts with TRIM6 (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. 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 (By similarity). Also required for dense-granule secretion in platelets (By similarity). 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 (PubMed:12737809). Involved in the homotypic fusion of early and late endosomes (PubMed:10982406, PubMed:11029036). Participates also in the activation of type I interferon antiviral response through a TRIM6-dependent mechanism (By similarity).
Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering substrate release. 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.
Interacts with HSPA8/HSC70. Interacts with HSPA1A (via NBD) and HSPA1B (via NBD).
Phosphorylation on Ser-509 may be important for regulation of the HSPA8/HSC70 chaperone activity.
Component of the biogenesis of lysosome-related organelles complex-2 (or BLOC2) composed of HPS3, HPS5 and HPS6.
Involved in early stages of melanosome biogenesis and maturation.
Belongs to the eukaryotic ribosomal protein eS24 family.
Required for processing of pre-rRNA and maturation of 40S ribosomal subunits.
Belongs to the KCNMB (TC 8.A.14.1) family. KCNMB1 subfamily.
Interacts with KCNMA1 tetramer. There are probably 4 molecules of KCMNB1 per KCNMA1 tetramer (By similarity).
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 (By similarity).
Weakly expressed. In brain, it is expressed in a few discrete populations of neurons that also express KCNMA1.
As T-kinin is preceded by a Met instead of an Arg or Lys, it is not released from its precursor by either tissue or plasma kallikrein.
In response to an inflammatory stimulant. T-kininogen II synthesis is induced and the plasma concentration of T-kininogen I is raised.
Kininogens are plasma glycoproteins with a number of functions: (1) as precursor of the active peptide bradykinin they effect smooth muscle contraction, induction of hypotension and increase of vascular permeability. (2) They play a role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII. (3) They are inhibitor of thiol proteases.
Rats express four types of kininogens: the classical HMW and LMW kininogens produced by alternative splicing of the same gene, and two additional LMW-like kininogens: T-I and T-II.
Regulatory subunit of the condensin-2 complex, a complex which establishes mitotic chromosome architecture and is involved in physical rigidity of the chromatid axis.
Belongs to the glycosyltransferase 54 family.
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 (By similarity). Involved in glucose transport by mediating SLC2A2/GLUT2 glycosylation, thereby controlling cell-surface expression of SLC2A2 in pancreatic beta cells (By similarity).
Interacts with STX1. May interact with CPNE6.
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 feeding behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.
Interacts with MPDZ. Interacts with ARRB2 (By similarity).
The PDZ domain-binding motif is involved in the interaction with MPDZ.
Expressed in many types of neurons in the brain.
Expressed throughout postnatal development of the brain and present at high levels in the adult.
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-31 by the prolyl endopeptidase FAP (seprase) activity (in vitro).
Expressed in hippocampus and cerebral cortex (at protein level). Expressed in hippocampus (dentate gyrus and CA1-CA4 regions), cerebellum (Purkinje cells), cortex, visual cortex (layers 1 and 2), mesencephalon, diencephalon and brain stem.
Interacts with kinesin, dynein, APLP1, APLP2, TENT2/GLD2 and APP. Both phosphorylated and non phosphorylated forms interact with APLP1 (By similarity). Interacts with TENT4B; the interaction is required for TENT4B-mediated translational control (By similarity).
Phosphorylated on serine/threonine residues by AURKA within positions 165 and 196. Phosphorylation and dephosphorylation on Thr-171 regulates cytoplasmic polyadenylation and translation of CPE-containing mRNAs. Phosphorylation on Thr-171 by AURKA and CAMK2A activates CPEB1. Phosphorylation on Thr-171 may be promoted by APLP1. Phosphorylation increases binding to RNA (By similarity).
Sequence-specific RNA-binding protein that regulates mRNA cytoplasmic polyadenylation and translation initiation during oocyte maturation, early development and at postsynapse sites of neurons. Binds to the cytoplasmic polyadenylation element (CPE), an uridine-rich sequence element (consensus sequence 5'-UUUUUAU-3') within the 3'-UTR of mRNAs. In absence of phosphorylation and in association with TACC3 is also involved as a repressor of translation of CPE-containing mRNA; a repression that is relieved by phosphorylation or degradation. Involved in the transport of CPE-containing mRNA to dendrites; those mRNAs may be transported to dendrites in a translationally dormant form and translationally activated at synapses. Its interaction with APLP1 promotes local CPE-containing mRNA polyadenylation and translation activation. Induces the assembly of stress granules in the absence of stress. Required for cell cycle progression, specifically for prophase entry.
The 2 RRM domains and the C-terminal region mediate interaction with CPE-containing RNA. The interdomain linker (411-429) acts as a hinge to fix the relative orientation of the 2 RRMs. The ZZ domain (509-566) coordinates 2 Zn ions and is probably implicated in mediating interactions with other proteins in addition to increasing the affinity of the RRMs for the CPEs. A continuous hydrophobic interface is formed between the 2 RRM.
Belongs to the eukaryotic ribosomal protein eS19 family.
Required for pre-rRNA processing and maturation of 40S ribosomal subunits.
Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor (By similarity).
Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor.
Directly interacts with VCP. Interacts with UBQLN1. Forms a complex with VCP and UBQLN1.
Involved in endoplasmic reticulum-associated protein degradation (ERAD). Acts as a platform to recruit both UBQLN1 and VCP to the ER during ERAD.
The UBX domain is required for interaction with VCP.
The intramembrane domain also contains the signal for ER targeting.
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. 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 protein and membrane transport to the cilium. May regulate the morphogenesis of hair follicles which depends on functional primary cilia (By similarity).
Belongs to the archaeal Rpo11/eukaryotic RPB11/RPC19 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. RPB11 is part of the core element with the central large cleft.
Acts as a modulator of nicotinic acetylcholine receptors (nAChRs) function in the brain (PubMed:27344019). Inhibits nicotine-induced Ca(2+) influx through nAChRs (By similarity). In vitro, specifically inhibits alpha-3:beta-4 and alpha-7 nAChR currents in an allosteric manner (By similarity). Acts as a positive regulator of Wnt/beta-catenin signaling (By similarity).
Expressed at high levels in the cortex and cerebellum of the brain, at moderate levels in the lung, kidney, and liver, and at low levels in the heart and prostate (at protein level) (PubMed:27344019). Expressed in neurons (at protein level) (PubMed:34631692).
Highly expressed during early development, showing high levels in the first postnatal days, followed by a decrease toward adulthood.
Interacts with nicotinic acetylcholine receptors (nAChRs) including CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNB2 and CHRNB4 (By similarity). Interacts (via NxI motif) with LRP6 (By similarity).
The UPAR/Ly6 domain is sufficient for inhibiting alpha-3:beta-4 and alpha-7-dependent nAChR currents.
Binds 1 or 2 heme groups per heterodimer.
Heterodimer of an alpha and a beta chain.
The HXXXXD motif is essential for acyltransferase activity.
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. May be required in mitosis for the processing of stalled or collapsed replication forks.
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 (By similarity).
Large intestine, caecum, stomach, pancreas, submaxillary gland and kidney (at protein level). Ubiquitous.
Posseses strong B transferase activity and a weak A transferase activity.
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.
Inhibited by N-ethylmaleimide, hydroxymercuribenzoate, methyl mercury iodide and heavy metals such as Hg2+, Cu2+, and Ag2+.
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:8660691, PubMed:6874697, PubMed:12855692). 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:8660691, PubMed:6874697, PubMed:12855692). 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 (By similarity). Can also act on valproyl-CoA, a metabolite of the valproic acid drug (PubMed:8660691).
Bone and testis. In the latter, restricted to the basal portion of the seminiferous tubule.
By parathyroid hormone and cAMP analogs.
May function in signaling pathways during bone remodeling, as well as serve a broader role in cell interactions associated with differentiation in bone and testis. Associated with differentiation in bone and testis.
Up-regulated in differentiating cultures of primary osteoblasts and down-regulated in late stage mineralizing cultures. In testis, expression is highest between stages I and VII when maturing spermatids remain buried within the Sertoli epithelium.
Belongs to the class I-like SAM-binding methyltransferase superfamily. MenG/UbiE family.
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9.
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).
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. Uncapping occurs either when Ca(2+) falls or when the concentration of polyphosphoinositide rises, both at low and high Ca(2+) (By similarity).
Interacts with NUP62. Interacts with NUTF2 and RAN; involved in CAPG nuclear import.
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 (PubMed:24735892). This effect may be mediated by binding to GPR107 and PKA activation (PubMed:26561648). May regulate cardiac contractile function (PubMed:22170057). May compromise cardiomyocyte viability (PubMed:22170057). In the central nervous system, may impair memory retention and may affect hippocampal excitability (PubMed:21978882). May also have anxiolytic and anorexigenic effects (PubMed:18753129, PubMed:21978882). May play a role in arterial pressure regulation (PubMed:18753129, PubMed:21978882). 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 (By similarity). Potentiates inhibitory action of somatostatin on ghrelin-stimulated secretion of GH1, but not that on GnRH-stimulated secretion of LH (By similarity).
Somatostatin is detected in neurons throughout the brain, including in the lateral septum, nucleus accumbens, amygdaloid complex, hypothalamic periventricular nucleus, hippocampus, cortex, cerebellum and several brainstem nuclei (at protein level) (PubMed:20056135). Neuronostatin is widely expressed with highest levels in pleen and pancreas, followed by cerebrum and hypothalamus (at protein level) (PubMed:18753129, PubMed:26561648). Neuronostatin plasma levels are higher in fasted, as compared to fed animals (PubMed:26561648). In the brain, neuronostatin is mainly present in the hypothalamic periventricular nucleus and median eminence (at protein level) (PubMed:20056135).
Autophosphorylation of Thr-287 following activation by Ca(2+)/calmodulin. Phosphorylation of Thr-287 locks the kinase into an activated state (By similarity).
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. Interacts with RRAD and CACNB2.
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' (PubMed:17923476). 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:17923476). 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:10825152). 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).
Isoform Delta 1 is the predominant form in the brain, isoform Delta 2 and isoform Delta 3 predominate in the aorta and isoform Delta 4 in skeletal muscle.
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 growth factors, like IGF1, PDGF and morphogenetic 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 (By similarity).
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.
Ubiquitously expressed. Expressed in dorsal root ganglia, trigeminal ganglia, spinal cord (Lissauer's tract, dorsal horn and dorsal columns) (at protein level).
Plays a role in transport between endoplasmic reticulum and Golgi.
3D-structure analysis of the human homolog indicates that the membrane topology differs from the predictions. Contrary to predictions, the N-terminus contains two short helices that dip into the membrane, but do not cross it. The C-terminus contains the single transmembrane helix. This gives rise to a topology where the N-terminus is cytoplasmic and the C-terminus is lumenal.
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). 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. PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity.
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.
Seems to antagonize 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. Plays a role during anterior segment eye development (By similarity).
The sequence shown has an N-terminus according to mammalian orthologs. The original sequence from PubMed:14684875 gives a longer N-terminus and suggests a signal sequence of 97 AA.
Ubiquitously expressed in neurogenic regions of the embryonic brain.
Expressed in osteocytes, osteoblasts, and chondrocytes in bone.
Transcription factor that binds the consensus DNA sequence [GC]AAAAA. Seems to bind and regulate the promoters of MMP1, MMP3, MMP7 and COL1A1.
Hydrolyzes fatty acids from S-acylated cysteine residues in proteins. Has depalmitoylating activity towards DLG4/PSD95.
Accessory subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis.
Belongs to the DNA polymerase alpha subunit B family.
Belongs to the glycosyltransferase 25 family.
Expressed in adrenal medulla (pheochromocytoma).
Interacts with PLAT (By similarity). Interacts with PLAUR.
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 (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).
Interacts with ATM, BRCA1, PRKDC and TP53BP1. Also exhibits ATM- and phosphorylation-dependent interaction with the MRN complex, composed of MRE11, RAD50, and NBN (By similarity).
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 (By similarity).
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. V(D)J recombination is initiated by the lymphoid specific RAG endonuclease complex, which generates site specific DNA double strand breaks (DSBs). These DSBs present two types of DNA end structures: hairpin sealed coding ends and phosphorylated blunt signal ends. These ends are independently repaired by the non homologous end joining (NHEJ) pathway to form coding and signal joints respectively. 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. The latter activity is required specifically for the resolution of closed hairpins prior to the formation of the coding joint. May also be required for the repair of complex DSBs induced by ionizing radiation, which require substantial end-processing prior to religation by NHEJ (By similarity).
G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation. Signals via G-protein and beta-arrestin pathways. LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G(11)), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs). After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (By similarity). In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation. Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry. Induces differentiation of brown and beige adipocytes probably via autocrine and endocrine functions of FGF21 hormone. Contributes to the thermogenic activation of brown adipose tissue and the browning of white adipose tissue. Activates brown adipocytes by initiating intracellular calcium signaling leading to mitochondrial depolarization and fission, and overall increased mitochondrial respiration. Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass. Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins. In response to dietary fats regulates hormone secretion and appetite. Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels. Negatively regulates glucose-induced SST secretion in pancreatic delta cells. Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone. In taste buds, contributes to sensing of dietary fatty acids by the gustatory system. During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue (By similarity). Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation (By similarity). In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1 (By similarity). Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release (By similarity). Mediates LCFAs anti-apoptotic effects (By similarity).
Interacts (via C-terminus) with ARRB2 following LCFAs stimulation.
Phosphorylated at two clusters of Ser and Thr residues located in the intracellular C-terminus. Prerequisite for FFAR4 internalization via an ARRB2-dependent pathway.
Exhibits both phospholipase A1/2 and acyltransferase activities (By similarity). 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 (By similarity). 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:17158102).
Receptor for the neuromedin-U and neuromedin-S neuropeptides.
The highest level is detected in the uterus. In the central nervous system, high expression levels were found in the hypothalamus and moderate levels in both the medulla oblongata and spinal cord. Expressed in the hypothalamic paraventricular nucleus (PVN) and suprachiasmatic nuclei (SCN) of the hypothalamus. Expression is low in the gastrointestinal tract. In other peripheral tissues, moderate expression was observed in the lung and ovary.
Belongs to the eukaryotic NMN adenylyltransferase family.
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 (By similarity).
Divalent metal cations. Mg(2+) confers the highest activity.
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. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate but with a lower efficiency. Cannot use triazofurin monophosphate (TrMP) as substrate. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity prefers NAD(+), NADH and NaAD as substrates and degrades nicotinic acid adenine dinucleotide phosphate (NHD) less effectively. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+). Also acts as an activator of ADP-ribosylation by supporting the catalytic activity of PARP16 and promoting mono-ADP-ribosylation of ribosomes by PARP16 (By similarity).
Palmitoylated; palmitoylation is required for membrane association.
Found predominantly on the basal layers of squamous epithelium. Expressed in the gravid uterus and on epithelial of the upper gastrointestinal tract. It has been found in tumor lines which metastasize via the lymphatic system.
Interacts with AGR2 and AGR3 (By similarity). Binds laminin-1 and laminin-5. Interacts with LGALS3.
Supports cell migration. May be involved in tumor progression.
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.
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 (PubMed:30021165, PubMed:29166604). Interacts with MADD (By similarity).
Motor for anterograde axonal transport of synaptic vesicle precursors (Probable). Also required for neuronal dense core vesicles (DCVs) transport to the dendritic spines and axons (PubMed:29166604, PubMed:30021165). The interaction calcium-dependent with CALM1 increases vesicle motility and interaction with the scaffolding proteins PPFIA2 and TANC2 recruits DCVs to synaptic sites (PubMed:30021165).
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. NifS/IscS subfamily.
By growth hormone. P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in 15% taste bud cells in circumvallate and foliate papillae but only in 2% in fungiform papillae. Expressed in the duodenum, antrum and fundus (part of the stomach).
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.
This protein was previously referred to as T2R26 or T2R12 but is now considered to be the ortholog of human TAS2R41.
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.
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 (By similarity). Interacts with TRAF4 (By similarity). Interacts with CRIP2 (By similarity). Interacts with HSPB1 (PubMed:11546764). Interacts with ILK (By similarity). Interacts with LIMS1 and LIMS2 (By similarity). Interacts with NCK2 (PubMed:10330411). Interacts with NUDT16L1 (By similarity). Interacts with PAK (PubMed:10330411). 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 (PubMed:10330411). Forms a complex with ARHGEF7 (PubMed:10330411). Interacts with AR/androgen receptor in a ligand-dependent manner (By similarity). Interacts with CSK (By similarity). Interacts with PTK2/FAK1 and PTK2B/PYK2 (PubMed:9422762, PubMed:10330411, PubMed:16546139). Interacts with SLC6A3 and SLC6A4 (By similarity). Interacts with NR3C1 (By similarity). Interacts with SMAD3 (By similarity). Interacts with MAPK15 (By similarity). Interacts with SRC (By similarity). Interacts with LYN (By similarity). Interacts with talin (By similarity). 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 (By similarity). Interacts with PARVA (PubMed:11134073). Interacts with PXN (PubMed:16546139).
Phosphorylated by gonadotropin-releasing hormone-activated SRC.
Strongly expressed in large intestine, lung, spleen, testis, uterus and to a lower extent in brain, kidney and liver (at protein level). In brain, expressed by neuronal and non neuronal cells (at protein level).
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 (By similarity).
Short-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats (PubMed:3968063). 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:3968063). Among the different mitochondrial acyl-CoA dehydrogenases, short-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 4 to 6 carbons long primary chains (PubMed:3968063).
Glycosylation is tissue specific. Sialylation of N-glycans at Asn-93 in brain and at Asn-42, Asn-93 and Asn-117 in thymus.
May play a role in cell-cell or cell-ligand interactions during synaptogenesis and other events in the brain.
Highly expressed in heart, brain, spleen, lung, liver, muscle, kidney and testis.
Highly expressed in pachytene spermatocytes during spermatogenesis.
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.
Reduces the ATPase activity of VCP (PubMed:9824302, PubMed:9214505). Necessary for the fragmentation of Golgi stacks during mitosis and for VCP-mediated reassembly of Golgi stacks after mitosis (PubMed:12411482). May play a role in VCP-mediated formation of transitional endoplasmic reticulum (tER) (PubMed:10930451). Inhibits the activity of CTSL (in vitro) (By similarity). Together with UBXN2B/p37, regulates the centrosomal levels of kinase AURKA/Aurora A during mitotic progression by promoting AURKA removal from centrosomes in prophase (By similarity). Also, regulates spindle orientation during mitosis (By similarity).
May be involved in the calcium-dependent regulation of rhodopsin phosphorylation. Binds three calcium ions (By similarity).
Belongs to the eukaryotic ribosomal protein eL15 family.
Allosteric enzyme with positive cooperativity toward the substrate N-carbamoyl-beta-alanine at low substrate concentrations (below 12 nM). Displays no cooperativity at substrate levels above 12 nM.
Belongs to the carbon-nitrogen hydrolase superfamily. BUP family.
Catalyzes a late step in pyrimidine degradation. Converts N-carbamoyl-beta-alanine (3-ureidopropanoate) into beta-alanine, ammonia and carbon dioxide. Likewise, converts N-carbamoyl-beta-aminoisobutyrate (3-ureidoisobutyrate) into beta-aminoisobutyrate, ammonia and carbon dioxide.
Homodimer, homotetramer, homooctamer; can also form higher homooligomers.
The purified enzyme was shown to contain 1.8 zinc atoms per subunit, and sequence analysis was used to predict the zinc binding site (PubMed:8449931). The crystal structure of the human ortholog indicates a lack of bound zinc ions, and shows that the residues that were predicted to bind zinc are too far apart in space to form a zinc binding site (By similarity).
Attenuates p73-mediated cell death signaling in transcriptional repression-induced atypical death (TRIAD) of neurons.
Binds to the SH3 domain of the YES kinase. Binds to WBP1 and WBP2. 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. Interacts (via WW domains) with LATS1 (via PPxY motif 2). Interacts with LATS2. Interacts (via WW domain 1) with ERBB4 (via PPxY motif 2). Interacts with TEAD1, TEAD2, TEAD3 and TEAD4. Interacts with TP73. Interacts with RUNX1. Interacts with HCK. 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 (By similarity). Interacts (when phosphorylated at Ser-112) with SMAD2, SMAD3 and WWTR1 (By similarity). Interacts with PRRG2 (via cytoplasmic domain) (By similarity). Interacts (via WW domains) with PRRG4 (via cytoplasmic domain) (By similarity).
Phosphorylated by LATS1 and LATS2; leading to cytoplasmic translocation and inactivation. Phosphorylated by ABL1; leading to YAP1 stabilization, enhanced interaction with TP73 and recruitment onto proapoptotic genes; in response to DNA damage. Phosphorylation at Ser-366 and Ser-369 by CK1 is triggered by previous phosphorylation at Ser-363 by LATS proteins and leads to YAP1 ubiquitination by SCF(beta-TRCP) E3 ubiquitin ligase and subsequent degradation (By similarity). Phosphorylated at Thr-104, Thr-136, Ser-333 and Thr-378 by MAPK8/JNK1 and MAPK9/JNK2, which is required for the regulation of apoptosis by YAP1 (By similarity).
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. 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. 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. 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. 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 (By similarity). Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (By similarity). 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.
Expression restricted to placental tissues. Trophoblast giant cells are found to be the major source.
Probable 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 (By similarity). Mitochondrial glutathione is required for the activity and stability of proteins containing iron-sulfur clusters, as well as erythropoiesis (By similarity).
May act as an adapter that regulates LRP2 function.
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.
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. 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. 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.
Interacts (via N-terminus) with ORAI1 (via N- and C-termini); this interaction regulates Ca(2+) influx at the plasma membrane.
The anchoring of this receptor to the plasma membrane is probably mediated by the palmitoylation of a cysteine residue.
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.
Does not exhibit any ribonuclease activity.
May have an involvement in muscle development or hypertrophy. Isoform 2 binds to RBP-J and plays a negative regulatory role in the RBP-J-mediated transcription in mammalian systems (By similarity).
Belongs to the potassium channel KCNN family. KCa2.3/KCNN3 subfamily.
Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:11533126, PubMed:11245600). Activation is followed by membrane hyperpolarization (PubMed:11533126). Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization (PubMed:11533126).
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 (By similarity).
Inhibited by bee venom neurotoxin apamin.
Appears on embryonic day 17 and gradually increases until day 19. Decreases between day 19 and birth.
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:7493971). 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.
GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.
Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G 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), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (By similarity). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation. Interacts with PAK2. Interacts (GTP-bound form) with SH3RF1 and SH3RF3. Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1 (By similarity). Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (PubMed:22128169). Interacts (GTP-bound form preferentially) with CYRIB (By similarity). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (By similarity). Interacts with GARRE1 (By similarity). Interacts with RAP1GDS1 (By similarity).
Plasma membrane-associated 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 secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles (PubMed:16040606, PubMed:16549782). Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity (By similarity). In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:16040606). In glioma cells, promotes cell migration and invasion (PubMed:20696765). In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning (PubMed:19029984). Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (By similarity). In neurons, is involved in dendritic spine formation and synaptic plasticity (PubMed:25498153). In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX (PubMed:12695502). In synapses, may mediate the regulation of F-actin cluster formation performed by SHANK3 (PubMed:24089484). In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization (PubMed:25284783).
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. GTP hydrolysis is stimulated by ARHGAP30 and ARHGAP44.
The effector region mediates interaction with DEF6.
Autophosphorylated in trans, meaning that in a dimer, one kinase molecule phosphorylates the other one. Activated by autophosphorylation at Thr-422 in response to a conformation change, triggered by interaction with GTP-bound CDC42 or RAC1. Activated by phosphorylation at Thr-422 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 (By similarity). Activated by phosphorylation at Thr-422 by BRSK2. Upon DNA damage, phosphorylated at Thr-211 and translocates to the nucleoplasm (By similarity). Phosphorylated at tyrosine residues, which can be enhanced by NTN1 (By similarity).
Expressed predominantly in the brain, with higher expression in neuronal groups associated with motor function, and at lower levels in the spleen.
Found in the embryonic CNS with little expression elsewhere.
Homodimer in its autoinhibited state. Active as monomer. Interacts with GIT1 (By similarity). 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 (By similarity). Interacts with ARHGEF7 (By similarity). Interacts with SCRIB (By similarity).Interacts with PDPK1 (By similarity). Interacts (via kinase domain) with RAF1 (By similarity). Interacts with NCK1 and NCK2 (By similarity). Interacts with TBCB (By similarity). Interacts with BRSK2 (By similarity). Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1 (PubMed:9032240). Interacts with SNAI1 (By similarity). Interacts with CIB1 (via N-terminal region); the interaction is direct, promotes PAK1 activity and occurs in a calcium-dependent manner. Interacts with INPP5K (By similarity). Interacts with gamma-tubulin (By similarity).
Phosphorylation of Thr-84 by OXSR1 inhibits activation (By similarity). 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-422.
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. 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. In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling (By similarity). 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 (PubMed:25284783). 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 (By similarity).
Belongs to the pseudouridine synthase TruB family.
Pseudouridine synthase that catalyzes pseudouridylation of mRNAs and tRNAs. Mediates pseudouridylation of mRNAs with the consensus sequence 5'-GUUCNANNC-3', harboring a stem-loop structure. Constitutes the major pseudouridine synthase acting on mRNAs. Also catalyzes pseudouridylation of some tRNAs, including synthesis of pseudouridine(55) from uracil-55, in the psi GC loop of a subset of tRNAs. Promotes the processing of pri-let-7 microRNAs (pri-miRNAs) independently of its RNA pseudouridylate synthase activity. 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.
Amyloid-beta peptides are degraded by IDE.
Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Binds transient metals such as copper, zinc and iron. Rat and mouse amyloid-beta peptides bind only weakly transient metals and have little reducing activity due to substitutions of transient metal chelating residues. Amyloid-beta protein 42 may activate mononuclear phagocytes in the brain and elicits inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Also binds GPC1 in lipid rafts (By similarity).
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 (By similarity). Amyloid-beta associates with HADH2 (By similarity). Interacts with CPEB1, ANKS1B, TNFRSF21 and AGER (By similarity). Interacts with ITM2B. Interacts with ITM2C. Interacts with IDE. Can form homodimers; dimerization is enhanced in the presence of Cu(2+) ions. Can form homodimers; this is promoted by heparin binding (By similarity). Amyloid-beta protein 40 interacts with S100A9 (By similarity). CTF-alpha product of APP interacts with GSAP (By similarity). 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 (By similarity). The C99 fragment also interacts with SORL1 (By similarity). Isoform APP751 interacts with SORL1 (By similarity). Isoform APP770 interacts with SORL1 (By similarity). Interacts with PLD3 (By similarity). Interacts with VDAC1 (By similarity). Interacts with NSG1; could regulate APP processing (By similarity). Amyloid-beta protein 42 interacts with FPR2 (By similarity). Interacts with SYT7 (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (By similarity). Interacts with LRRK2 (By similarity). Interacts (via cytoplasmic domain) with KIF5B (PubMed:23011729). Interacts (via C-terminus) with APBB2/FE65L1 (via C-terminus) (By similarity). Interacts (via intracellular domain) with APBB3 (By similarity).
Chelation of metal ions, notably copper, iron and zinc, can induce histidine-bridging between amyloid-beta molecules resulting in amyloid-beta-metal aggregates. Rat and mouse amyloid-beta peptides have an arginine residue substituted for the bridging histidine residue and are thus less capable of forming amyloid aggregates. Extracellular zinc-binding increases binding of heparin to APP and inhibits collagen-binding (By similarity).
Expressed in the brain (PubMed:23011729). In the brain, non-L-APP isoforms are expressed in neurons, isoform APP695 being the predominant form. In astrocytes and microglial cells, almost 50% is L-isoform (appican).
Extracellular binding and reduction of copper, results in a corresponding oxidation of Cys-144 and Cys-158, and the formation of a disulfide bond.
From 6 days to 7 months, levels of KPI-containing isoforms increase in the brain cortex and hippocampus. Levels of L-APP increase in all brain regions during the same period, but levels are low compared to non-L-APP isoforms.
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. Involved in cell mobility and transcription regulation through protein-protein interactions (By similarity). Can promote transcription activation through binding to APBB1-KAT5 and inhibit Notch signaling through interaction with Numb (By similarity). Couples to apoptosis-inducing pathways such as those mediated by G(o) and JIP. Inhibits G(o)-alpha ATPase activity. 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 (By similarity). May be involved in copper homeostasis/oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV (By similarity). 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 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 (By similarity).
N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).
O-glycosylated. O-linkage of chondroitin sulfate to the L-APP isoforms produces the APP proteoglycan core proteins, the appicans. The chondroitin sulfate chain of appicans contains 4-O-sulfated galactose in the linkage region and chondroitin sulfate E in the repeated disaccharide region.
Phosphorylation in the C-terminal on tyrosine, threonine and serine residues is neuron-specific (PubMed:9085254, PubMed:10329382, 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:10936190). The Thr-743 phosphorylated form causes a conformational change which reduces binding of Fe65 family members (By similarity). 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 (By similarity). Phosphorylation on Tyr-757 is required for SHC binding. Phosphorylated in the extracellular domain by casein kinases on both soluble and membrane-bound APP (By similarity). This phosphorylation is inhibited by heparin (By similarity).
Phosphorylation of mature, glycosylated APP occurs 48-72 hours after treatment of neuronal cells with nerve growth factor which correlates with the timing of neurite outgrowth.
Proteolytically cleaved by caspases during neuronal apoptosis. Cleavage at Asp-739 by either caspase-3, -8 or -9 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). Amyloid-beta protein 40 and Amyloid-beta protein 42 are cleaved by ACE. 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.
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 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).
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.
Interacts (via C-terminus) with SRSF1. Interacts (via C-terminus) with SRSF2 (By similarity).
RNA-binding protein that mediates pre-mRNA alternative splicing regulation.
Belongs to the cyclophilin-type PPIase family. PPIase B subfamily.
Higher levels occur in the proximal convoluted tubule of strain SHR than strain Wistar Kyoto.
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.
It is uncertain whether Met-1 or Met-9 is the initiator.
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding.
Widely expressed with highest levels in kidney.
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 (By similarity).
Dorsal root ganglia neurons (at protein level). Expressed in the heart, brain, spleen, kidney, lung and liver.
Synthesizes the galactose-alpha(1,3)-galactose group by catalyzing the transfer of a galactose residue, with an alpha-1,3 linkage, on terminal lactosaminide (Gal-beta-1,4-GlcNAc-R) disaccharide borne by a glycoprotein or a glycolipid. Preferentially glycosylates proteins, can synthesize galactose-alpha(1,3)-galactose on glycoproteins but cannot synthesize the glycosphingolipid isoglobotrihexosylceramide or isogloboside 3 (iGb3).
Disulfide-linked heterodimer with the amino acid transport protein SLC3A1. Interacts with CAV1.
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 proximal tubule.
Outer medulla of kidney (at protein level). Kidney and small intestine. In the kidney localized to the apical membrane of the proximal tubules.
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.
CLPS stimulates triacylglycerol lipase activity. Triacylglycerol lipase activity is not inhibited by increasing bile salt concentration.
Expressed in pancreatic acinar cells (at protein level).
Lipase that primarily hydrolyzes triglycerides and galactosylglycerides (PubMed:8656075, PubMed:9822688). In neonates, may play a major role in pancreatic digestion of dietary fats such as milk fat globules enriched in long-chain triglycerides (By similarity). Hydrolyzes short-, medium- and long-chain fatty acyls in triglycerides without apparent positional specificity (PubMed:8656075). Can completely deacylate triacylglycerols (By similarity). When the liver matures and bile salt synthesis increases, likely functions mainly as a galactolipase and monoacylglycerol lipase (By similarity). Hydrolyzes monogalactosyldiglycerols (MGDG) and digalactosyldiacylglycerols (DGDG) present in a plant-based diet, releasing long-chain polyunsaturated fatty acids (By similarity). Hydrolyzes medium- and long-chain fatty acyls in galactolipids (PubMed:9822688). May act together with LIPF to hydrolyze partially digested triglycerides (By similarity). Hydrolyzes long-chain monoglycerides with high efficiency. In cytotoxic T cells, contributes to perforin-dependent cell lysis, but is unlikely to mediate direct cytotoxicity (By similarity). Also has low phospholipase activity (PubMed:8656075, PubMed:9822688). In neurons, required for the localization of the phospholipid 1-oleoyl-2-palmitoyl-PC (OPPC) to neurite tips through acyl chain remodeling of membrane phospholipids (PubMed:32963038). The resulting OPPC-rich lipid membrane domain recruits the t-SNARE protein STX4 by selectively interacting with the STX4 transmembrane domain and this promotes surface expression of the dopamine transporter SLC6A3/DAT at neurite tips by facilitating fusion of SLC6A3-containing transport vesicles with the plasma membrane (PubMed:32963038).
Belongs to the TGF-beta family. GDNF subfamily.
Acetylated on Lys-6. 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 is deacetylated by SIRT1 (By similarity).
Belongs to the DNA repair enzymes AP/ExoA family.
Cleaved at Lys-30 by granzyme A to create the mitochondrial form; leading in reduction of binding to DNA, AP endodeoxyribonuclease 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 (By similarity).
Cys-64 and Cys-92 are nitrosylated in response to nitric oxide (NO) and lead to the exposure of the nuclear export signal (NES).
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. 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 (By similarity).
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, 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-232 by CDK5 in response to MPP(+)/MPTP (1-methyl-4-phenylpyridinium) reduces AP-endodeoxyribonuclease activity resulting in accumulation of DNA damage and contributing to neuronal death (By similarity).
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 (By similarity).
The specific activity of the cleaved mitochondrial endodeoxyribonuclease appeared to be about 3-fold higher than of the full-length form. Extract of mitochondria, but not of nuclei or cytosol, cleaves recombinant APEX1 to generate a mitochondrial APEX1-sized product (By similarity).
Ubiquitinated by MDM2; leading to translocation to the cytoplasm and proteasomal degradation.
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. The C-terminal carboxyl transferase (CT) domain catalyzes the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA to produce malonyl-CoA.
Cytosolic enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis. 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.
Inhibited by phosphorylation (By similarity). Citrate promotes oligomerization of the protein into filaments that correspond to the most active form of the carboxylase (By similarity).
Monomer, homodimer, and homotetramer. Can form filamentous polymers. Interacts in its inactive phosphorylated form with the BRCT domains of BRCA1 which prevents ACACA dephosphorylation and inhibits lipid synthesis. Interacts with MID1IP1; interaction with MID1IP1 promotes oligomerization and increases its activity.
Phosphorylation at Ser-79 by AMPK inactivates enzyme activity. Phosphorylated in vitro at Ser-1200 and Ser-1215 by AMPK; the relevance of phosphorylation of these sites in vivo is however unclear.
Phosphorylation on Ser-1262 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.
May be a centrosome-associated protein. Interacts with MYOC; affects its secretion and its aggregation (By similarity).
Phosphorylated. Phosphorylation by GRK5 appears to occur on residues distinct from the residue phosphorylated by other kinases (By similarity).
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. May also function in modulating the keratin network in skin. Activates the MAPK and Elk-1 signal transduction pathway (By similarity).
Specifically expressed in the peripheral nervous system. High expression in motoneurons of the brainstem. Also found in neurons of many other brain regions including the cerebellar cortex, thalmus, hypothalamus and CA1, CA2, CA3 and CA4 regions of the hippocampus.
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.
Interacts (via N-terminal domain) with MARCHF6. Interacts with SMIM22; this interaction modulates lipid droplet formation.
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. 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. 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.
Ubiquitinated by MARCHF6 in response to high cholesterol levels in intracellular membranes, leading to proteasomal degradation.
Proteolytically removes the C-terminal three residues of farnesylated proteins.
Both mature cathepsin L1 and procathepsin L are found in the upper epidermis. The lower epidermis predominantly contains procathepsin L. In seminiferous tubules expression is greater at stages VI-VII than at stages IX-XII.
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 (By similarity).
Expression in Sertoli cells is repressed by germ cells.
Inhibited by the propeptide produced by autocleavage (By similarity). 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. Inhibited by amantadine (By similarity).
Thiol protease important for the overall degradation of proteins in lysosomes (By similarity). 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. 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 (By similarity). 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 (PubMed:7777858).
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. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. OSGEP likely plays a direct catalytic role in this reaction, but requires other protein(s) of the complex to fulfill this activity.
Down-regulated by chronic stress in dentate gyrus granule neurons and CA3 pyramidal neurons.
Expressed in hippocampus (at protein level). Isoform 1 is the predominant isoform expressed in brain, specifically in hippocampus. Isoform 2 is expressed at low levels in brain and kidney.
Interacts with OPRM1 (PubMed:17548356). Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction leads to palmitoylation of GPM6A (By similarity).
Involved in neuronal differentiation, including differentiation and migration of neuronal stem cells (By similarity). Plays a role in neuronal plasticity and is involved in neurite and filopodia outgrowth, filopodia motility and probably synapse formation. Gpm6a-induced filopodia formation involves mitogen-activated protein kinase (MAPK) and Src signaling pathways. May be involved in neuronal NGF-dependent Ca(2+) influx. May be involved in regulation of endocytosis and intracellular trafficking of G-protein-coupled receptors (GPCRs); enhances internalization and recycling of mu-type opioid receptor.
Up-regulated in the medial prefrontal cortex.
Calcium-binding protein (PubMed:19271754). Essential for maintaining the structural integrity of the sperm flagella (By similarity).
Expressed in seminiferous tubules of the testis in step 10 spermatids (stage X), subsequently increasing to reach maximal levels of step 18 elongated spermatids (stage VI) (at protein level). Strongly expressed in testis. Weakly expressed in olfactory epithelium. Expressed in spermatids of seminiferous tubules at steps 4-14 (stages IV to XIV of the seminiferous epithelium classification).
Essential for normal spermatogenesis and male fertility. 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.
In the inner ear, it is first detectable at embryonic day 11.5 (11.5 dpc), broadly in the dorsolateral region of the otocyst, which gives rise to the vestibular organ. At 12.5 dpc, it becomes restricted to the presumptive sensory region, mainly to the BMP4-positive presumptive cristae, and expression becomes reduced at later stages.
Preferentially expressed in the developing inner ear and the dorsal neural tube.
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 (By similarity).
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).
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.
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.
Belongs to the N-CoR nuclear receptor corepressors family.
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.
Involved in fertilization ability of sperm.
A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates. 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). 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. 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.
Specifically expressed in thymus and brain. In brain, expressed in cortex, cerebellum, olfactory bulbs, pons and medulla and the limbic structures (at protein level).
Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate and inositol 3,4-bisphosphate (PubMed:9295334). Plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3,4-bisphosphate in membrane ruffles (By similarity). 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 (By similarity).
Strongly inhibited by inositol hexakisphosphate.
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 ATP5MPL.
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.
(Microbial infection) Interacts with C.botulinum neurotoxin type B (BoNT/B, botB). Has lower affinity for BoNT/B than Syt2; mutating its residues to match those in Syt2 increases its affinity (PubMed:17167421, PubMed:17167418).
(Microbial infection) Interacts with C.botulinum neurotoxin type G (BoNT/G, botG).
(Microbial infection) Receptor for C.botulinum neurotoxin type B (BoNT/B, botB); interaction is improved in the presence of gangliosides (PubMed:8144634, PubMed:14504267, PubMed:17167418). BoNT/B toxin binds to the membrane proximal vesicular domain of Syt1 (residues 32-51) (PubMed:14504267, PubMed:17167421).
(Microbial infection) Receptor for C.botulinum neurotoxin type G (BoNT/G, botG); unlike the case with BoNT/B, interaction is not improved in the presence of gangliosides (PubMed:15123599, PubMed:20219474). BoNT/G toxin binds to the vesicular domain of Syt1 (residues 32-53) (PubMed:15123599, PubMed:20219474).
Calcium sensor that participates in triggering neurotransmitter release at the synapse (PubMed:30107533). 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. 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.
Expressed in the brain (at protein level) (PubMed:17190793). Predominantly expressed in rostral, phylogenetically younger brain regions, and in some endocrine tissues.
Homotetramer (Probable). Interacts with SCAMP5 (By similarity). Interacts with STON2 (By similarity). Forms a complex with SV2B, syntaxin 1 and SNAP25 (By similarity). Interacts with SV2A, SV2B and SV2C (PubMed:8910372, PubMed:15866046). Interacts with RIMS1 (PubMed:11438518). Interacts with PRRT2 (By similarity). Interacts with DNAJC5 in a phosphorylation-dependent manner (PubMed:11931641). Interacts (via N-terminus) with RAB3A (PubMed:28057568). Interacts with SYT12 (PubMed:17190793). 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.
Belongs to the PpiC/parvulin rotamase family. PIN4 subfamily.
Essential for the assembly of the distal half of centrioles, required for centriole elongation.
Hyperphosphorylated during recruitment to procentrioles in G2/M phase.
May be part of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane. Involved in ammonia transport across the erythrocyte membrane. Seems to act in monovalent cation transport.
Belongs to the RFamide neuropeptide family.
Expressed in the brain with highest expression levels in the hypothalamus and optic nerve. Also expressed in the trachea and mammary gland.
Ligand for the G-protein coupled receptor QRFPR/GPR103.
Stimulates feeding and grooming behavior, metabolic rate and locomotor activity and increases blood pressure. May have orexigenic activity. May promote aldosterone secretion by the adrenal gland.
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 (By similarity). 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 (By similarity). Interacts with MDM2 and 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 (By similarity). Essential for catalysing the entry and efficient transfer of electrons within complex I (By similarity). 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 (By similarity).
Highly expressed in cerebral microvessels and choroid plexus (at protein level) (PubMed:17667996, PubMed:18687783, PubMed:12923172). Brain-specific (PubMed:12923172, PubMed:17667996). Not detected in glial cells, kidney, heart, lung, skeletal muscle, spleen, liver, nor testis (PubMed:12923172, PubMed:17667996).
Mediates the Na(+)-independent high affinity transport of thyroid hormones at the plasma membrane of brain capillary endothelial cells (PubMed:12923172, PubMed:17667996, PubMed:19819953). The transport activity of substrates L-thyroxine (T4) and 3,3',5'-triiodo-L-thyronine (reverse T3, rT3) is much greater than that of 3,3',5-triiodo-L-thyronine (T3) (PubMed:12923172, PubMed:17667996, PubMed:19819953). The prehormone, T4, is the major form in the circulating blood and is converted to the active form, T3, by the iodothyronine-deiodinase in peripheral organs (PubMed:12923172). T3 plays an essential role in brain development via binding to specific nuclear receptors (thyroid hormone receptor) (PubMed:12923172). Also transports organic anions such as the conjugated steroid 17-beta-glucuronosyl estradiol (17beta-estradiol 17-O-(beta-D-glucuronate)) (PubMed:12923172, PubMed:17667996, PubMed:19819953). Transports T4 and estrone-3-sulfate in a pH-insensitive manner (By similarity). May serve as a drug efflux system at the blood brain barrier (PubMed:12923172, PubMed:17667996).
Interacts with the chaperone complex consisting of HSC70 and SGTA.
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 (By similarity).
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 (By similarity).
Homooctamer; active form. Homohexamer; low activity form (By similarity).
Component of a complex composed of PALS1, CRB1 and EPB41L5 (By similarity). Within the complex, interacts (via FERM domain) with PALS1 (via HOOK domain) and with CRB1 (via intracellular domain) (By similarity). Interacts with CRB2 (via intracellular domain) (By similarity). Interacts with CRB3 (via intracellular domain) (By similarity).
Expressed in the outer limiting membrane, retinal pigment epithelium, outer nuclear layer and outer plexiform layer of the retina (at protein level).
Plays a role in the formation and organization of tight junctions during the establishment of polarity in epithelial cells.
Belongs to the complex I NDUFA11 subunit family.
Functions in post-Golgi recycling pathways. Acts as a recycling carrier to the cell surface.
Interacts with SLC9A7 (By similarity). Interacts with SYNRG and ITSN1.
Belongs to the AAA ATPase family. Katanin p60 subunit A1 subfamily. A-like 1 sub-subfamily.
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 (By similarity).
Associates with myosin-Vb (MYO5B) and alpha-actinin-4 (ACTN4) (PubMed:10391919, PubMed:10673389). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (By similarity). Interacts with ZFYVE28/LST2 (By similarity). Interacts with KIF21B (By similarity).
Highly expressed in the brain, moderate levels in the lung, very low levels in the liver, kidney and heart. In the brain, expression was highest in the cerebellum.
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. Positively regulates motility of microtubule-dependent motor protein KIF21B.
The interaction with MYO5B is dependent upon its NHL repeats, which form a beta-propeller (NHL) domain containing six blades.
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. Protein cleavage by OMA1 can take place at different positions, and apparently does not require a specific sequence motif.
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. 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. Essential for the induction of death receptor-mediated apoptosis through the regulation of caspase activation.
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. 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.
The TPR repeats bind to and activate EIF2AK1/HRI.
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:3202973, PubMed:2110056). In the pancreas, protects against trypsin-catalyzed premature activation of zymogens (By similarity).
Belongs to the DEAD box helicase family. DDX41 subfamily.
Interacts with RTN1; regulates the ceramide glucosyltransferase activity of UGCG.
Participates in the initial step of the glucosylceramide-based glycosphingolipid/GSL synthetic pathway at the cytosolic surface of the Golgi. Catalyzes the transfer of glucose from UDP-glucose to ceramide to produce glucosylceramide/GlcCer (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) (PubMed:10393098, PubMed:1532799). Glucosylceramide is the core component of glycosphingolipids/GSLs, amphipathic molecules consisting of a ceramide lipid moiety embedded in the outer leaflet of the membrane, linked to one of hundreds of different externally oriented oligosaccharide structures (By similarity). Glycosphingolipids are essential components of membrane microdomains that mediate membrane trafficking and signal transduction (By similarity). They are implicated in many fundamental cellular processes, including growth, differentiation, migration, morphogenesis, cell-to-cell and cell-to-matrix interactions (By similarity). They are required for instance in the proper development and functioning of the nervous system. As an example of their role in signal transduction, they regulate the leptin receptor/LEPR in the leptin-mediated signaling pathway (By similarity). They also play an important role in the establishment of the skin barrier regulating keratinocyte differentiation and the proper assembly of the cornified envelope (By similarity). The biosynthesis of GSLs is also required for the proper intestinal endocytic uptake of nutritional lipids (By similarity). Catalyzes the synthesis of xylosylceramide/XylCer (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) using UDP-Xyl as xylose donor (By similarity).
The D1, D2, D3, (Q/R)XXRW motif is a critical part of the GCS active site, involved in catalysis and UDP-sugar binding.
Hydrolyzes lysoglycerophospholipids to produce lysophosphatidic acid (LPA) and the corresponding amines. Shows a preference for 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF), lysophosphatidylethanolamine (lyso-PE) and lysophosphatidylcholine (lyso-PC). May be involved in bioactive N-acylethanolamine biosynthesis from both N-acyl-lysoplasmenylethanolamin (N-acyl-lysoPlsEt) and N-acyl-lysophosphatidylethanolamin (N-acyl-lysoPE). In addition, hydrolyzes glycerophospho-N-acylethanolamine to N-acylethanolamine. Does not display glycerophosphodiester phosphodiesterase activity, since it cannot hydrolyze either glycerophosphoinositol or glycerophosphocholine.
Lysophospholipase D activity is increased by magnesium and manganese and inhibited by calcium in a concentration dependent manner (By similarity). Loss of lysophospholipase D activity by addition of EDTA (By similarity).
Associates with microtubules via the Mn regions.
May play a role in the regulation of cilium length. Stabilizes microtubules at low temperature.
The Mn regions are involved in microtubule-binding and stabilization at low temperature. They are required and sufficient for cilium targeting.
The N-terminal region (residues 1-29) might play a role in centriole retention.
Component of the large ribosomal subunit. Interacts with DHX33.
Constitutively monomethylated at His-245 by METTL18. 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. It is not required for incorporation of RPL3 into ribosomes.
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. The two ATP-binding domains interact with each other, forming a head-to-tail dimer. Normal ATPase activity requires interaction between the two domains. The first ABC transporter nucleotide-binding domain has no ATPase activity by itself.
Detected in epithelial cells in nasopharynx, submandibular gland, pancreas and ileum (at protein level) (PubMed:12519745). Expressed in the epididymis (PubMed:30659401). In the caput section of the epididymis, expressed uniformly on both the luminal and basolateral sides of the ducts and on sperm in the caput lumen (at protein level) (PubMed:30659401). In the cauda, detected along the luminal border but not continuously and is also expressed on the basolateral surface (PubMed:30659401). Within the caudal lumen, detected on sperm (PubMed:30659401).
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 (By similarity). 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. Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7. Can inhibit the chloride channel activity of ANO1 (By similarity). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (By similarity).
Monomer; does not require oligomerization for channel activity. May form oligomers in the membrane (By similarity). Interacts with SLC4A7 through SLC9A3R1 (By similarity). Interacts with SHANK2 (PubMed:14679199). Interacts with SLC9A3R1 and MYO6. Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity (PubMed:11707463). Interacts with SLC4A7 through SLC9A3R1. Found in a complex with MYO5B and RAB11A. Interacts with ANO1. Interacts with SLC26A8 (By similarity). Interacts with AHCYL1; the interaction increases CFTR activity (By similarity). Interacts with CSE1L (By similarity). The core-glycosylated form interacts with GORASP2 (via PDZ GRASP-type 1 domain) in respone to ER stress (By similarity). Interacts with MARCHF2; the interaction leads to CFTR ubiqtuitination and degradation (By similarity).
Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel. Dephosphorylation decreases the ATPase activity (in vitro). Phosphorylation at PKA sites activates the channel. Phosphorylation at PKC sites enhances the response to phosphorylation by PKA. Phosphorylated by AMPK; this inhibits channel activity.
The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, SLC9A3R1/EBP50 complex.
The disordered R region mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation.
Ubiquitinated, leading to its degradation in the lysosome. Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane. Ubiquitinated by RNF185 during ER stress. Ubiquitinated by MARCHF2 (By similarity).
Characteristic constituent of osteoclasts and some mononuclear preosteoclasts. Preferentially expressed in skeletal tissues.
Exists either as monomer or, after proteolytic processing, as a dimer of two chains linked by disulfide bond(s).
May play a role in the process of bone resorption. The osteoclastic trap acts on nucleotide tri- and diphosphates with higher affinity, compared with other substrates.
Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner (By similarity). Recruits mitochondrial HSP70 to drive protein translocation into the matrix using ATP as an energy source (By similarity).
Probable component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19 (By similarity). The complex interacts with the TIMM23 component of the TIM23 complex. Interacts with SLC25A4/ANT1 and SLC25A5/ANT2; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
Belongs to the universal ribosomal protein uS4 family.
DNA-binding protein that may be implicated in chromatin remodeling and/or transcriptional regulation during spermiogenesis, the process of spermatid maturation into spermatozoa.
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. Binds RNA containing 5'-terminal GpppC.
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. 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. Interacts with elongating form of polymerase II and RNGTT. Interacts with RAMAC, this interaction significantly enhances RNA-binding and cap methyltransferase activity.
Methyltransferase activity is activated by RAMAC.
Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.
Binds 2 Zn(2+) ions per subunit. Required for NAALADase activity.
Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides (By similarity). 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.
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 and 2-(phosphonomethyl)glutaric acid (PMG).
Widely expressed throughout brain regions with highest levels in the hippocampus, dentate gyrus, priform cortex, choroid plexus of ventricles, pineal gland, anterior lobe of the pituitary gland and supraoptic nucleus. High levels also found in the cerebral cortex, substantia nigra, pontine nucleus and the granule cell layer of cerebellum. Highly expressed in astrocytes and non-myelinating Schwann cells. Also expressed in kidney, localizing to the proximal brush border of the renal tube.
Interacts with GTP bound ARL2 and ARL3; the complex ARL2-ARL2BP as well as ARL2BP alone, binds to SLC25A4/ANT1. Interaction with ARL2 may be required for cilia basal body localization (By similarity). Interacts with STAT3; interaction is enhanced with ARL2. Found in a complex with ARL2BP, ARL2 and SLC25A6. Found in a complex with ARL2, ARL2BP and SLC25A4. Interacts with STAT2, STAT3 and STAT4.
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 (By similarity).
Ubiquitous with higher expression in brain, especially in hippocampus and cortex. Also expressed in lung, cerebellum, liver, kidney, spleen and heart (at protein level).
Binds gabapentin, an antiepileptic drug.
Dimer formed of alpha-2-2 and delta-2 chains; disulfide-linked. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and delta (CACNA2D) subunits in a 1:1:1:1 ratio (By similarity).
In heart, it is highly expressed in atrium and at lower level in ventricle.
May be proteolytically processed into subunits alpha-2-2 and delta-2 that are disulfide-linked. It is however unclear whether such cleavage really takes place in vivo and has a functional role (By similarity).
The MIDAS-like motif in the VWFA domain binds divalent metal cations and is required to promote trafficking of the alpha-1 (CACNA1) subunit to the plasma membrane by an integrin-like switch.
The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosis (By similarity).
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 (By similarity). Interacts in a calcium-dependent manner with calmodulin (By similarity). Interacts with CDK5R1 and probably 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. Detected in brain, lung, spleen, pancreas, kidney, liver, heart, mammary gland and skeletal muscle.
Belongs to the cytochrome c oxidase VIIa family.
Involved in protein trafficking. May serve as a receptor for ARFRP1.
Aorta and heart. Also detected in lung and kidney.
Interacts with RNF10 (By similarity). Interacts with TCF15 (By similarity).
Mesodermal transcription factor that plays a key role in somitogenesis and somitogenesis and limb muscle differentiation. 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 (PubMed:8098844). Also acts as a negative regulator of angiogenesis. Activates expression of CDKN1A and CDKN2A in endothelial cells, acting as a regulator of vascular cell proliferation. While it activates CDKN1A in a DNA-dependent manner, it activates CDKN2A in a DNA-independent manner (By similarity). Together with TCF15, regulates transcription in heart endothelial cells to regulate fatty acid transport across heart endothelial cells (By similarity).
Rapidly and transiently down-regulated during the transition from G0 to G1 induced by mitogen stimulation.
The polyhistidine repeat may act as a targeting signal to nuclear speckles.
Belongs to the repulsive guidance molecule (RGM) family.
High expression in brain, particularly in the cerebellum, hippocampus, thalamus, frontal lobes, sensory cortex. Found in the myelin sheaths of peripheral nerves, chromaffin cells within the adrenal medulla, and in extra-adrenal chromaffin cells associated with celiac ganglia.
Interacts with HOMER1. Interacts with AMPA receptor complexes. Interacts with SH3GL2 (endophilin-A1). Interacts (via C-terminus) with NR1D1.
Stimulates GTP hydrolysis of members of the Rho family. Its action on RHOA activity and signaling is implicated in growth and stabilization of dendritic spines, and therefore in synaptic function, in hippocampal neurons. Critical for the stabilization of AMPA receptors at postsynaptic sites. Critical for the regulation of synaptic vesicle endocytosis at pre-synaptic terminals. Required for the localization of NR1D1 to dendrites, can suppress its repressor activity and protect it from proteasomal degradation.
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' (By similarity).
Belongs to the NAD(P)-dependent epimerase/dehydratase family. Fucose synthase subfamily.
Catalyzes the two-step NADP-dependent conversion of GDP-4-dehydro-6-deoxy-D-mannose to GDP-fucose, involving an epimerase and a reductase reaction.
In the nucleus, phosphorylated by PKC/PRKCD.
Monomer. Homodimer. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGFBP1. Part of a Cu(2+)-dependent multiprotein aggregate containing FGF1, S100A13 and SYT1. Interacts with SYT1. Interacts with S100A13 (By similarity). Interacts with LRRC59 (By similarity). Interacts with CSNKA, CSNKB and FIBP (By similarity). While binding with LRRC59, CSNKA and FIBP seem mutually exclusive, CSNKB and FIBP may cooperatively interact with FGF1. Forms a ternary complex with FGFR1 and ITGAV:ITGB3 and induces the recruitment of PTPN11 to the complex (By similarity).
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrin ITGAV:ITGB3. Its binding to integrin, subsequent ternary complex formation with integrin and FGFR1, and the recruitment of PTPN11 to the complex are essential for FGF1 signaling. Induces the phosphorylation and activation of FGFR1, FRS2, MAPK3/ERK1, MAPK1/ERK2 and AKT1. Can induce angiogenesis.
Plays an important role in the regulation of cell survival, cell division, angiogenesis, cell differentiation and cell migration. Functions as potent mitogen in vitro. Acts as a ligand for FGFR1 and integrins. Binds to FGFR1 in the presence of heparin leading to FGFR1 dimerization and activation via sequential autophosphorylation on tyrosine residues which act as docking sites for interacting proteins, leading to the activation of several signaling cascades. Binds to integrins. Its binding to integrins and subsequent ternary complex formation with integrins and FGFR1 are essential for FGF1 signaling.
Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the third alpha-1,2-mannose to Man2-GlcN-acyl-PI during GPI precursor assembly.
Detected in whole wall and separated mucosa in the distal ileum and colon. Expressed by enteroendocrine cells expressing peptide YY (PYY) (at protein level).
G protein-coupled receptor that is activated by a major product of dietary fiber digestion, the short chain fatty acids (SCFAs), and that plays a role in the regulation of whole-body energy homeostasis and in intestinal immunity. In omnivorous mammals, the short chain fatty acids acetate, propionate and butyrate are produced primarily by the gut microbiome that metabolizes dietary fibers. SCFAs serve as a source of energy but also act as signaling molecules. That G protein-coupled receptor is probably coupled to the pertussis toxin-sensitive, G(i/o)-alpha family of G proteins but also to the Gq family (PubMed:23589301). Its activation results in the formation of inositol 1,4,5-trisphosphate, the mobilization of intracellular calcium, the phosphorylation of the MAPK3/ERK1 and MAPK1/ERK2 kinases and the inhibition of intracellular cAMP accumulation. May play a role in glucose homeostasis by regulating the secretion of GLP-1, in response to short-chain fatty acids accumulating in the intestine. May also regulate the production of LEP/Leptin, a hormone acting on the central nervous system to inhibit food intake. Finally, may also regulate whole-body energy homeostasis through adipogenesis regulating both differentiation and lipid storage of adipocytes. In parallel to its role in energy homeostasis, may also mediate the activation of the inflammatory and immune responses by SCFA in the intestine, regulating the rapid production of chemokines and cytokines. May also play a role in the resolution of the inflammatory response and control chemotaxis in neutrophils. In addition to SCFAs, may also be activated by the extracellular lectin FCN1 in a process leading to activation of monocytes and inducing the secretion of interleukin-8/IL-8 in response to the presence of microbes.
Interacts with FCN1 (via Fibrinogen C-terminal domain).
Acetylated. Positively correlates with ability to bind RNA (By similarity).
Arginine methylation is required for nuclear localization, Inhibits interaction with Src-like SH3 domains, but not interaction with WW domains of WBP4/FBP21 and FNBP4/FBP30.
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. May not be involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species. 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. In cooperation with HNRNPA1 modulates alternative splicing of BCL2L1 by promoting splicing toward isoform Bcl-X(S), and of SMN1. 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. Interacts with KHDRBS3/SLIM-2 (By similarity). Interacts with KHDRBS2/SLIM-1; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity (PubMed:15345239). Interacts with PIK3R1, PLCG1 (PubMed:10437794, PubMed:10748127). Interacts with RASA1, GRB2, SRC, RBMY1A1, CBP, PRMT1, APC, HNRNPA1. Interacts with PTK6 (via SH3 and SH2 domains). Forms a complex with ILF2, ILF3, YLPM1, RBMX, NCOA5 and PPP1CA (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) (PubMed:10748127). Interacts with the non-receptor tyrosine kinase SRMS; the interaction leads to phosphorylation of KHDRBS1 (By similarity). Interacts with ZBTB7A; negatively regulates KHDRBS1 splicing activity toward BCL2L1 (By similarity).
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.
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. Phosphorylation by PTK6 negatively regulates its RNA binding ability. Phosphorylation by PTK6 at Tyr-440 dictates the nuclear localization of KHDRBS1.
Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate.
Isoform C is most abundant in liver, kidney, gut, spleen and pancreas. Low levels of isoform A found in adrenal, spleen and brain.
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. In association with CCAR1 enhances GATA1- and MED1-mediated transcriptional activation from the gamma-globin promoter during erythroid differentiation of K562 erythroleukemia cells (By similarity).
Part of a calphoglin complex consisting of CALCOCO1, PPA1 and PGM (By similarity). 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 (By similarity).
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).
Up-regulated in neuronal cells upon ischemia.
Binds DNA as a monomer or a homodimer (By similarity). Interacts with NCOA5 coactivator, leading to a strong increase of transcription of target genes (By similarity). Interacts (via N-terminus) with KAT5 (By similarity). Interacts (via C-terminus) with HDAC1 (By similarity). Interacts with ZNHIT1 (By similarity). Interacts with SIAH2 (By similarity).
Deacetylated by HDAC1 (By similarity). Acetylation and deacetylation regulate its transcriptional regulatory activity (By similarity).
The heme-bound form can bind gaseous signaling molecules such as CO and nitric oxide (NO) and NO can reverse its transcriptional repressor activity.
Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle (By similarity). Plays a role in the regulation of circadian sleep/wake cycle; essential for maintaining wakefulness during the dark phase or active period (By similarity). Key regulator of skeletal muscle mitochondrial function; negatively regulates the skeletal muscle expression of core clock genes and genes involved in mitochondrial biogenesis, fatty acid beta-oxidation and lipid metabolism (By similarity). May play a role in the circadian control of neutrophilic inflammation in the lung (By similarity).
Ubiquitinated by SIAH2; leading to its proteasomal degradation.
Under more reducing intracellular redox conditions, Cys-383 is in its heme-bound state, which is optimal for recruitment of the NCOR1/HDAC3 corepressor complex and repression of target genes (By similarity). When subjected to oxidative stress conditions, Cys-383 undergoes oxidation to form a disulfide bridge with Cys-373, also triggering a ligand switch that results in release of bound heme and derepression of target genes (By similarity).
Belongs to the peptidase M24 family. SPT16 subfamily.
Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II.
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. 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. The isozyme B does not hydrolyze each of these substrates, however hydrolyzes efficiently neutral oligosaccharide. Only the isozyme A is responsible for the degradation of GM2 gangliosides in the presence of GM2A.
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. The composition of the dimer (isozyme A versus isozyme S) has a significant effect on the substrate specificity of the alpha subunit active site.
Histone binding-protein that regulates chromatin dynamics and minichromosome maintenance (MCM) loading at replication origins, possibly by promoting chromatin openness.
Interacts with METTL18. Interacts with CDT1; origin binding of GRWD1 is dependent on CDT1. Interacts with CDC6; origin binding of GRWD1 is dependent on CDC6. Binds to histone H2A-H2B and H3-H4 complexes.
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 (By similarity).
Belongs to the bacterial ribosomal protein bL34 family.
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). L-3-hydroxybutyrate (L-3-OHB) is also a substrate for HOT when using 2-KG as hydrogen acceptor, resulting in the formation of D-2-HG (By similarity).
Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports catecholamines and indolamines with higher affinity for serotonin (PubMed:1505023, PubMed:8125935). 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 (By similarity).
Strongly inhibited by reserpine, ketanserin and methamphetamine. Also inhibited weakly by tetrabenazine.
Expressed in the hippocampal CA1 region (at protein level).
Receptor for gastrin-releasing peptide (GRP) (PubMed:8391296). 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 (PubMed:26855425).
Belongs to the protein kinase superfamily. Tyr protein kinase family. Fes/fps subfamily.
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 RIMS1 and RIMS2 (PubMed:11797009). Interacts with GIT1 and GIT2 (PubMed:12629171). Interacts with GRIP1 (PubMed:11931740). Interacts with KIF1A (PubMed:12522103).
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).
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.
Component of a multiprotein complex with RPA2 and SPATA22. Interacts with the complex BRME1:HSF2BP:BRCA2.
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.
Although the active site residues are conserved, lacks the conserved His residue which is normally found 9 residues before the catalytic His.
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).
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.
Interacts with RASA1 (By similarity). Interacts with the general transcription factor GTF2I, the interaction sequesters GTF2I in the cytoplasm (By similarity).
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 (By similarity). 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 (By similarity). 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 (PubMed:20439493). 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). Binds several acidic phospholipids which inhibits the Rho GAP activity to promote the Rac GAP activity (PubMed:9852136, PubMed:20439493). This binding is inhibited by phosphorylation by PRKCA (By similarity). 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 (PubMed:9852136, PubMed:20439493). 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 (By similarity).
The pG1 pseudoGTPase domain does not bind GTP.
Belongs to the zinc-containing alcohol dehydrogenase family. Class-I subfamily.
Dimer of identical or non-identical chains of three types (A, B, C), which are coded by 3 separate genes at different loci.
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.
Belongs to the protein kinase superfamily. Tyr protein kinase family. CSK subfamily.
Could play a significant role in the signal transduction of hematopoietic cells. May regulate tyrosine kinase activity of SRC-family members in brain.
Belongs to the grh/CP2 family. CP2 subfamily.
Undergoes proteolytic cleavage by furin protease to yield a 60 kDa soluble form that forms a homotrimer and exhibits a low affinity interaction with heparin.
Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer (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 (PubMed:17724123). Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation (PubMed:17724123). Interacts with SQSTM1; bridges NTRK1 to NGFR. 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. Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation. Interacts (phosphorylated) with SH2B1 and SH2B2. Interacts with GRB2. Interacts with PIK3R1. Interacts with FRS2. Interacts with SORT1; may regulate NTRK1 anterograde axonal transport. Interacts with SH2D1A; regulates NTRK1. Interacts with NRADD (PubMed:18624909). Interacts with RAB7A (PubMed:16306406). Interacts with PTPRS (PubMed:17967490). Interacts with USP36; USP36 does not deubiquitinate NTRK1 (By similarity). Interacts with GGA3 (PubMed:26446845).
Isoform Trka-II is primarily expressed in neuronal cells; isoform Trka-I is found in non-neuronal tissues.
Ligand-mediated autophosphorylation. Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-499 mediates interaction and phosphorylation of SHC1.
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:1312719, PubMed:1850821). 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. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. 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.
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 (By similarity). SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. Regulated by NGFR (By similarity).
The transmembrane domain mediates interaction with KIDINS220.
Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination by NEDD4L leads to degradation (By similarity). Ubiquitination regulates the internalization of the receptor (By similarity).
Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. May also promote the heterodimerization with the EGF receptor.
ERBB receptor binding is elicited entirely by the EGF-like domain.
Expressed in most parts of the brain, especially the olfactory bulb and cerebellum where it localizes in granule and Purkinje cells. In the hippocampus, found in the granule cells of the dentate gyrus. In the basal forebrain, found in the cholinergic cells. In the hindbrain, weakly detectable in the motor trigeminal nucleus. Not detected in the hypothalamus. Also found in the liver and in the thymus. Not detected in heart, adrenal gland, or testis.
Expressed in the brain of 11.5 dpc embryos where it is found in the telencephalon, but not in the hindbrain. Not found in the heart. In the adult, found in brain and thymus.
Extensive glycosylation precedes the proteolytic cleavage.
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).
May be involved in ciliary biogenesis or function.
Expressed in epididymal sperm but not in testicular sperm (at protein level).
Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells.
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. 'Arg-314' in the bZIP domain of CREB1 is essential for this interaction. Interaction, via its C-terminal, with TAF4, enhances recruitment of TAF4 to CREB1. Interacts with SIK2. Interacts with 14-3-3 proteins, YWHAB and YWHAG. Interacts (probably when phosphorylated at Ser-171) with YWHAE. Interacts with calmodulin-dependent catalytic subunit PPP3CA/calcineurin A (By similarity). Interaction with COP1 mediates nuclear export and degradation of CRTC2 (By similarity).
Phosphorylation/dephosphorylation states of Ser-171 are required for regulating transduction of CREB activity. CRTCs/TORCs are inactive when phosphorylated, and active when dephosphorylated at this site. 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 (By similarity). 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. Phosphorylation at Ser-274 by MARK2 is induced under low glucose conditions and dephosphorylated in response to glucose influx. Phosphorylation at Ser-274 promotes interaction with 14-3-3 proteins and translocation to the cytoplasm (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 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 (By similarity).
Expressed in a variety of tissues. Strongly expressed in ovary and to a lesser extent in kidney.
Has an anti-hypocalcemic action on calcium and phosphate homeostasis.
Belongs to the potassium channel family. D (Shal) (TC 1.A.1.2) subfamily. Kv4.3/KCND3 sub-subfamily.
Highly expressed in brain, in particular in the retrosplenial cortex, medial habenula, anterior thalamus, hippocampus, cerebellum and lateral geniculate and superior colliculus. Highly expressed in heart atrium (at protein level) and throughout the ventricle wall, in lung and vas deferens.
Homotetramer or heterotetramer with KCND1 and/or KCND2. Interacts with DLG1. Associates with the regulatory subunits KCNIP1, KCNIP2, KCNIP3 and KCNIP4. Interacts with KCNE1, KCNE2, SCN1B and KCNAB1 (By similarity).
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.
Catalyzes the transfer of L-fucose, from a guanosine diphosphate-beta-L-fucose, to the terminal galactose residue of glycoconjugates through an alpha(1,2) linkage leading to H antigen synthesis that is an intermediate substrate in the synthesis of ABO blood group antigens. H antigen is essential for maturation of the glomerular layer of the main olfactory bulb, in cell migration and early cell-cell contacts during tumor associated angiogenesis (By similarity). Preferentially fucosylates soluble lactose and to a lesser extent fucosylates glycolipids gangliosides GA1 and GM1a (By similarity).
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.
Belongs to the bZIP family. PAR subfamily.
Binds DNA as a homodimer or a heterodimer. Can form a heterodimer with TEF.
Expressed in the suprachiasmatic nuclei (SCN) and in most peripheral tissues, with a strong circadian rhythmicity.
This transcriptional activator recognizes and binds to the sequence 5'-RTTAYGTAAY-3' found in the promoter of genes such as albumin, CYP2A4 and CYP2A5. It is not essential for circadian rhythm generation, but modulates important clock output genes. May be a direct target for regulation by the circadian pacemaker component clock. May affect circadian period and sleep regulation (By similarity).
May play a role in regulated exocytosis (PubMed:10383386). 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 (PubMed:12928441, PubMed:15590695). May also play a role in GLUT4 storage and transport to the plasma membrane (PubMed:26071524).
Ubiquitously expressed with lower expression in brain (at protein level).
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. Positive regulator of PRKN translocation to damaged mitochondria.
Interacts with RNA polymerase II and HELZ. Interacts with SIN3A and HDAC1. Interacts (via MYND-type zinc finger) with EPB41L3. Interacts (via SET domain) with p53/TP53. Interacts with RB1 and HSP90AA1 (By similarity).
Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. Specifically trimethylates histone H3 'Lys-4' (H3K4me3) in vivo. The activity requires interaction with HSP90alpha. Shows even higher methyltransferase activity on p53/TP53. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates RB1 at 'Lys-860'.
May activate the NF-kappa-B signaling pathway.
Undergoes ER-associated degradation (ERAD).
Acetylation on Lys-395 activates transcriptional activity. Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation (By similarity). Hyperacetylation by p300 leads to enhanced cardiac myocyte growth and heart failure.
Binds DNA as a homo- or heterodimer (By similarity). Dimerizes with MEF2D. Interacts with HDAC7. Interacts with PIAS1; the interaction enhances sumoylation. Interacts with HDAC4, HDAC9 and SLC2A4RG. Interacts (via the N-terminal) with MAPK7; the interaction results in the phosphorylation and transcriptional activity of MEF2A (By similarity).
Constitutive phosphorylation on Ser-400 promotes Lys-395 sumoylation thus preventing acetylation at this site. Dephosphorylation on Ser-400 by PPP3CA upon neuron depolarization promotes a switch from sumoylation to acetylation on residue Lys-395 leading to inhibition of dendrite claw differentiation. Phosphorylation on Thr-304 and Thr-311 are the main sites involved in p38 MAPK signaling and activate transcription. Phosphorylated on these sites by MAPK14/p38alpha and MAPK11/p38beta, but not by MAPK13/p38delta nor by MAPK12/p38gamma. Phosphorylation on Ser-400 by CDK5 induced by neurotoxicity inhibits MEF2A transcriptional activation leading to apoptosis of cortical neurons. Phosphorylation on Thr-304, Thr-311 and Ser-347 can be induced by EGF (By similarity).
Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 3 and caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation (By similarity).
Sumoylation on Lys-395 is enhanced by PIAS1 and represses transcriptional activity. Phosphorylation on Ser-400 is required for sumoylation. Has no effect on nuclear location nor on DNA binding. Sumoylated with SUMO1 and, to a lesser extent with SUMO2 and SUMO3. PIASx facilitates sumoylation in postsynaptic dendrites in the cerebellar cortex and promotes their morphogenesis (By similarity).
Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific genes. Also involved in the activation of numerous growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. In cerebellar granule neurons, phosphorylated and sumoylated MEF2A represses transcription of NUR77 promoting synaptic differentiation. Associates with chromatin to the ZNF16 promoter (By similarity).
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.
Prosaposin: 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.
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 is a homodimer. Prosaposin exists as a roughly half-half mixture of monomers and disulfide-linked dimers. Monomeric prosaposin interacts (via C-terminus) with sortilin/SORT1, the interaction is required for targeting to lysosomes. Interacts with GRN; facilitates lysosomal delivery of progranulin from the extracellular space and the biosynthetic pathway (By similarity).
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-enzymatic proteins, they participate in the lysosomal degradation of sphingolipids, which takes place by the sequential action of specific hydrolases.
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.
Binds DNA as a monomer or a homodimer. Interacts (via the AF2 domain) with coactivator PPARGC1A (via the L3 motif); the interaction greatly enhances transcriptional activity of genes involved in energy metabolism. Interacts with PIAS4; the interaction enhances sumoylation (By similarity). Interacts with MAPK15; promotes re-localization of ESRRA to the cytoplasm through a XPO1-dependent mechanism then inhibits ESRRA transcriptional activity (By similarity).
Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle.
Phosphorylation on Ser-19 enhances sumoylation on Lys-14 increasing repression of transcriptional activity.
Reversibly acetylated. Acetylation by PCAF/KAT2 at Lys-129, Lys-138, Lys-160 and Lys-162 and PCAF/KAT2 decreases transcriptional activity probably by inhibiting DNA-binding activity; deacetylation involves SIRT1 and HDAC8 and increases DNA-binding (By similarity).
Sumoylated with SUMO2. Main site is Lys-14 which is enhanced by phosphorylation on Ser-19, cofactor activation, and by interaction with PIAS4. Sumoylation enhances repression of transcriptional activity, but has no effect on subcellular location nor on DNA binding (By similarity).
Appears to be the first example of a new class of functional RNAs also able to encode a protein. Rat SRAP1 may act as a protein rather than an RNA transcript.
Expressed in various prostate cancer cell lines.
Functional RNA which acts as a transcriptional coactivator that selectively enhances steroid receptor-mediated transactivation ligand-independently through a mechanism involving the modulating N-terminal domain (AF-1) of steroid receptors. Also mediates transcriptional coactivation of steroid receptors ligand-dependently through the steroid-binding domain (AF-2). Enhances cellular proliferation and differentiation and promotes apoptosis in vivo. May play a role in tumorigenesis.
SRA1 RNA exists in a ribonucleoprotein complex containing NCOA1. The RNA also forms a complex with PUS1 and RARG in the nucleus. Interacts with AR.
Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1. 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. Involved in the regulation of lymphangiogenesis.
Interacts with TEK/TIE2, competing for the same binding site as ANGPT1. Interacts with ITGA5.
The Fibrinogen C-terminal domain mediates interaction with the TEK/TIE2 receptor.
Transcriptional repressor which binds to the consensus sequence 5'-GGTGTG-3'. 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. May play a role in the cell cycle regulation (By similarity). 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.
Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation.
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:9092568). Able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans (By similarity). Transporter activity is pH-dependent and maximized in the acidic lysosomal environment (PubMed:9092568). 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. Required for TLR7, TLR8 and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs). 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 (By similarity). Required for isotype class switch recombination to IgG2c isotype in response to TLR9 stimulation. Required for mast cell secretory-granule homeostasis by limiting mast cell functions and inflammatory responses (By similarity).
Widely expressed in the gastrointestinal tract. Highly expressed in the brain and eye, and weakly in the lung and spleen. In brain highly expressed in the hippocampus, cerebellum and pontine nucleus, and weakly in other regions of the brain, including the cerebral cortex, brain stem, thalamus and hypothalamus.
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.
Potent pro-inflammatory cytokine. 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. Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells. Plays a role in angiogenesis by inducing VEGF production synergistically with TNF and IL6. 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.
Forms calcium-sensitive chloride channels. Permeable to bicarbonate.
Complex of five different subunits; alpha, beta, gamma, delta and epsilon.
Bifunctional enzyme that acts both as an endopeptidase and 2-oxoglutarate-dependent monooxygenase. 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. 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. 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. 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. 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. Negatively regulates cell cycle repressor CDKN1A/p21, which controls G1/S phase transition. Required for G2/M phase cell cycle progression. Regulates expression of CCNA1/cyclin-A1, leading to cancer cell proliferation. Also, plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition (By similarity). 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 (By similarity). Negatively regulates the protein stability and function of CRY1; required for AMPK-FBXL3-induced CRY1 degradation (By similarity).
Can form homodimers (via JmjC domain). Found in a complex with RCCD1. Interacts (via N-terminus) with RCCD1 (via N-terminus); this interaction stimulates H3K36me3 and H3K36me2 demethylation. Interacts (via JmjC domain) with H3C1 (By similarity). 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 towards H3K36me2 was observed in vivo and in vitro. In addition, demethylase activity towards H3K36me3 when in a complex with RCCD1 has been observed. 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.
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) (By similarity).
Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.
Involved in the early part of the secretory pathway.
Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1.
Self-associates. Component of the RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2. Note that the trimeric RLC/miRLC is also referred to as RISC. Interacts with EIF2AK2/PKR and inhibits its protein kinase activity. Interacts with DHX9 and PRKRA. Interacts with DICER1, AGO2, MOV10, EIF6 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC).
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.
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 (By similarity).
Belongs to the glycosyltransferase 17 family.
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. Addition of bisecting N-acetylglucosamine to CDH1/E-cadherin modulates CDH1 cell membrane location. Inhibits NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc- formation which modulates sialylation levels and plays a role in cell migration regulation (By similarity). 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).
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.
Belongs to the histidine acid phosphatase family. VIP1 subfamily.
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).
Belongs to the potassium channel KCNN family. KCa2.2/KCNN2 subfamily.
Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:8781233, PubMed:20562108). Activation is followed by membrane hyperpolarization. Thought to regulate neuronal excitability by contributing to the slow component of synaptic afterhyperpolarization.
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.
Inhibited by bee venom neurotoxin apamin (PubMed:8781233, PubMed:20562108). Inhibited by UCL 1684 and tetraethylammonium (TEA) (PubMed:20562108).
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. Recognizes a C-end rule (CendR) motif R/KXXR/K on its ligands which causes cellular internalization and vascular leakage. It binds to semaphorin 3A, the PLGF-2 isoform of PGF, the VEGF165 isoform of VEGFA and VEGFB (By similarity). 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 (By similarity).
Found in the embryonic nervous system (PubMed:9288754). Expressed in dorsal root ganglia (PubMed:28270793).
Homodimer, and heterodimer with NRP2. Binds PLXNB1 (By similarity). Interacts with FER. Interacts with VEGFA (By similarity). Interacts with ABCB8/MITOSUR in mitochondria (By similarity).
Increased in dorsal root ganglia in response to injury caused by dorsal rhizotomy (PubMed:28270793). Increased in dorsal root ganglia in response to both sciatic nerve crush and transection injury (PubMed:28270793).
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.
Catalyzes both the synthesis and degradation of fructose 2,6-bisphosphate.
In the C-terminal section; belongs to the phosphoglycerate mutase family.
Phosphorylation by AMPK stimulates activity.
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. 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.
Exhibits night/day variations with a 5-fold increased expression at night in the pineal gland (at protein level). Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway.
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.
In mammalian tissues, there are three distinct forms of AdoMet synthases designated as alpha, beta, and gamma. Alpha and beta are expressed only in adult liver, while gamma is widely distributed in extrahepatic tissues. In addition, the gamma form predominantly exists in fetal rat liver and is progressively replaced by the alpha and beta forms during development. In the brain, highly expressed at night in pinealocytes (at protein level). Low expression in the medial habenular nucleus, granular layer of the cerebellum, layer II of the neocortex and the pyramidal cells and granular cells of the hippocampal formation.
Highly expressed in the adipose tissue (PubMed:1770312). Also expressed in the heart, adrenal gland and testis (PubMed:1770312, PubMed:8812477).
Levels do not vary in adipose tissue from epididymal fat pads between 3 weeks and 2 years of age (PubMed:1770312). In heart, levels are lowest in the fetus, increase rapidly within the first day postnatally, and then gradually increase to stable adult levels by 2 months that are 3-fold higher than observed in fetal rats (PubMed:1770312). Levels in the adrenals are lowest in fetal rats, increase 4-fold during the first day and peak at levels that are 9-fold higher by the end of the first week (PubMed:1770312). Thereafter, levels fall and remain 3-to 4-fold higher than at birth throughout adult life (PubMed:1770312). Undetectable in testis before 4 weeks of age and increase 25-fold to stable adult levels between 4 and 12 weeks (PubMed:1770312).
Lipase with broad substrate specificity, catalyzing the hydrolysis of triacylglycerols (TAGs), diacylglycerols (DAGs), monoacylglycerols (MAGs), cholesteryl esters and retinyl esters (PubMed:6643478, PubMed:9162045, PubMed:10694408). Shows a preferential hydrolysis of DAGs over TAGs and MAGs and preferentially hydrolyzes the fatty acid (FA) esters at the sn-3 position of DAGs (By similarity). Preferentially hydrolyzes fatty acids at the sn-1 and sn-2 positions of TAGs (PubMed:6643478). 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 (PubMed:1770312).
Monomer and homodimer (PubMed:10694408). Interacts with CAVIN1 in the adipocyte cytoplasm (By similarity). Interacts with PLIN5 (PubMed:24303154).
Phosphorylation by AMPK reduces its translocation towards the lipid droplets.
Rapidly activated by cAMP-dependent phosphorylation under the influence of catecholamines (PubMed:6374655). Dephosphorylation and inactivation are controlled by insulin (PubMed:6374655). cAMP stimulates its retinyl ester hydrolase activity (PubMed:9162045).
Detected in brain cortex, and at low levels in testis.
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 (By similarity).
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 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 (By similarity).
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 (By similarity). Costimulates T-cell proliferation and cytokine production (By similarity). 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 (By similarity). Induces the activation of NF-kappa-B (By similarity). Induces the activation of kinases MAPK8 and PAK2 in T-cells (By similarity). 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 (By similarity). Interacts with CD28 (By similarity). CD40 ligand, soluble form: Exists as either a monomer or a homotrimer (By similarity). Forms a ternary complex between CD40 and integrins for CD40-CD40LG signaling (By similarity).
Interacts with KIF16B. Interacts with ZFYVE20 (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 (By similarity). 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.
Widely expressed (at protein level). Highest levels found in whole brain, spinal cord, heart, kidney and lung.
Belongs to the NADP-dependent oxidoreductase L4BD family.
Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2. Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation.
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 (By similarity). Inhibits cell activation by microbial products (By similarity). Recruits IRAK1 to the IL-1 receptor complex (By similarity). Inhibits IRAK1 phosphorylation and kinase activity. Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates (By similarity). The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates (By similarity). In a complex with TOM1, recruits ubiquitin-conjugated proteins onto early endosomes (By similarity). Binds to phosphatidylinositol 3-phosphate (PtdIns(3)P) (By similarity).
Oligomerizes. Binds to TLR2 and the TLR4-MD2 complex via its C-terminus. Exists as complex with IRAK1 in unstimulated cells. Upon IL-1 signaling, Tollip 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. MyD88 then triggers IRAK1 autophosphorylation, which in turn leads to the dissociation of IRAK1 from Tollip and IL-1RAcP. 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 (By similarity). Interacts with TOM1L2 (By similarity). Interacts with ATG8 family proteins (via the AIM motifs), and ubiquitin (via the CUE domain) (By similarity). Interacts with LRBA (By similarity).
The N-terminal TOM1-binding domain (residues 1-53) is a disordered domain that partially folds when bound to the GAT domain of TOM1.
Expressed in prostate. Detected in other organs at low levels, these include the heart and various tissues of the urogenital tract. Not detected in mammary gland.
Highly N-glycosylated and O-glycosylated.
Induced in prostate, after castration. This induction is reversed by androgen supplementation.
May regulate TLP1 expression and telomerase activity, thus enabling certain prostatic cells to resist apoptosis.
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
Homotrimer. Interacts with elastin. Interacts with MASP1 and MASP2.
May function in innate immunity through activation of the lectin complement pathway. Calcium-dependent and GlcNAc-binding lectin (By similarity).
The fibrinogen-like domain (FBG) contains calcium-binding sites that may be involved in carbohydrate binding.
First detected at 18 dpc, expression increases with growth and development in spite of a temporal decrease at P14. Still expressed in adult animals, in both the cerebrum and the cerebellum, although at lower levels in adults than in younger animals (at protein level).
In brain, specifically expressed in astrocytes (at protein level).
Interacts with spectrin via SPTBN1; the interaction is direct. Interacts with calmodulin; calcium-dependent it prevents interaction with spectrin.
Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization (PubMed:19508979, PubMed:24117850). Specifically recognizes growing microtubule minus-ends and stabilizes microtubules (By similarity). Acts on free microtubule minus-ends that are not capped by microtubule-nucleating proteins or other factors and protects microtubule minus-ends from depolymerization (By similarity). 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 (By similarity). Through interaction with spectrin may regulate neurite outgrowth (PubMed:24117850).
Found in a complex with SMAD4 and YY1. Upon C-terminus phosphorylation: forms trimers with another SMAD1 and the co-SMAD SMAD4. Interacts with PEBP2-alpha subunit, CREB-binding protein (CBP), NANOG, p300, SMURF1, SMURF2, HOXC8, USP15 and HGS. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. Interacts with SKOR1 and ZCCHC12. 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. Interacts (via MH2 domain) with FAM83G (via MH2 domain); in a SMAD4-independent manner. Interacts with ZC3H3. Interacts with TMEM119. 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 (By similarity).
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 (By similarity). Dephosphorylation, probably by PPM1A, induces its export from the nucleus to the cytoplasm (By similarity).
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). Has been shown to be also activated by TGF-beta (transforming growth factor) type I receptor kinase in rat intestinal epithelial cells (IEC 4-1). 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 (By similarity).
Ubiquitinated by SMAD-specific E3 ubiquitin ligase SMURF1, leading to its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (By similarity).
Ubiquitous; present in liver, lung, stomach and spleen with lower level in heart, testes and skeletal muscle.
Acetylated on Lys-538 by CLOCK during the repression phase of the circadian cycle. Acetylation facilitates recruitment of CRY1 protein and initiates the repression phase of the circadian cycle. Acetylated at Lys-538 by KAT5 during the activation phase of the cycle, leading to recruitment of the positive transcription elongation factor b (P-TEFb) and BRD4, followed by productive elongation of circadian transcripts. Deacetylated by SIRT1, which may result in decreased protein stability.
Component of the circadian clock oscillator which includes the CRY1/2 proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 proteins (By similarity). Forms a heterodimer with CLOCK (By similarity). The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and BMAL1 (By similarity). Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian manner (By similarity). Interacts with NPAS2 (By similarity). Interacts with EZH2 (By similarity). Interacts with SUMO3 (By similarity). Interacts with SIRT1 (By similarity). Interacts with AHR (By similarity). Interacts with ID1, ID2 and ID3 (By similarity). Interacts with DDX4 (By similarity). Interacts with OGT (By similarity). Interacts with EED and SUZ12 (By similarity). Interacts with MTA1 (By similarity). Interacts with CIART (By similarity). Interacts with HSP90 (By similarity). Interacts with KAT2B and EP300 (By similarity). Interacts with BHLHE40/DEC1 and BHLHE41/DEC2 (By similarity). Interacts with RELB and the interaction is enhanced in the presence of CLOCK (By similarity). Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus (By similarity). Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation (By similarity). Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA (By similarity). The CLOCK-BMAL1 heterodimer interacts with GSK3B (By similarity). Interacts with KDM5A (By similarity). Interacts with KMT2A; in a circadian manner (By similarity). Interacts with UBE3A (By similarity). Interacts with PRKCG (By similarity). Interacts with MAGEL2 (By similarity). Interacts with NCOA2 (By similarity). Interacts with THRAP3 (By similarity). The CLOCK-BMAL1 heterodimer interacts with PASD1 (By similarity). Interacts with PASD1 (By similarity). Interacts with USP9X (By similarity). Interacts with PIWIL2 (via PIWI domain) (By similarity). Interacts with HDAC3 (By similarity). Interacts with HNF4A (By similarity).
O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2/3 and CRY1/2.
Phosphorylated upon dimerization with CLOCK. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the CLOCK-BMAL1 heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver with a peak between CT10 to CT14. Phosphorylation at Ser-90 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry. Dephosphorylation at Ser-78 is important for dimerization with CLOCK and transcriptional activity.
Sumoylated on Lys-259 upon dimerization with CLOCK. Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation localizes it exclusively to the PML body and promotes its ubiquitination in the PML body, ubiquitin-dependent proteasomal degradation and the transcriptional activity of the CLOCK-BMAL1 heterodimer.
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. BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. May play a role in spermatogenesis; contributes to the chromatoid body assembly and physiology. The NPAS2-BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5'-CACGTGA-3', which contains a flanking Ala residue in addition to the canonical 6-nucleotide E-box sequence (By similarity). CLOCK specifically binds to the half-site 5'-CAC-3', while BMAL1 binds to the half-site 5'-GTGA-3' (By similarity). The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5'-AACGTGA-3' and 5'-CATGTGA-3'. Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1 (By similarity). Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner (By similarity). Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B) (By similarity).
Ubiquitinated, leading to its proteasomal degradation. Deubiquitinated by USP9X.
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.
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:12930796, PubMed:26894959).
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.
Probable chloride channel. May be involved in cell adhesion.
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 (By similarity). Nucleoporins may be involved both in binding and translocating proteins during nucleocytoplasmic transport.
Interacts with GLE1. Able to form a heterotrimer with GLE1 and NUP42 in vitro (By similarity). 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.
Involved in the retrieval of endoplasmic reticulum membrane proteins from the early Golgi compartment.
Accessory protein for the calcitonin gene-related peptide (CGRP) receptor. It modulates CGRP responsiveness in a variety of tissues (By similarity).
Belongs to the eukaryotic RPC9 RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits. Interacts with POLR3H/RPC8. POLR3H/RPC8 and CRCP/RPC9 probably form a Pol III subcomplex (By similarity).
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).
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 upon TCR or BCR activation; which leads to the recruitment of GRB2, PIK3R1 and GRAP2.
When phosphorylated, interacts with GRB2, PIK3R1 and GRAP2.
Expressed in peripheral blood leukocytes, mainly in T-lymphocytes.
Up-regulated during induction and maintenance of graft acceptance and down-regulated during graft rejection.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. 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. 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. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, except 'Lys-48'-linked polyubiquitination.
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. Interacts with CDC20, FZR1/CDH1 and VHL.
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 (PubMed:10856240). 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 (By similarity). Interacts with ATF7; the interaction does not phosphorylate ATF7 but acts as a docking site for ATF7-associated partners such as JUN (By similarity). Interacts with BCL10 (By similarity). Interacts with CTNNB1 and GSK3B (By similarity). Interacts with DCLK2 (By similarity). Interacts with MAPKBP1 (By similarity). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-347'. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity).
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. Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation.
Belongs to the eukaryotic ribosomal protein eL29 family.
Homotetramer, dimer of dimers (By similarity). Does not assemble into higher oligomers (By similarity). Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with the PDZ domain of TAX1BP3 (By similarity).
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.
Homotrimer. Interacts with DAB2. Interacts with NOS3, DNM2, WASL and CAV1 (By similarity).
Multivalent adapter protein which may decrease NOS3 activity by inducing its translocation away from the plasma membrane.
Over-expressed in brain microcapillaries from spontaneously hypertensive rats.
The F-BAR domain is necessary for membrane targeting.
The SH3 domain mediates interaction with NOS3, DNM2 and WASL.
Expression increases during oligodendrocyte differentiation.
May play a role in the regulation of oligodendrocyte differentiation. May play a role in the regulation of myelin formation (PubMed:27532821). Involved in the regulation of Erk1/2 phosphorylation in Schwann cells; the signaling may be linked to the regulation of myelination (PubMed:27891578). May dephosphorylate MAPK13, ATF2, ERBB3, PDGFRB and SNX6 (By similarity).
May play a role in the trafficking of a subset of G-protein coupled receptors.
Could play a role in cell proliferation during neuronal differentiation and in protection against cell death.
Interacts with CLN5. Interacts with CLN3 (By similarity).
Belongs to the universal ribosomal protein uL1 family.
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
Trimethylated at Lys-165 by EEF1AKMT3. 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. Trimethylated at the N-terminus and dimethylated at Lys-55 by METTL13.
Binds the type 2 receptor protein ACVR2A.
Expressed in brain, kidney, lung, liver, testis, ovary, adrenal gland, heart, prostate, gastrointestinal tract, and spleen. Distributed throughout both adult and embryonic central nervous system and pancreatic islet cells.
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.
Belongs to the Dus family. Dus3 subfamily.
Catalyzes the synthesis of dihydrouridine, a modified base, in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs). Mainly modifies the uridine in position 47 (U47) in the D-loop of most cytoplasmic tRNAs. Also able to mediate the formation of dihydrouridine in some mRNAs, thereby regulating their translation.
Belongs to the ABC transporter superfamily. ABCA family.
Promotes cholesterol efflux from sperm which renders sperm capable of fertilization. Has also been shown to decrease levels of intracellular esterified neutral lipids including cholesteryl esters, fatty acid esters and triacylglycerols.
Oxidizes L-tryptophan to 5-hydroxy-l-tryptophan in the rate-determining step of serotonin biosynthesis.
Phosphorylated; triggering degradation by the proteasome.
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitinated is triggered by phosphorylation.
Despite its name, no basic helix-loop-helix (bHLH) domain is detected by any prediction tool.
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.
Belongs to the clathrin light chain family.
Clathrin coats are formed from molecules containing 3 heavy chains and 3 light chains. Interacts (via N-terminus) with HIP1. Interacts with HIP1R.
Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.
Forms a complex composed of a calmodulin-dependent catalytic subunit (also known as calcineurin A) and a regulatory Ca(2+)-binding subunit (also known as calcineurin B) (PubMed:24018048). 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). The regulatory subunit confers calcium sensitivity. Interacts with catalytic subunit PPP3CA/calcineurin A (PubMed:24018048). Interacts with catalytic subunit PPP3CB/calcineurin A (By similarity). Interacts with CIB1 (via C-terminal region); the interaction increases upon cardiomyocyte hypertrophy. Interacts with RCAN1 (By similarity). Interacts with SPATA33 (via PQIIIT motif) (By similarity).
Component of the BCR(KLHL21) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL21 and RBX1.
Substrate-specific adapter of 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 (By similarity).
Inhibited by high potassium ions-induced membrane depolarization.
Uniporter that mediates the uptake of cationic L-amino acids such as L-arginine, L-lysine and L-ornithine (PubMed:9079705). The transport is sodium ions- and pH-independent, moderately trans-stimulated and is mediated by passive diffusion (PubMed:9079705).
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). Interacts with IL13RA1. Binds to microtubules, TRAF3 and DISC1 (By similarity). Interacts with MAP4 (By similarity).
Plays an inhibitory role on IL13 signaling by binding to IL13RA1. Involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding. Recruits TRAF3 and DISC1 to the microtubules (By similarity). Involved in kidney development and epithelial morphogenesis. Involved in the regulation of microtubule cytoskeleton organization. Is a negative regulator of microtubule stability, acting through the control of MAP4 levels. Involved in ciliogenesis (By similarity).
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.
Plays a role in the control of cell shape and motility in the trabecular meshwork.
Interacts with RHOT1/Miro-1 and RHOT2/Miro-2 (By similarity). Interacts with GABA-A receptor and O-GlcNAc transferase. Interacts with HGS.
May regulate endosome-to-lysosome trafficking of membrane cargo, including EGFR.
Present in heart and brain (at protein level).
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.
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.
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-730 and Tyr-741 is important for interaction with PIK3R1. Phosphorylation at Tyr-719 and Tyr-753 is important for interaction with PTPN11. Phosphorylation at Tyr-761 is important for interaction with CRK. Phosphorylation at Tyr-571 and Tyr-573 is important for interaction with SRC and SRC family members. Phosphorylation at Tyr-987 and Tyr-1017 is important for interaction with PLCG1 (By similarity).
Interacts with homodimeric PDGFA, PDGFB and PDGFC, and with heterodimers formed by PDGFA and PDGFB. Monomer in the absence of bound ligand.
Interacts with homodimeric PDGFA, PDGFB and PDGFC, and with heterodimers formed by PDGFA and PDGFB. Monomer in the absence of bound ligand. Interaction with dimeric PDGFA, PDGFB and/or PDGFC leads to receptor dimerization, where both PDGFRA homodimers and heterodimers with PDGFRB are observed. Interacts (tyrosine phosphorylated) with SHB (via SH2 domain). Interacts (tyrosine phosphorylated) with SHF (via SH2 domain). Interacts (tyrosine phosphorylated) with SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1. Interacts (tyrosine phosphorylated) with PLCG1 (via SH2 domain). Interacts (tyrosine phosphorylated) with CRK, GRB2 and GRB7 (By similarity).
Present in an inactive conformation in the absence of bound ligand. Binding of PDGFA and/or PDGFB leads to dimerization and activation by autophosphorylation on tyrosine residues.
Present in an inactive conformation in the absence of bound ligand. Binding of PDGFA and/or PDGFB leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by imatinib, nilotinib and sorafenib (By similarity).
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor (By similarity).
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development.
Ubiquitinated, leading to its internalization and degradation.
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. 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.
Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription. Might be involved in transcriptional regulation by modulating the binding of the RARA nuclear receptor to RARE DNA elements (By similarity).
CD2 interacts with lymphocyte function-associated antigen CD58 (LFA-3) and CD48/BCM1 to mediate adhesion between T-cells and other cell types. CD2 is implicated in the triggering of T-cells, the cytoplasmic domain is implicated in the signaling function.
Interacts with CD48 (PubMed:16803907). Interacts with CD58 (LFA-3) (By similarity). Interacts with CD2AP (By similarity). Interacts with PSTPIP1 (By similarity). Interacts with FCGR3A; this interaction modulates NK cell activation and cytotoxicity.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK3 subfamily.
Expressed in both adult and embryonic CNS.
Expressed in the deep cortical layers, dentate gyrus, reticular thalamic nucleus, mammillary bodies, pons, and cerebellum of the adult.
Homotetramer, and heterotetramer with GRIK4 or GRIK5. Homomeric GLUR7A and GLUR7B form functional kainate receptors. GLUR7A receptors have a very low sensitivity to glutamate. GLUR7A can also coassemble with either GRIK4 or GRIK5 to form heteromeric receptors. Interacts with PRKCABP. Interacts with NETO2 (By similarity).
Mass spectrometry data suggest the protein is N-glycosylated at five distinct sites.
Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.
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.
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 (By similarity).
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 (By similarity). 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.
Expressed in granule neurons, with levels decreasing with neuronal maturation.
Belongs to the aldo/keto reductase family. Glutamate--cysteine ligase light chain subfamily.
Belongs to the inositol monophosphatase superfamily.
Belongs to the apolipoprotein C4 family.
May participate in lipoprotein metabolism.
Belongs to the neutral ceramidase family.
By interleukin-1-beta in renal mesangial cells.
Highly expressed in brain, kidney and heart (PubMed:11328816). Expressed at lower level in other tissues such as liver (PubMed:11328816). Expressed in intestine, kidney and liver (at protein level) (PubMed:11328816, PubMed:11330410). Localizes in the epithelia of the jejunum and ileum (PubMed:11330410).
N-glycosylated (PubMed:11328816, PubMed:15123644). Required for enzyme activity (PubMed:11328816).
O-glycosylated (PubMed:12499379). Required to retain it as a type II membrane protein at the cell surface (PubMed:12499379).
Phosphorylated. May prevent ubiquitination and subsequent degradation.
Plasma membrane ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at neutral pH (PubMed:11328816, PubMed:10488143, PubMed:15217782). 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:11328816). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (PubMed:15123644, PubMed:11278489). 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:15217782). Also participates in the hydrolysis of ceramides from the extracellular milieu allowing the production of sphingosine-1-phosphate inside and outside cells. This is the case for instance with the digestion of dietary sphingolipids in the intestinal tract (By similarity).
Proteolytic cleavage of the N-terminus removes the signal-anchor and produces a soluble form of the protein.
The reverse reaction is inhibited by Zn(2+) and Cu(2+) (PubMed:11278489). Inhibited by cardiolipin and phosphatidic acid (PubMed:11278489).
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is triggered by nitric oxide.
Component of the lateral elements of synaptonemal complexes (PubMed:9592139, PubMed:9933407). Interacts with TEX11 (By similarity). Heterodimer with SYCP3. Interacts with SYCP3, SMC1A and SMC3 (PubMed:10652260).
Detected in spermatocytes and testis (at protein level) (PubMed:9592139, PubMed:9933407). Spermatocytes and oocytes. Meiotic prophase cells.
Major component of the axial/lateral elements of synaptonemal complexes (SCS) during meiotic prophase (PubMed:9592139, PubMed:9933407). 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.
Meiosis-specific. Highly expressed in meiotic prophase cells, low expression persists in spermatids.
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 complex seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5. Required for retrograde transport of lysosomal enzyme receptor IGF2R. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA). Required for the endosomal localization of WASHC2 (indicative for the WASH complex). Required for the endosomal localization of TBC1D5. Mediates retromer cargo recognition of SORL1 and is involved in trafficking of SORL1 implicated in sorting and processing of APP. Involved in retromer-independent lysosomal sorting of F2R. Involved in recycling of ADRB2. Acts redundantly with VSP26B in SNX-27 mediated endocytic recycling of SLC2A1/GLUT1. 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. 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, SNX27, SNX1, SNX2, SNX5, SNX6, SNX3, RAB7A, ECPAS, EHD1, WASHC5, SORL1 (By similarity).
Endosomal ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Participates in erythroid iron homeostasis by reducing Fe(3+) to Fe(2+). Also mediates reduction of Cu(2+) to Cu(1+), suggesting that it participates in copper homeostasis. Uses NADP(+) as acceptor. Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP (By similarity). May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression.
Homodimer. Interacts with BNIP3L, MYT1, RHBDL4/RHBDD1 and TCTP (By similarity).
Proteolytically cleaved by RHBDL4/RHBDD1. RHBDL4/RHBDD1-induced cleavage occurs at multiple sites in a glycosylation-independent manner (By similarity).
Expressed in the small intestine. Expression in the mucosal cells of the ileum extends from the midvillar region to the villus tips.
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 (By similarity).
Forms a beta-barrel structure that accommodates the hydrophobic ligand in its interior.
Belongs to the threonine aldolase family.
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.
ADP-ribosylated at Tyr-155 by PARP1 in presence of HPF1.
Belongs to the eukaryotic ribosomal protein eS1 family.
Component of the small ribosomal subunit. Mature ribosomes consist of a small (40S) and a large (60S) subunit. The 40S subunit contains about 33 different proteins and 1 molecule of RNA (18S). The 60S subunit contains about 49 different proteins and 3 molecules of RNA (28S, 5.8S and 5S). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Binds with high affinity to IPO4. Interacts with DDIT3.
May play a role during erythropoiesis through regulation of transcription factor DDIT3.
The protein designated S3b has the same amino acid sequence as S3a except that it lacks the C-terminal 12 residues. It is probable that S3a is converted by proteolysis, either physiologically or fortuitously, to S3b.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM1 sub-subfamily.
Interacts with GPRASP2 (By similarity). Interacts with TMEM147 (By similarity).
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) (By similarity). Interacts when tyrosine-phosphorylated with GRB2.
Phosphorylation probably regulates the interaction with NPHS2 (By similarity). Phosphorylated at Tyr-637 and Tyr-638 by FYN, leading to GRB2 binding.
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 (By similarity). It is a signaling protein that needs the presence of TEC kinases to fully trans-activate the transcription factor AP-1 (By similarity).
May play an important role in acrosome formation and nucleus shaping during spermiogenesis.
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.
Involved in mitochondrial metabolism by regulating the balance between mitochondrial fusion and fission (By similarity). May act as a regulator of mitochondrial fission that promotes DNM1L-dependent fission through activation of DNM1L (By similarity). May be involved in peroxisome organization (PubMed:17522052).
A high molecular weight form was detected in Schwann cells and peripheral nerve. A lower, probably processed form, is detected in all other tissues tested (at protein level).
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 (By similarity).
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 (By similarity).
Essential for Golgi structural integrity.
Belongs to the SLC34A transporter family.
Interacts via its C-terminal region with PDZK2. Interacts with SLC9A3R1.
Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane (PubMed:8327470, PubMed:9058191, PubMed:10198426, PubMed:10370077, PubMed:10926678). The cotransport has a Na(+):Pi stoichiometry of 3:1 and is electrogenic (PubMed:10198426).
Transport activity is significantly increased in response to dietary phosphate deprivation.
Up-regulated by a low-phosphate diet (PubMed:9058191). Down-regulated by PTH at brush border membrane of proximal tubules (PubMed:8691716).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A7 subfamily.
Brain specific sodium (and chloride)-dependent proline transporter (PubMed:10414958). Terminates the action of proline by its high affinity sodium-dependent reuptake into presynaptic terminals (Probable).
Expressed in subpopulations of putative glutamatergic pathways of rat brain.
Interacts with SLC9A3R1, HGS and AGAP2. Interacts with SGSM3. Interacts (via FERM domain) with MPP1. Interacts with LAYN and 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. Interacts with SCHIP1; the interaction is direct.
Phosphorylation of Ser-514 inhibits nuclear localization by disrupting the intramolecular association of the FERM domain with the C-terminal tail. The dephosphorylation of Ser-514 favors the interaction with NOP53.
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 Plays a role in lens development and is required for complete fiber cell terminal differentiation, maintenance of cell polarity and separation of the lens vesicle from the corneal epithelium.
Ubiquitinated by the CUL4A-RBX1-DDB1-DCAF1/VprBP E3 ubiquitin-protein ligase complex for ubiquitination and subsequent proteasome-dependent degradation.
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:32165585). 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:32165585). Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity (By similarity).
Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment. Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity.
V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex. The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H. The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'', rotary subunit d, subunits e and f, and two accessory subunits.
During pregnancy and lactation (PubMed:10525157).
Endogenous ligand for the apelin receptor (APLNR) (PubMed:11336787, PubMed:11359874, PubMed:26611206). Drives internalization of the apelin receptor (PubMed:11359874). Apelin-36 dissociates more hardly than (pyroglu)apelin-13 from APLNR (PubMed:11336787). 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 (PubMed:26611206). May also have a role in the central control of body fluid homeostasis by influencing vasopressin release and drinking behavior (PubMed:10617103, PubMed:11359874).
Expressed in the lung, testis, ovary, uterus and mammary gland (PubMed:11336787). Expressed in neurons in the thalamic paraventricular and hypothalamic supraoptic nuclei (PubMed:11359874). The lung, testis and uterus mainly contain a large form that looks like apelin-36, whereas the mammary gland seems to contain 2 forms of apelin, a large form close to apelin-36 and a small form close to apelin-13 (at protein level) (PubMed:11336787). Widely expressed in the adult, with highest levels in the mammary gland of lactating animals, very high levels in the lung, intermediate levels in the spinal cord, ovary, adipose tissue, brain (neuronal cell bodies and fibers in the supraoptic and the paraventricular nuclei), heart and testis, and lowest levels in the pituitary gland, kidney, stomach, uterus and pancreas (PubMed:10525157, PubMed:10617103, PubMed:11336787).
Highly expressed in neonatal tissues. In the adult, reaches a maximal level around parturition.
Several active peptides may be produced by proteolytic processing of the peptide precursor.
Its activity is synergistically stimulated by magnesium and dithiothreitol (DTT) in vitro.
Specifically acts as an arginine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to arginine residues on proteins.
Binds 1 divalent metal cation per subunit. Most active with Zn(2+) and Mn(2+) ions. The physiological cofactor for gluconolactonase activity is most likely Ca(2+) or Mg(2+). Mg(2+), Mn(2+) and Co(2+) are equally efficient for the hydrolysis of diisopropyl phosphorofluoridate.
Detected in liver (at protein level). Hepatocytes and renal proximal tubular epithelium.
Gluconolactonase with low activity towards other sugar lactones, including gulonolactone and galactonolactone. Catalyzes a key step in ascorbic acid (vitamin C) biosynthesis. 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.
In liver, the first peak of expression was found in 5-day-old neonates. Expression increases from day 7 and reaches a plateau at day 10. 3-6.5 moth-old adults express about a third the amount of neonates level. In kidney, expression increases from day 21 and reaches a maximal level at day 35, remains high until 3 months of age.
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.
Belongs to the connexin family. Alpha-type (group II) subfamily.
Detected in eye lens (at protein level). Most abundant in lens, but also present in heart and kidney.
Structural component of lens fiber gap junctions (Probable). 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 (Probable).
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 (By similarity). Interacts with APBB1IP, NRAP and 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 SORBS1 (By similarity). Interacts with SYNM (By similarity). Interacts with CTNNA1 (By similarity). Binds to ACTN4; this interaction triggers conformational changes (By similarity).
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-1065 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. 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.
Activated by manganese and, to a lesser extent, by calcium.
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. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs) (By similarity). 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.
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) (By similarity).
The glycine cleavage system is composed of four proteins: P (GLDC), T (GCST), L (DLD) and H (GCSH). Interacts with GLDC (By similarity).
Acrosomal protein that maintains proacrosin (pro-ACR) as an enzymatically inactive zymogen in the acrosome. Involved also in the acrosome formation.
Binds pro-ACR. Does not bind mature form of ACR.
Binds pro-ACR. Does not bind the mature form of ACR.
Maintains pro-ACR as an enzymatically inactive zymogen in the acrosome until acrosomal exocytosis. Partially contributes also to the assembly of acrosomal proteins to form an acrosomal granule.
Phosphorylated on Tyr residues in capacitated sperm.
Rodent specific isoform that participates in the formation of the acrosomal granule into the center of the acrosomal vesicle during early spermiogenesis. In the fertilization process promotes ACR release from the acrosome during acrosomal exocytosis.
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 UPL family. K-HECT subfamily.
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.
Acetylation is enhanced after treatment either with trichostin A (TCA) or with nicotinamide (NAM) with the appearance of tri- and tetraacetylations. Glucose also increases acetylation.
Belongs to the LDH/MDH superfamily. MDH type 1 family.
Enzyme activity is enhanced by acetylation.
Belongs to the universal ribosomal protein uL22 family.
Associates with NXF1, NXF2, NXF3 and NXF5.
Regulator of protein export for NES-containing proteins. Also plays a role in mRNA nuclear export (By similarity).
Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.
Expressed in the node, notochord, floor plate, and posterior limb bud mesenchyme.
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 (By similarity). Interacts with DISP1 via its cholesterol anchor (By similarity). Interacts with SCUBE2 (By similarity). 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 (By similarity).
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 (By similarity). 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 (By similarity). The N-terminal palmitoylated peptide is cleaved at the Heparan sulfate-binding Cardin-Weintraub (CW) motif site (By similarity). The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2 (By similarity).
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 (By similarity). 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 (By similarity). In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO (By similarity).
The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding) (By similarity). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site (By similarity). The cleavage reduced the interactions with heparan sulfate (By similarity). The cleavage is enhanced by SCUBE2 (By similarity).
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. Once released, the fully processed Shh can signal within embryonic tissues both at short and long-range.
Belongs to the AB hydrolase superfamily. ABHD16 family.
Phosphatidylserine (PS) lipase that mediates the hydrolysis of phosphatidylserine to generate lysophosphatidylserine (LPS). LPS constitutes a class of signaling lipids that regulates immunological and neurological processes (By similarity). Has no activity towards diacylglycerol, triacylglycerol or lysophosphatidylserine lipase (By similarity). 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) (By similarity).
Could inhibit both insulin-receptor tyrosine kinase activity and insulin-stimulated receptor autophosphorylation and, concomitantly, antagonize the mitogenic effect of the hormone in cultured rat hepatoma cells.
Synthesized in liver and secreted by the hepatocytes in the blood.
Undergoes complex post-translational modification involving N-glycosylation, and addition of fucose and sialic acid residues. Phosphorylation occurs at a serine residue.
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. Essentially dedicated to O-mannosylation of alpha-DAG1 and few other proteins but not of cadherins and protocaherins.
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-578, and to a lesser degree, Tyr-580 is important for interaction with SRC. Phosphorylation at Tyr-715 is important for interaction with GRB2. Phosphorylation at Tyr-739 and Tyr-750 is important for interaction with PIK3R1. Phosphorylation at Tyr-750 is important for interaction with NCK1. Phosphorylation at Tyr-770 and Tyr-856 is important for interaction with RASA1/GAP. Phosphorylation at Tyr-856 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-1008 is important for interaction with PTPN11. Phosphorylation at Tyr-1008 and Tyr-1020 is important for interaction with PLCG1. Dephosphorylated by PTPRJ at Tyr-750, Tyr-856, Tyr-1008 and Tyr-1020. Dephosphorylated by PTPN2 at Tyr-578 and Tyr-1020 (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Ubiquitinated. After autophosphorylation, the receptor is polyubiquitinated, leading to its degradation (By similarity).
Functions as a transcriptional repressor.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. 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. 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. 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.
Homodimer. Interacts with FANCL. Interacts with STUB1/CHIP.
Belongs to the SIMIBI class G3E GTPase family. ArgK/MeaB subfamily.
Lactose synthase (LS) is a heterodimer of a catalytic component, beta1,4-galactosyltransferase (beta4Gal-T1) and a regulatory component, alpha-lactalbumin (LA).
Regulatory subunit of lactose synthase, changes the substrate specificity of galactosyltransferase in the mammary gland making glucose a good acceptor substrate for this enzyme. This enables LS to synthesize lactose, the major carbohydrate component of milk. In other tissues, galactosyltransferase transfers galactose onto the N-acetylglucosamine of the oligosaccharide chains in glycoproteins.
Tyrosine-protein phosphatase targeted to sites of actin polymerization in response of varied extracellular stimuli. Has tyrosine phosphatase activity towards various tyrosyl phosphorylated substrates (By similarity).
Homodimer. Interacts with NRIP1, NCOA1 and NCOR2. Binds TLE1, PNRC1 and PNRC2. Binds GRIP1 (By similarity).
Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements. Induces the expression of PERM1 in the skeletal muscle (By similarity).
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).
Belongs to the eukaryotic ribosomal protein eL6 family.
Component of the large ribosomal subunit (By similarity). May bind IPO9 with low affinity (By similarity).
Receptor for the hormone galanin and spexin-1.
Belongs to the WD repeat G protein beta family.
G proteins are composed of 3 units, alpha, beta and gamma (By similarity). The heterodimer formed by GNB1 and GNG2 interacts with ARHGEF5 (By similarity). The heterodimer formed by GNB1 and GNG2 interacts with GRK2 (By similarity). Forms a complex with GNAO1 and GNG3. Interacts with ARHGEF18 and RASD2 (By similarity).
Phosphorylation at His-266 by NDKB contributes to G protein activation by increasing the high energetic phosphate transfer onto GDP.
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.3/KCNG3 sub-subfamily.
Expressed strongly in neuronal cells and weakly in glial cells (PubMed:11852086).
Heterotetramer with KCNB1. Does not form homomultimers.
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.
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 ATP5MPL (By similarity). Interacts with DNAJC30; interaction is direct (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. Key component of the proton channel; it may play a direct role in the translocation of protons across the membrane.
Detected as early as postnatal day one with increasing expression levels through 20 weeks after birth.
Expressed in heart, lung, liver and kidney. Expressed in brain (at protein level).
Interacts probably directly with DLG1, DLG4, HOMER1. Interacts with DLGAP1, INA, CAMK2A, GRIN2B and GRIA1. Interacts with TNIK and MINK1.
May be a scaffold component in the postsynaptic density.
Phosphorylated; by MINK1 and TNIK upon stimulation by RAP2A.
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.
Glycogen phosphorylase that regulates glycogen mobilization (By similarity). Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
Homodimer. Dimers associate into a tetramer to form the enzymatically active phosphorylase A.
Phosphorylation of Ser-15 converts phosphorylase B (unphosphorylated) to phosphorylase A.
Associates with EPS15 and NOTCH1 (By similarity). Interacts (via PTB domain) with MAP3K7IP2 (via C-terminal). Interacts (via C-terminal) with TRAF6 (via TRAF domains).
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 (By similarity).
The PTB domain is necessary for the inhibition of MAP3K7IP2-mediated activation of NF-kappa-B.
Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (PubMed:8021284). Receptor for the pro-inflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2, either independently of IL18R1, or as a complex with IL18R1 (By similarity).
Expressed in kidney, predominantly in the outer cortex in short tubule segments.
Interacts with KLHL3 (By similarity). Interacts with IL18R1; this interaction is increased by IL18 treatment (By similarity).
Ubiquitinated; ubiquitination is essential for regulation of endocytosis.
Component of the ESCRT-I complex (endosomal sorting complex required for transport I), a regulator of vesicular trafficking process.
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 (By similarity).
Belongs to the fibroblast growth factor-binding protein family.
Expressed in gut, eye, thymus, skin, lung, tongue, Purkinje cells and cerebral chorioid plexus (at protein level).
Found in a complex with FGFBP1, FGF1 and FGF2. Interacts with FGF1, FGF2, FGF7, FGF10, FGF22 and HSPG2 (By similarity).
Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry (PubMed:10850716, PubMed:15075186, PubMed:14673192). 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 (By similarity). 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 (By similarity).
Expressed in aorta, ventricles, atrium, mesenteric artery, kidney, spleen, duodenum, jejunum, ileum, colon, lung, trachea, gastric fundus and pylorus, cerebrum, cerebellum, pancreas, liver, parotid gland, and epididymis. Expressed in the inner ear by cochlear outer and inner hair cells (at protein level). Highly expressed in testis and spleen.
Interacts with USH1C. Forms a complex with ATP6V1B1 and SLC9A3R1/EBP50. Interacts in a pH dependent-manner with CA2/carbonic anhydrase 2 (By similarity). Interacts with CFTR probably through SLC9A3R1/EBP50.
Specifically expressed in hippocampal neurons.
The PDZ-binding motif mediates interaction with the CFTR, SLC9A3R1/EBP50 complex and probably with USH1C.
Undergoes lysosome-mediated degradation.
Up-regulated in kidney upon metabolic acidosis.
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. Resistant to dipyridamole and dilazep inhibition (anticancer chemotherapeutics drugs).
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.
Heterodimer with BIN1 (PubMed:9341169). Binds SH3GLB1 (By similarity). Interacts with REPS1 and SGIP1 (By similarity). Binds AP2A2 (PubMed:10380931, PubMed:10430869). Interacts with AP2B1 (PubMed:16516836, PubMed:16903783). Interacts with DNM1 and SYNJ1 (PubMed:9341169).
May participate in mechanisms of regulated exocytosis in synapses and certain endocrine cell types. May control the properties of the membrane associated cytoskeleton (By similarity).
Substrate for phosphorylation by PKA and PKC. Reversible phosphorylation appears to modulate contraction.
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.
Expressed in the brain, pituitary gland and testis.
Receptor with constitutive G(s) signaling activity that activates cyclic AMP. Promotes neurite outgrowth and blocks myelin inhibition in neurons.
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 isoform 2, PRKACA isoform 2 and TCP11. Interacts with MROH2B isoform 2. Interacts with PRKACA isoform 2. Interacts with ODF1 (via leucine zipper motif).
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.
Chloride channel activity is allosterically activated by lumenal H(+) and Cl(-) leading to synaptic vesicles acidification (PubMed:27133463). The L-glutamate transport activity is allosterically activated by lumenal H(+) and Cl(-) (PubMed:27133463, PubMed:19169251). 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 (PubMed:27133463).
Expressed in the cerebellum, cerberal cortex and hippocampus. Isoform 2 is expressed specifically in retina.
Expression of isoform 2 increases sharply during the first ten days of postnatal life, and also increases with increasing numbers of rhodopsin cells in the retina.
Induced within cerebellar granule cells by exposure to N-methyl-D-aspartate (NMDA).
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 (PubMed:27133463).
Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, proton, potassium, sodium and phosphate (PubMed:11001057, PubMed:10938000, PubMed:18080752, PubMed:19169251, PubMed:8202535, PubMed:27133463, PubMed:25433636, PubMed:33440152, PubMed:29642010, PubMed:11698619). 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 (PubMed:29642010, PubMed:11001057, PubMed:10938000, PubMed:11698619, PubMed:18080752). 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:29642010). 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 (PubMed:10938000, PubMed:27133463, PubMed:25433636, PubMed:29642010, PubMed:19169251). 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 (PubMed:25433636). The vesicular K(+)/H(+) antiport activity is electroneutral (PubMed:25433636). 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:33440152, PubMed:8202535, PubMed:29642010). The symporter activity is driven by an inside negative membrane potential and is electrogenic (PubMed:29642010). Is necessary for synaptic signaling of visual-evoked responses from photoreceptors (By similarity).
Acetylated during spermatogenesis. Acetylated form is most abundant in spermatogonia compared to spermatocytes and round spermatids.
Methylated at Lys-118 in spermatogonia, spermatocytes and round spermatids.
Monoubiquitination at Lys-36 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 of 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 (By similarity).
Phosphorylated at Thr-117 in spermatogonia, spermatocytes and round spermatids.
Testis. Expressed in pachytene spermatocytes during meiotic prophase I in the absence of any significant DNA synthesis.
Variant histone specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells. 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. 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.
Homodimer. May also form higher-order oligomers (By similarity). Interacts (when phosphorylated) with ARRB1 and ARRB2; the interaction is associated with internalization of C5aR (PubMed:12464600).
Phosphorylated on serine residues in response to C5a binding, resulting in internalization of the receptor and short-term desensitization to the ligand.
Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a (PubMed:9464523). 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. Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production (By similarity).
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 peptide agonist.
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:7665087, PubMed:10544287, PubMed:11328599). 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:7665087, PubMed:10544287, PubMed:11328599).
Inhibited by azalanstat (PubMed:7665087). Inhibited by azole antifungal agents ketoconazole, itraconazole and fluconazole (PubMed:10544287).
Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP.
Belongs to the adaptor complexes medium subunit family. Delta-COP subfamily.
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).
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. Channel opening is also triggered by taurine and beta-alanine (PubMed:2176511). Plays a role in synaptic plasticity. Contributes to the generation of inhibitory postsynaptic currents, and is involved in the down-regulation of neuronal excitability. Plays a role in cellular responses to ethanol.
Homopentamer (in vitro). Interacts with GLRB. Heteropentamer composed of GLRA2 and GLRB. Both homopentamers and heteropentamers form functional ion channels, but their characteristics are subtly different.
Identical to the human subunit alpha-2, except for 5 substitutions at positions 18, 24, 37, 194 and 404. Substitution at position 194 (G -> E) accounts for the lower strychnine sensitivity observed in neonatal rats.
The alpha-2* subunit isoform is present in neonatal rats, but not in older animals (PubMed:2176511, PubMed:1707830). Isoform Alpha-2* and isoform Alpha-2B are detected in embryonic and neonatal brain. At later postnatal stages, isoform Alpha-2* levels greatly decrease while isoform Alpha-2B is barely detectable (PubMed:1645300).
Belongs to the LAPTM4/LAPTM5 transporter family.
Homooligomer; upon reaching the lysosomes. Interacts with MCOLN1. Interacts with NEDD4; may play a role in the lysosomal sorting of LAPTM4B; enhances HGS association with NEDD4; mediates inhibition of EGFR degradation. 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. Interacts with HGS; promotes HGS ubiquitination. Interacts with SNX5. Interacts with SLC3A2 and SLC7A5; recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation. Interacts with LRRC32; decreases TGFB1 production in regulatory T cells. Interacts with BECN1; competes with EGFR for LAPTM4B binding; regulates EGFR activity. Interacts with EGFR; positively correlates with EGFR activation.
Required for optimal lysosomal function. 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. 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. Plays a role as negative regulator of TGFB1 production in regulatory T cells. Binds ceramide and facilitates its exit from late endosome in order to control cell death pathways.
Undergoes proteolytic cleavage following delivery to the lysosomes.
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 (By similarity).
Highest levels in brain and testis. Lower levels in adipose tissue, kidney, heart, lung and skeletal muscle. Barely detectable in liver and spleen.
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 (By similarity). Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2. Interacts with TP53. Interacts with AXIN1; the interaction dephosphorylates AXIN1. Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3. Interacts with RAF1. Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination. Interacts with GSK3B (via C2 domain). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus. Interacts with PABIR1/FAM122A. Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin. Interacts with CRTC3 (when phosphorylated at 'Ser-391'). Interacts with SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2, possibly by vesicular sequestration of SPRY2. Interacts with TRAF3IP3. Interacts with AMBRA1 (via PxP motifs); enhancing interaction between PPP2CA and MYC or FOXO3 (By similarity). Forms a complex with AMBRA1 and BECN1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways (By similarity).
PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase (By similarity). Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'. Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint. Mediates dephosphorylation of MYC; promoting its ubiquitin-mediated proteolysis: interaction with AMBRA1 enhances interaction between PPP2CA and MYC (By similarity). Mediates dephosphorylation of FOXO3; promoting its stabilization: interaction with AMBRA1 enhances interaction between PPP2CA and FOXO3 (By similarity).
Polyubiquitinated, leading to its degradation by the proteasome.
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.
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 (By similarity). Has an essential role in the stimulation of B cell activation (By similarity).
Can self-associate and form homotetramers (By similarity). Interacts with MAGI2, PDCD6IP, CBL, GRB2 and PI3KR3. Interacts with CD2, F-actin capping protein, EGFR, MET, BLNK, MAP3K4, SPRY2, ARHGAP17, 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. Probably part of a complex consisting of at least SH3KBP1, ASAP1 and ARAP3 (By similarity). Interacts with ARHGAP27. Interacts (via SH3 domains) with SHKBP1 (via PXXXPR motifs) (PubMed:11152963). Interaction with CBL is abolished in the presence of SHKBP1 (By similarity). Interacts (via SH3 domains) with ZFP36 (via extreme C-terminal region). Interacts with MAP3K4; this interaction enhances the association with ZFP36 (By similarity).
Monoubiquitinated by CBL and CBLB after EGF stimulation; probably on its C-terminus.
Catalyzes the reduction of the C14-unsaturated bond of lanosterol, as part of the metabolic pathway leading to cholesterol biosynthesis (By similarity). 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 (By similarity).
Interacts with CBX5 (By similarity). Interacts with DNA (By similarity). Interaction with DNA is sequence independent with higher affinity for supercoiled and relaxed circular DNA than linear DNA (By similarity). Interacts with lamin B (By similarity). Interacts with CLNK (By similarity).
Phosphorylated by CDK1 in mitosis when the inner nuclear membrane breaks down into vesicles that dissociate from the lamina and the chromatin (By similarity). It is phosphorylated by different protein kinases in interphase when the membrane is associated with these structures (By similarity). 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 (By similarity). Phosphorylated by SRPK1 (By similarity). In late anaphase LBR is dephosphorylated, probably by PP1 and/or PP2A, allowing reassociation with chromatin (By similarity).
The Tudor domain may not recognize methylation marks, but rather bind unassembled free histone H3.
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity. Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore. The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules.
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 (By similarity).
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-516', 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 (By similarity). Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-275' and 'Ser-294'. 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.
Dendrite development is blocked in hippocampal neurons silencing CAKM1.
Phosphorylated by CaMKK1 and CaMKK2 on Thr-177.
Polybiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL12), leading to proteasomal degradation.
The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate.
Expressed in the cortical tissue (at protein level).
Interacts with ADORA2A (via its cytoplasmic C-terminal domain) (PubMed:23994616). Interacts with GNAS, GNAL, GNAQ, and GNA13 (By similarity). Interacts with MAPRE1 (By similarity).
Involved in the cross-linking of microtubules and microfilaments (By similarity). Regulates microtubule dynamics and stability by interacting with microtubule plus-end tracking proteins, such as MAPRE1, to regulate microtubule growth along actin stress fibers (By similarity). Enhances ADORA2-mediated adenylyl cyclase activation by acting as a scaffold to recruit trimeric G-protein complexes to ADORA2A (By similarity).
Belongs to the type IB topoisomerase family.
Phosphorylation at Ser-508 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. 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.
Sumoylated. Lys-119 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.
Cytokine that binds to TNFRSF4. Co-stimulates T-cell proliferation and cytokine production (By similarity).
Detected in T-cell lines, but not in a macrophage cell line.
Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides. May cooperate with auxiliary protein SEC62, SEC63 and HSPA5/BiP to enable post-translational transport of small presecretory proteins. Component of a ribosome-associated ER translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis. The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER. 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 (By similarity). Plays a critical role in nephrogenesis, specifically at pronephros stage (By similarity).
The SEC61 channel-forming translocon complex consists of channel-forming core components SEC61A1, SEC61B and SEC61G and different auxiliary components such as SEC62 and SEC63 (By similarity). The 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 (By similarity).
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. Interacts with CHCHD3, DNAJC7, IRAK1BP1, PPP5C and TSC2. Interacts with TERT; the interaction occurs in the absence of the RNA component, TERC, and dissociates once the TERT complex has formed. Interacts with METTL21A. Interacts with TRIM5 (via B30.2/SPRY domain). Interacts with PRKN. Interacts with FOXP3. Interacts with NOD2; the interaction enhances NOD2 stability. Interacts with DNAJC9 (via J domain). Interacts with ATF5; the interaction protects ATF5 from degradation via proteasome-dependent and caspase-dependent processes. Interacts with NAA10, HSP40, HSP90 and HDAC4. The acetylated form and the non-acetylated form interact with HOPX and STUB1 respectively. Interacts with NEDD1 and SMAD3. Interacts (via NBD) with BAG1, BAG2, BAG3 and HSPH1/HSP105. Interacts with DNAJC8.
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. 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. 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. Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation.
EF-hand domains are paired. EF-hand 1 is paired with EF-hand 2 and EF-hand 3 is paired with EF-hand 4. The fifth EF-hand domain, left unpaired, does not bind the calcium but is responsible of the dimerization by EF-embrace. The first four EF-hand domains bind calcium, however it is not sure if the binding of EF-hand 4 to calcium is physiologically relevant.
Homodimer or heterodimer of a large (catalytic) and a small (regulatory) subunit. In presence of calcium, the heterodimer dissociates (By similarity).
Regulatory subunit of the calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Essential for embryonic development (By similarity).
The contact of the 5th EF-hand domain from each monomer allows the formation of the homodimer and also appears to mediate the contact between the large catalytic subunit and small regulatory subunit for the formation of the heterodimer.
Homotrimer (via collagen-like domain). May form higher order oligomers by supercoiling of the trimers. May interact with ERFE (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-1E gives rise to R-type calcium currents.
May be involved in N-linked oligosaccharide assembly.
Forms homooligomers, independently of the DNA-binding domain.
Transcription repressor. Sequence-specific ssDNA and dsDNA binding protein, with preference for GCT end CTG repeats (By similarity). Cell migration modulator which enhances the glioma-specific migration ability of neural stem cells (NSC) and neural precursor cells (NPC).
Component of nuclear RNase P and RNase MRP complexes. RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40. 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. 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. Interacts with SMN1. POP7 forms a heterodimer with RPP25 that binds to the P3 stem loop of the catalytic RNA.
Phosphorylation at Thr-214 by PRKCA induces significant reduction in myofilament calcium sensitivity and actomyosin ATPase activity.
Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage. The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines.
Detected in red blood cells (at protein level). Widely distributed, high amounts found in kidney, brain, aorta and pancreas.
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.
Expressed in the ventricle and atrium of adult rats. Also detected in the lung, kidney, liver, skeletal muscle, stomach and urinary bladder. Not detected in brain, colon, testis, spleen or thymus. Overexpressed in the ventricles in the case of hypertension and hypertrophy.
Induces cardiac myocyte hypertrophy in vitro. Binds to and activates the ILST/gp130 receptor.
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.
Belongs to the NAD-dependent glycerol-3-phosphate dehydrogenase family.
Associates with cytochrome c oxidase (COX, complex IV); proposed complex component. Also associates with respiratory chain supercomplexes (By similarity).
Expression is increased between P1 and P15 in the spinal cord and a differential spatial pattern. In the P1 spinal cord there is a preferential expression in regions of dorsal laminae II and III and laminae IX ventrally; while in P8, the distribution is more widespread and overall expression is increased.
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 (By similarity).
Highly expressed in tooth-associated epithelia. In tooth, it is only detected in the ameloblast layer of the enamel organ, starting at post-secretory transition and extending throughout the maturation stage. Also detected in epithelial cells of the gingiva which bind it to the tooth surface (junctional epithelium) (at protein level). Predominantly expressed in mandible, but also expressed at weak level in nasal and salivary glands, and at much lower level in epididymis.
Interacts (via C-terminus) with ARHGEF5.
Specifically expressed in ameloblasts during maturation stages. Not expressed in pre-ameloblasts, weakly expressed in secretory ameloblasts, and strongly expressed in maturation-stage ameloblasts as well as in the junctional epithelium attached to the enamel of erupted molars.
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.
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 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.
Regulates high density lipoprotein (HDL) cholesterol metabolism by promoting the ubiquitination and degradation of the oxysterols receptors LXR (NR1H2 and NR1H3).
Belongs to the Orn/Lys/Arg decarboxylase class-II family.
Catalyzes the first and rate-limiting step of polyamine biosynthesis that converts ornithine into putrescine, which is the precursor for the polyamines, spermidine and spermine. Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis.
Homodimer. Only the dimer is catalytically active, as the active sites are constructed of residues from both monomers.
Inhibited by antizymes (AZs) OAZ1, OAZ2 and OAZ3 in response to polyamine levels. AZs inhibit the assembly of the functional homodimer by binding to ODC monomers. Additionally, OAZ1 targets ODC monomers for ubiquitin-independent proteolytic destruction by the 26S proteasome.
ADP-ribosylated by PARP16 upon ER stress, which increases kinase activity.
Autophosphorylated. Phosphorylated at Tyr-611 following endoplasmic reticulum stress, leading to activate its tyrosine-protein kinase activity. Dephosphorylated by PTPN1/TP1B, leading to inactivate its enzyme activity (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.
Interacts with DNAJC3 and MFN2 (By similarity). Forms dimers with HSPA5/BIP in resting cells (By similarity). Oligomerizes in ER-stressed cells (PubMed:10854322). Interacts with TMEM33 (By similarity). Interacts with PDIA6 (By similarity). Interacts with LACC1 (By similarity).
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 (By similarity). 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).
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.
Identified in the spliceosome C complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with SEPT6. Interacts with C9orf72. Interacts with KHDRBS1. Interacts with UBQLN2 (By similarity). Interacts with PPIA/CYPA (By similarity).
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. 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. Binds to the IRES and thereby inhibits the translation of the apoptosis protease activating factor APAF1. May bind to specific miRNA hairpins.
A proteinase activates the inhibitor by specific proteolysis in the bait region, which, by an unknown mechanism leads to reaction at the cysteinyl-glutamyl internal thiol ester site and to a conformational change, whereby the proteinase is trapped and/or covalently bound to the inhibitor. While in the tetrameric proteinase inhibitors steric inhibition is sufficiently strong, monomeric forms need a covalent linkage between the activated glutamyl residue of the original thiol ester and a terminal amino group of a lysine or another nucleophilic group on the proteinase, for inhibition to be effective.
Expression level in the liver as well as protein level in plasma down-regulated by up to 70% during acute inflammation or tumor development.
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 (By similarity). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).
Heterodimer of an alpha and a beta subunit. Alpha-1 associates with beta-1 (By similarity). Interacts with RAB21 (By similarity). Interacts (via cytoplasmic domain) with PTPN2; activates PTPN2 phosphatase activity towards EGFR and negatively regulates EGF signaling (By similarity).
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 (By similarity).
The integrin I-domain (insert) is a VWFA domain. Integrins with I-domains do not undergo protease cleavage.
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.
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 (By similarity). 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 (By similarity). Can transport UTP or UDP in exchange for ATP, but the physiological relevance of this process remains to be established (By similarity).
Belongs to the aspartyl/asparaginyl beta-hydroxylase family.
May function as 2-oxoglutarate-dependent dioxygenase.
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.
By phosphorylation. Activated by N-methylethanolamine (PubMed:8185307). Activated by oleic acid-containing phosphatidylcholine vesicles (PubMed:8381041).
Monoubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation.
The cytidylyltransferase may interact with membranes through its amphipathic helix.
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.
Highly expressed in the testis, low expression was detected in brain, kidney, heart and lung.
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 (By similarity).
Interacts with MYOD1 (By similarity). Component of the SLC (SFMBT1-LSD1-CoREST) corepressor complex, which also contains KDM1A/LSD1 and RCOR1/CoREST. Interacts with KDM1A/LSD1 and RCOR1/CoREST. Interacts with MYOD1 (By similarity).
The MBT repeats mediate binding to histones tails; however, in contrast to other MBT repeats, does not bind specific histone lysine modifications. The MBT repeats lack the conserved Asp and aromatic cage at conserved positions (By similarity).
Highest levels found in lung, kidney, whole brain and spinal cord. Expressed in all tissues tested including Sertoli and germ cells (at protein level). Also detected in osteoclasts.
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 (By similarity). 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.
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'. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors (By similarity). Required for RNA splicing, possibly by phosphorylating SRSF1/SF2.
Expressed in embryonic tissues such as brain, spinal cord, heart, lung, liver, gut and limb. Levels are lower in adult tissues.
Phosphorylation at Thr-889 increases kinase activity.
Binds mRNA and regulates the stability of target mRNA.
Can be phosphorylated by DYRK2 (in vitro) (By similarity). Dephosphorylated by calcineurin in a Ca(2+) dependent manner, and probably by PP2A or PP4 serine phosphatases in cAMP- and PKC-mediated pathways.
Homodimer. Interacts with STYX (By similarity).
Interacts with STEAP3 (By similarity). Seems to self-interact.
Involved in calcium binding and microtubule stabilization.
Abundantly expressed in both cardiac and slow skeletal muscle (soleus), with no detectable expression in fast skeletal muscle (vastus lateralis) or non-muscle tissue.
Contractile protein that plays a role in heart development and function (By similarity). 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 (PubMed:15331360). During cardiogenesis plays an early role in cardiac contractility by promoting cardiac myofibril assembly (By similarity).
Myosin is a hexamer of 2 heavy chains and 4 light chains (By similarity). Interacts with MYOC (By similarity).
N-terminus is methylated by METTL11A/NTM1.
Phosphorylated by MYLK3 and MYLK2; promotes cardiac muscle contraction and function (By similarity) (PubMed:17885681). Dephosphorylated by PPP1CB complexed to PPP1R12B (PubMed:16431080). 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).
C-terminus is a mobile self-inhibitory loop which interferes directly with active site.
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 (PubMed:8407861). Contributes significantly to heme formation during erythropoiesis (By similarity).
Implicated in oncotic cell death, characterized by cell swelling, organelle swelling, vacuolization and increased membrane permeability.
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 (By similarity).
Expressed in cardiomyocytes and neurons (at protein level). Expressed during early neural development.
Monomer. 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. Interacts with BCL2. 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. 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 with MYO1C. Interacts with ITGA2B (via C-terminal cytoplasmic tail region). Interacts (via C-terminal region) with PPP3R1; the interaction increases upon cardiomyocytes hypertrophy. Interacts with CACNA1C; the interaction increases upon cardiomyocytes hypertrophy (By similarity). Interacts with TAS1R2 (via C-terminus); this interaction is independent of the myristoylation state of CIB1. Interacts and forms a complex with TMC6 and TMC8 (By similarity).
The EF-hands may also bind magnesium ions in the presence of high Mg(2+) levels and low Ca(2+) levels.
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).
Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90.
Self-associates. Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1.
Binds to the retinoblastoma protein (RB). Interacts with GATA3 (By similarity).
S-adenosyl-L-methionine-dependent histone methyltransferase that specifically methylates 'Lys-9' of histone H3. May function as a DNA-binding transcription factor. Binds to the macrophage-specific TPA-responsive element (MTE) of the HMOX1 (heme oxygenase 1) gene and may act as a transcriptional activator of this gene (By similarity).
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 (By similarity).
Interacts with RII subunit of PKA, phosphatase 2B (calcineurin) and AKAP79. Interacts with SYNPO2.
Detected in liver and in brain (at protein level). Detected in liver, spleen, lung, brain, hypothalamus, cerebellum, pituitary, heart and skeletal muscle.
May contribute to the regulation of cell proliferation.
The rat protein was reported to play a role in DNA repair (PubMed:9406864), based on its ability to complement E.coli deficient in the DNA repair enzyme mutT that hydrolyzes oxidized guanine nucleotides. PubMed:17569023 found no such activity, neither for the human nor the rat protein.
This protein is coded from a FGF2 (BFGF) gene antisense transcript.
In the C-terminal section; belongs to the GART family.
In the N-terminal section; belongs to the GARS family.
In the central section; belongs to the AIR synthase family.
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. Modulates transcription regulation mediated by ESR1. Involved in mitochondrial depolarization and neurite outgrowth (By similarity).
By nerve growth factor. At lower levels by epidermal growth factor and membrane depolarization. At much lower levels by fibroblast growth factor and interleukin 6.
In brain at embryonic day 13.5, placenta, amnion, and spleen, which are proliferating and/or differentiating.
Interacts with PRKCABP. 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.
Detected at synapses in the stratum lucidum in the hippocampus CA3 region (at protein level).
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. 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. Not required for outer dynein arm complexes assembly.
Interacts (via extracellular domain) with FLRT2 and FLRT3 (via extracellular domain); the interaction is direct. Has higher affinity for FLRT2 (PubMed:25374360). Identified in a complex with FLRT3 and ADGRL3; does not interact with ADGRL3 by itself (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 (By similarity).
Receptor for the netrin NTN4 that promotes neuronal cell survival. Plays a role in cell-cell adhesion and cell guidance. Receptor for netrin involved in cell migration. Plays a role in axon guidance by mediating axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. May play a role in apoptosis in response to DNA damage. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (By similarity). Mediates cell-cell adhesion via its interaction with FLRT3 on an adjacent cell (By similarity).
Contains one covalently linked retinal chromophore. Upon light absorption, the covalently bound 11-cis-retinal is converted to all-trans-retinal. After hydrolysis of the Schiff base and release of the covalently bound all-trans-retinal, active rhodopsin is regenerated by binding of a fresh molecule of 11-cis-retinal.
Homodimer. May form a complex composed of RHO, GRK1 and RCVRN in a Ca(2+)-dependent manner; RCVRN prevents the interaction between GRK1 and RHO (By similarity). Interacts with GRK1 (By similarity). Interacts (phosphorylated form) with SAG (By similarity). Interacts with GNAT1 (By similarity). Interacts with GNAT3. SAG and G-proteins compete for a common binding site (By similarity). Interacts with PRCD; the interaction promotes PRCD stability (By similarity).
Photoreceptor required for image-forming vision at low light intensity. Required for photoreceptor cell viability after birth (By similarity). Light-induced isomerization of 11-cis to all-trans retinal triggers a conformational change that activates signaling via G-proteins. Subsequent receptor phosphorylation mediates displacement of the bound G-protein alpha subunit by the arrestin SAG and terminates signaling (By similarity).
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 (By similarity).
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 (By similarity).
Heterodimer with AMPH (PubMed:9348539, PubMed:9341169). Binds SH3GLB1 (By similarity). Interacts (via SH3 domain) with DNM1 (PubMed:9736607, PubMed:9341169). Interacts with SYNJ1 (PubMed:9341169). Interacts (via SH3 domain) with DNM2 (By similarity). Interacts with CLTC (By similarity). Interacts with AP2A2 (PubMed:10430869, PubMed:10380931). Interacts with AP2B1 (PubMed:16516836). Interacts with MYC (via N-terminal transactivation domain); the interaction requires the integrity of the conserved MYC box regions 1 and 2 (By similarity). Interacts with BIN2 (By similarity). Interacts with SNX4 (By similarity). Interacts (via BAR domain) with BACE1 (By similarity). Binds (via BAR domain) F-actin (By similarity).
Highly expressed in the brain and muscle. Isoform AMPH2-1 is expressed only in the brain where it is concentrated in axon initial segments and nodes of Ranvier. Isoform AMPH2-2 is widely expressed.
Is a key player in the control of plasma membrane curvature, and membrane shaping and remodeling. Required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling. Required in muscle cells for the formation of T-tubules, tubular invaginations of the plasma membrane that function in depolarization-contraction coupling (By similarity). Is a negative regulator of endocytosis (PubMed:9736607, PubMed:27760323). Is also involved in the regulation of intracellular vesicles sorting, modulation of BACE1 trafficking and the control of amyloid-beta production (By similarity). In neuronal circuits, endocytosis regulation may influence the internalization of PHF-tau aggregates (PubMed:27760323). May be involved in the regulation of MYC activity and the control cell proliferation (By similarity).
Belongs to the protein phosphatase inhibitor 2 family.
Phosphorylation on Ser-44 by ATM activates PP1 by dissociating the PP1-PPP1R2 complex. Phosphorylation on Thr-73 by GSK3 activates PP1 by dissociating the PP1-PPP1R2 complex.
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).
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 (By similarity).
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). Interacts with the CCAAT displacement protein (CDP2) to bind the tyrosine hydroxylase enhancer.
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.
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 (By similarity).
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (By similarity). Interacts with FADD, CFLAR and PEA15 (By similarity). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (By similarity). Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2 (By similarity). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15383280). Interacts with UBR2 (By similarity). Interacts with RIPK1 (By similarity). Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
Phosphorylation on Ser-389 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 (By similarity).
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:10197541). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (By similarity). Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A (PubMed:10197541). The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (By similarity). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (By similarity). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (By similarity). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (By similarity). 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 (By similarity). Cleaves PARP1 and PARP2 (By similarity).
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 (By similarity).
The TBM domain mediates interaction with TERF1.
The TID (telomerase inhibiting domain) domain is sufficient to bind TERT and inhibits its activity.
Required for the activation of AURKA at the onset of mitosis.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE8 subfamily.
Acts in combination with TSN as an endonuclease involved in the activation of the RNA-induced silencing complex (RISC). Possible role in spermatogenesis (By similarity).
Ring-shaped heterooctamer of six TSN and two TSNAX subunits. Interacts with GOLGA3, TSNAXIP1, SUN1 and AKAP9. Interacts with the homodimeric form of C1D following gamma-radiation. Interacts with TSN and C1D in a mutually exclusive manner (By similarity).
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 (By similarity).
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Detected in spermatozoa (at protein level). Predominantly expressed in testis and in spermatozoa from the caput and corpus epididymis.
Increased after 3 weeks of postnatal development.
Belongs to the ABC transporter superfamily. ABCB family. Heavy Metal importer (TC 3.A.1.210) subfamily.
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 (By similarity). 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 (By similarity). In cardiomyocytes, regulates cellular iron homeostasis and cellular reactive oxygen species (ROS) levels through its interaction with COX4I1 (PubMed:31511561). May also play a role in hematopoiesis (By similarity).
Homodimer or heterodimer. Interacts with C10orf88/PAAT. 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 (By similarity). Interacts with FECH (By similarity). Interacts with ATP5F1A (PubMed:31511561). Interacts with COX4I1; this interaction allows the regulation of cellular iron homeostasis and cellular reactive oxygen species (ROS) levels in cardiomyocytes (PubMed:31511561).
Abundant in brain, especially in the olfactory bulb, hippocampus, and cerebellum. A moderate expression is seen in the lung, kidney and adrenal gland.
Belongs to the chloride channel (TC 2.A.49) family. ClC-3/CLCN3 subfamily.
Monomer and homodimer (By similarity). Forms heterodimers with CLCN4 (By similarity).
Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:10915634). May play an important role in neuronal cell function through regulation of membrane excitability by protein kinase C (PubMed:8155321). It could help neuronal cells to establish short-term memory (PubMed:8155321).
Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:10915634). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (By similarity). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity).
Probable palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates.
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 (By similarity). Interacts with PLXNB3 (PubMed:20696765). Forms a heterodimer with RAC1 (PubMed:20696765). Interacts with RHOA, the affinity is increased by three orders of magnitude when RHOA is prenylated (By similarity). Interacts with PSMD10; the interaction increases ARHGDIA association with RHOA, leading to ARHGDIA-mediated inactivation of RHOA and ROCK and prolonged AKT activation (By similarity). Interacts with KANK2; the interaction is direct and may regulate the interaction of ARHGDIA with RHOA, RAC1 and CDC42 (PubMed:25961457). Interacts with RHOC (By similarity). Interacts with CDC42 (By similarity). Interacts with NGFR (via death domain); NGFR binding decreases the affinity for RHOA (By similarity).
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 (By similarity). Catalyzes mainly the conversion of phosphatidylcholine but also converts, in vitro and to a lesser extent, phosphatidylethanolamine (By similarity).
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.
Belongs to the eukaryotic/archaeal PrmC-related family.
Activated by proteolytic processing. In vitro activation is commonly achieved by cleavage with dispase, a neutral bacterial protease. Physiological activation may be catalyzed by CTSL and, to a lesser extent, by CTSS (By similarity).
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 and LOR cross-linking to form small interchain oligomers, which are further cross-linked by TGM1 onto the growing CE scaffold. In hair follicles, involved in cross-linking structural proteins to hardening the inner root sheath (By similarity).
Consists of two polypeptide chains, which are synthesized as a precursor form of a single polypeptide.
Mediates sulfate transport with high affinity. Mediates oxalate transport. Mediates bicarbonate transport. Does not accept succinate as cosubstrate.
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 (By similarity). 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 (By similarity). Promotes the recycling of internalized transferrin receptor (TFRC) to the plasma membrane through interaction with endosome-associated recycling protein (EARP) complex (By similarity). Controls proper insulin distribution and secretion, and retention of cargo in mature dense core vesicles (PubMed:3172165). Required for the stability of the endosome-associated retrograde protein (EARP) complex subunits and for proper localization and association of EARP with membranes (PubMed:3172165).
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 (PubMed:27440922, PubMed:27191843). Interacts with SNAP29 (PubMed:27191843).
Ubiquitous. Highly expressed in brain, adipose tissue, spleen and kidney (at protein level).
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.
Expressed in the brain (PubMed:9341169). Expressed at low level in the kidney.
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 (By similarity).
Monomer; in cytoplasm. Homodimer; when associated with membranes (By similarity). Interacts with OPHN1 (By similarity). Interacts with SYNJ1 (PubMed:9341169, PubMed:9238017, PubMed:11384986). Interacts with DNM1 (PubMed:9238017, PubMed:11384986). Interacts with MAP4K3; the interaction appears to regulate MAP4K3-mediated JNK activation (PubMed:11384986). Interacts with PDCD6IP (By similarity). Interacts with ATXN2 (By similarity). Interacts with ADAM9 and ADAM15 cytoplasmic tails (By similarity). Interacts with BIN2 (By similarity). Interacts with TMEM108 (By similarity). Interacts with ADGRB2 (By similarity).
The N-BAR domain binds liposomes and mediates dimerization of BAR domains upon liposome binding. It induces formation of tubules from liposomes as well as fusion of liposome tubules. Cells overexpressing Sh3gl2 show no effect on transferrin uptake.
Receptor with an affinity for galactose and fucose. Could be involved in endocytosis.
Belongs to the potassium channel KCNN family. KCa2.1/KCNN1 subfamily.
Forms a voltage-independent potassium channel activated by intracellular calcium (PubMed:8781233). 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:8781233). Inhibited by d-tubocurarine and tetraethylammonium (TEA) (By similarity).
Has high L-gulonate 3-dehydrogenase activity. It also exhibits low dehydrogenase activity toward L-3-hydroxybutyrate (HBA) and L-threonate.
Exhibits lysophospholipase, transacylase, PAF acetylhydrolase and asparaginase activities (PubMed:9575212, PubMed:8119970, PubMed:10320809). 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) (PubMed:10320809). 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 (PubMed:10320809).
Expressed at high levels in liver and kidney and at a low level in stomach. Barely detectable in lung, heart, spleen and brain.
In the N-terminal section; belongs to the asparaginase 1 family.
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 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. Prefers (3R)-3-hydroxyacyl-CoA over (3S)-3-hydroxyacyl-CoA and displays enzymatic activity only in the presence of NAD(+). 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. 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.
Binds 1 divalent metal cation per subunit; can use either Mg(2+) or Mn(2+).
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.
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.
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 (PubMed:2140361). 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 (PubMed:10893223). Interacts with BICD2 (By similarity). Interacts with DNALI1 (By similarity).
Transcriptional repressor that contribute to growth arrest during terminal macrophage differentiation by repressing target genes involved in Ras-dependent proliferation. Represses MMP1 promoter activity.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6; in the complex, is required for optimal binding of ELP3 to ELP4.
Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (By similarity). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (By similarity). Involved in cell migration (By similarity).
It is uncertain whether Met-1 or Met-19 is the initiator.
Abundantly expressed in developing embryos, especially in mesenchymal condensations of limbs, vertebral perichondrium and mesenchymal cells of the intervertebral disks.
Expressed specifically in the musculoskeletal system (skeletal muscle and tendon). Highly expressed during bone regeneration, especially during the early phases (post fracure days 3 and 5). Expression within the fracture callus is localized in osteoprogenitor cells of the periosteum, proliferating chondrocytes, and young active osteoblasts.
May be involved in the development and regeneration of the musculoskeletal system.
Detected between 15 dpc and 20 dpc, between P0 and P10, and in adult in different regions of the telencephalon and diencephalon.
In adult brains expressed in the hippocampus, cerebral cortex, and olfactory bulb but not in the cerebellum. In embryo expressed in cerebral cortex.
Interacts with ROBO1 (By similarity) and GREM1.
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 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 (By similarity).
Cleaved by CASP3 during apoptosis, yielding a pro-apoptotic C-terminal fragment.
Detected in neonate ovaries and expressed at constant levels in 3 to 6 day old animals. Levels are increased in at day 12 and thereafter.
Interacts with HIF3A (via C-terminus domain) (By similarity). Interacts with BOK, BIK, BAX, BAK1, and TPT1. Interacts with unphosphorylated BAD (PubMed:10579309). Interacts with BMF, BBC3 and PMAIP1 (By similarity). Interacts with BOP (By similarity). Interacts with BCL2L11; may sequester BCL2L11 to prevent its pro-apoptotic activity (By similarity) (PubMed:10579309). Interacts with GIMAP5 and HSPA8/HSC70; the interaction between HSPA8 and MCL1 is impaired in the absence of GIMAP5 (By similarity).
Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis.
Phosphorylated on Ser-139, by GSK3, in response to IL3/interleukin-3 withdrawal. Phosphorylation at Ser-139 induces ubiquitination and proteasomal degradation, abrogating the anti-apoptotic activity. Treatment with taxol or okadaic acid induces phosphorylation on additional sites (By similarity).
Rapidly degraded in the absence of phosphorylation in the PEST region.
Ubiquitinated. Ubiquitination is induced by phosphorylation at Ser-139 (By similarity).
Ubiquitous. Highly expressed in heart, spleen, lung, liver, skeletal muscle and kidney. Detected at lower levels in brain, ovary, oviduct and testis.
Interacts with PGRMC1 (By similarity). Interacts with AAAS (By similarity).
Required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan. May serve as a universal non-classical progesterone receptor in the uterus. Intracellular heme chaperone required for delivery of labile, or signaling heme, to the nucleus. Plays a role in adipocyte function and systemic glucose homeostasis. In brown fat, which has a high demand for heme, delivery of labile heme in the nucleus regulates the activity of heme-responsive transcriptional repressors such as NR1D1 and BACH1.
The cytochrome b5 heme-binding domain lacks the conserved iron-binding His residues at positions 131 and 155.
Down-regulated in puromycin aminonucleoside nephrosis (PAN).
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 (By similarity).
Homodimer. Interacts with CLEC1B; the interaction is independent of CLEC1B glycosylation and activates CLEC1B; the interaction is dependent of sialic acid on O-glycans. Interacts with CD9; this interaction is homophilic and attenuates platelet aggregation and pulmonary metastasis induced by PDPN. Interacts with LGALS8; the interaction is glycosylation-dependent; may participate in connection of the lymphatic endothelium to the surrounding extracellular matrix. Interacts with HSPA9. 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. Interacts (via cytoplasmic domain) with MSN and EZR; activates RHOA and promotes epithelial-mesenchymal transition. Interacts with CCL21; relocalized PDPN to the basolateral membrane.
In adult kidney, expressed on the urinary surface and foot processes of podocytes and in parietal epithelial cells of Bowman's capsule where it is localized to luminal surfaces. In lung, expressed exclusively on luminal surfaces of type I alveolar epithelial cells and pleural mesothelial cells. Not expressed in type II alveolar cells. In bone, expressed in osteocytes and osteoblasts. In spleen, liver, stomach and intestine, expressed in mesoepithelium. Also expressed in thymic epithelial cells, choroid plexus and leptomeninges.
In newborn kidney, not detected at the vesicle stage. First detected in S-shaped bodies.
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. Interaction with CD9, on the contrary, attenuates platelet aggregation and pulmonary metastasis induced by PDPN. Mediates effects on cell migration and adhesion through its different partners. 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. Interaction with CD44 promotes directional cell migration in epithelial and tumor cells (By similarity). 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. 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. 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 (By similarity). 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 (By similarity). 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 (By similarity).
Only expressed in the pituitary, adrenal gland, stomach and in the upper gastrointestinal tract.
Putative sodium-dependent amino acid/proton antiporter.
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 (By similarity). Interacts with protein of the S100 family S100A1, S100A6, S100B, S100P and S100A12 in a calcium-dependent manner.
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) (By similarity).
Phosphorylated on serine residues. Phosphorylated upon induction by RA or at high calcium concentrations (By similarity).
Belongs to the eukaryotic ribosomal protein eS17 family.
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics (PubMed:8198567, PubMed:7705364). Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol (By similarity). 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. 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 (By similarity).
Binds to actin and to fibronectin. Identified in a complex composed of ACTA1, COBL, GSN and TMSB4X (By similarity). 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 (By similarity). Plays a role in ciliogenesis (By similarity).
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. Binding calcium may release the connections that join the N- and C-terminal halves of gelsolin, enabling each half to bind actin relatively independently. G1 and G4 bind two Ca(2+) in a type I and in a type II manner. G2, G3, G5 and G6 bind only one Ca(2+) in a type II manner. Type I Ca(2+) binding sites are shared between actin and gelsolin-like repeats G1 and G4. Type I binding governs the strength of interactions between gelsolin and actin by direct participation at the binding interface. 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. Binding to phosphoinositides may inhibit the severing and capping properties of gelsolin.
Phosphorylated on tyrosine residues in vitro.
May play a role in placental development.
Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, RBL2, 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 (By similarity).
Component of the DREAM complex, a multiprotein complex that can both act as a transcription activator or repressor depending on the context. In G0 phase, the complex binds to more than 800 promoters and is required for repression of E2F target genes. 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. In the complex, acts as a DNA-binding protein that binds the promoter of CDK1 in a sequence-specific manner. Specifically recognizes the consensus motif 5'-TTYRAA-3' in target DNA.
The CRC domain mediates DNA-binding. It contains two CXC subdomains (joined by a flexible linker) which are both required for efficient association with target DNA. Each CXC subdomain coordinates three Zn(2+) ions.
Spleen, lung, skeletal muscle, and testis.
Deamidation and transpeptidation at the beta carboxyl of Asn-105 forms an isoaspartyl residue found in an isoform of the DE-III fraction. This rearrangement gives rise to an extra negative charge carried by the acid form.
Plays a role in lipoprotein-mediated cholesterol uptake in hepatocytes (By similarity). 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).
There are three fractions of Z-protein: DE-I, DE-II and DE-III. DE-I is virtually lipid free, DE-II binds palmitic, stearic, oleic, linoleic and arachidonic acids and DE-III binds mainly arachidonic acid.
Belongs to the Mediator complex subunit 19 family.
Highly expressed in pancreatic islets and parotid. High to moderate expression in adrenal gland, pituitary gland and ovary.
Rab GTPase effector involved in the late steps of regulated exocytosis, both in endocrine and exocrine cells. Regulates the exocytosis of dense-core vesicles in neuroendocrine cells through interaction with RAB27A. 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.
The N-terminus of the RabBD domain is necessary and sufficient for interaction with RAB27A.
Part of BBSome complex, that contains BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10.
The BBSome complex is thought to function as a coat complex required for sorting of specific membrane proteins to the primary cilia. The BBSome complex is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Firstly the BBSome associates with the ciliary membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and promotes docking and fusion of carrier vesicles to the base of the ciliary membrane. The BBSome complex, together with the LTZL1, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Required for BBSome complex ciliary localization but not for the proper complex assembly.
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. Interacts with DDX11.
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).
Interacts with BRD7 and INVS. Interacts (via PDZ domain) with the VANGL1 and VANGL2 (via C-terminus). Interacts (via PDZ domain) with NXN. Interacts with CXXC4. Interacts with ARRB1; the interaction is enhanced by phosphorylation of DVL1. Interacts with CYLD. 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. 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. Interacts (via PDZ domain) with TMEM88 (By similarity). Interacts with DCDC2. Interacts with FOXK2 (By similarity). Interacts with PKD1 (via extracellular domain) (By similarity). 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 (By similarity).
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) (By similarity).
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).
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.
Heterodimer composed of LIFR and IL6ST. The heterodimer formed by LIFR and IL6ST interacts with the complex formed by CNTF and CNTFR (By similarity).
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 (By similarity).
DNA-binding protein that accumulates at DNA double-strand breaks (DSBs) following DNA damage and promotes DNA resection and homologous recombination. 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. Inhibits non-homologous end joining (NHEJ). Required for the dynamic movement of AURKA at the centrosomes and spindle apparatus during the cell cycle.
Interacts (via C-terminus) with AURKA (via C-terminus). Interacts (via N-terminus) with NIN; this interaction blocks NIN phosphorylation by both AURKA and GSK3B. Identified in a complex with NIN and AURKA. Interacts with RBBP8/CtIP.
Acts as a RAC1 guanine nucleotide exchange factor (GEF).
Interacts with PAK kinases through the SH3 domain. Interacts with GIT1. Interacts with PARVB. Component of cytoplasmic complexes, which also contain PXN, GIT1 and PAK1. Interacts with BIN2. Identified in a complex with BIN2 and GIT2 (By similarity).
Phosphorylated by TBK1, leading to restrict bacterial proliferation in case of infection.
Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8. Links myosin VI to the Golgi complex and plays an important role in Golgi ribbon formation. Negatively regulates the induction of IFNB in response to RNA virus infection. Plays a neuroprotective role in the eye and optic nerve. Probably part of the TNF-alpha signaling pathway that can shift the equilibrium toward induction of cell death. 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. 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) and appears to function in the same pathway as SQSTM1 and CALCOCO2/NDP52.
Self-associates (By similarity). Interacts with HD, GTF3A, TRAF3, TBK1 and MYO6. Interacts (via UBAN) with ubiquitinated TFRC. Interacts with active GTP-bound Rab8 (RAB8A and/or RAB8B). Interacts with TBC1D17. Binds to linear ubiquitin chains. 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 (By similarity). Interacts with palmitoyltransferase ZDHHC17/HIP14; the interaction does not lead to palmitoylation of OPTN (By similarity). Interacts with CYLD (By similarity). Interacts with TOM1; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and OPTN (By similarity).
The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins.
Ubiquitin-binding motif (UBAN) is essential for its inhibitory function, subcellular localization and interaction with TBK1.
Binds fibroblast growth factor and E-selectin (cell-adhesion lectin on endothelial cells mediating the binding of neutrophils).
Fucosylation is essential for binding to E-selectin.
N-glycosylated. Contains sialic acid residues.
Widely expressed; found in kidney, pancreatic islets, parathyroid, thyroid, adrenal tissue, brain neurons, astrocytes, adenohypophysis, cultured pheochromocytoma cells.
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 (By similarity).
The 329-DSEL-332 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 (By similarity). Thr-351 is a major site for PKC-induced internalization of the receptor (By similarity).
Belongs to the TRAFAC class dynamin-like GTPase superfamily. Very large inducible GTPase (VLIG) family.
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 (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK1 subfamily.
Expressed in subsets of neurons throughout the developing and adult central and peripheral nervous systems. In the CNS principally in the medial amygdaloid nuclei, medial habenulae, pyriform and cingulate cortices, and Purkinje cell layer. Also highly expressed in embryonic and adult dorsal root ganglia.
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.
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.
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.
(Microbial infection) Copurifies with C.botulinum neurotoxin type B (BoNT/B, botB) and synaptotagmin 1 (SYT1) (PubMed:19476346). Interaction does not require glycosylation of SV2 or SYT1 proteins (PubMed:19476346). Another group finds only copurification with SYT1 and SYT2 (PubMed:19650874).
(Microbial infection) Copurifies with C.botulinum neurotoxin type F (BoNT/F) and synaptotagmin 1 (SYT2) (PubMed:19476346). Another group finds only copurification with BoNT/F (PubMed:19650874). Interaction requires SV2 glycosylation (PubMed:19476346).
(Microbial infection) Interacts with C.botulinum neurotoxin type A1 and type A2 (BoNT/A, botA) (PubMed:16543415, PubMed:19650874, PubMed:21632541, PubMed:21483489, PubMed:29649119). Interaction is improved by glycosylation of SV2 (PubMed:29649119).
(Microbial infection) Interacts with C.botulinum neurotoxin type E (BoNT/E) (PubMed:18815274, PubMed:19476346, PubMed:19650874). Interaction requires glycosylation of SV2 proteins (PubMed:18815274, PubMed:19476346, PubMed:19650874).
(Microbial infection) Receptor for C.botulinum neurotoxin type A (BoNT/A, botA); the toxin binds via extracellular loop 4 (PubMed:16543415). Restores uptake of BoNT/A in mouse cells that are deleted for SV2 receptor (PubMed:16543415, PubMed:18815274). Glycosylation of Asn-573 is not essential for receptor activity, but enhances uptake (PubMed:18815274, PubMed:19650874). Also serves as a receptor for the closely related C.botulinum neurotoxin type A2; glycosylation is not essential but enhances the interaction (PubMed:29649119).
(Microbial infection) Receptor for C.botulinum neurotoxin type E (BoNT/E); the toxin probably binds via extracellular loop 4 and requires glycosylation of Asn-573 (PubMed:18815274, PubMed:19650874). Restores uptake of BoNT/E in mouse cells that are deleted for SV2 receptor (PubMed:18815274).
(Microbial infection) Receptor for C.botulinum neurotoxin type F (BoNT/F) (PubMed:19476346, PubMed:19650874). Binding requires glycosylation of Asn-573 (PubMed:19476346).
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.
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.
Possible receptor for C.botulinum neurotoxin type D (BoNT/D, botD); BoNT/D does not bind to extracellular loop 4 as do BoNT/A and BoNT/E, nor to loop 1 or loop 3 (PubMed:21483489). Another group does not find a convincing interaction with SV2 (PubMed:21632541).
Short hairpin-mediated RNA knockdown of the protein in PC12 cells leads to increased resistance to C.botulinum neurotoxin type A (BoNT/A, botA) as assayed by reduced SNAP25 cleavage; uptake and degradation are restored by expression of SV2B or SV2C (PubMed:16543415).
The use of this protein as a coreceptor for C.botulinum type D (BoNT/D, botD) is controversial. In double SV2A/SV2B knockout mice BoNT/D does not degrade its synaptobrevin target; introducing SV2A, SV2B or SV2C restores target cleavage (PubMed:21483489). However another group does not find a convincing interaction with SV2 (PubMed:21632541).
Widely expressed throughout the brain (at protein level). Expressed by neural and endocrine cells of brain and spinal cord.
Two types of rat hepatic lectin have been identified, RHL-1 and RHL-2/3, having a relative abundance of 4:1. RHL-2 and RHL-3 only differs in their carbohydrate structures.
Milk-specific; major protein component of milk whey.
May function as a negative regulator of endoplasmic reticulum-stress induced autophagy.
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.
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.
Autopalmitoylated (By similarity). Palmitoylation of the C-terminal tail regulates stimulation-dependent plasma membrane motility (PubMed:31547976).
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:31547976). 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. Neuronal activity enhances the internalization and trafficking of DHHC5 from spines to dendritic shafts where it palmitoylates delta-catenin/CTNND2. Regulates cell adhesion at the plasma membrane by palmitoylating GOLGA7B and DSG2. 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. 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.
Phosphorylation regulates association with endocytic proteins and its subcellular localization. Phosphorylation by LYN during fatty acid uptake leads to inactivation of the activity.
Required for the mitochondrial tubular network and cristae organization. Involved in apoptotic release of cytochrome c (By similarity).
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 (By similarity).
Heterodimer; heterodimer formation between the 8 kDa and the 50 kDa subunits is required for enzyme activity (By similarity). 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 (By similarity).
Inhibited by laminarin sulfate and, to a lower extent, by heparin and sulfamin (By similarity). Activated by calcium and magnesium. Inhibited by EDTA.
N-glycosylated. Glycosylation of the 50 kDa subunit appears to be essential for its solubility (By similarity).
Proteolytically processed. The cleavage of the 65 kDa form leads to the generation of a linker peptide, and the 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 (By similarity).
Component of the PEX2-PEX10-PEX12 retrotranslocation channel, composed of PEX2, PEX10 and PEX12.
E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:1750930). 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. PEX2 also regulates peroxisome organization by acting as a E3 ubiquitin-protein ligase. 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. 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 (By similarity).
Forms intramolecular and intermolecular disulfide bonds in response to reactive oxygen species (ROS), promoting higher stability.
The three subunits of the retrotranslocation channel (PEX2, PEX10 and PEX12) coassemble in the membrane into a channel with an open 10 Angstrom pore. The RING-type zinc-fingers that catalyze PEX5 receptor ubiquitination are positioned above the pore on the cytosolic side of the complex.
Catalytic activity is higher with Mg(2+) (By similarity). According to PubMed:7998949 the cofactor is Mn(2+), while Mg(2+) is much less effective.
Catalyzes the biosynthesis of phosphatidylinositol (PtdIns) as well as PtdIns:inositol exchange reaction. May thus act to reduce an excessive cellular PtdIns content. The exchange activity is due to the reverse reaction of PtdIns synthase and is dependent on CMP, which is tightly bound to the enzyme.
Detected in liver (at protein level). Widely expressed. Highly expressed in the brain and kidney; lower levels in heart, spleen, lung, liver, skeletal muscle and testis.
Inhibited by PtdIns (product inhibition).
Expressed in muscle, heart, liver, kidney, lung, brain, spleen, but not in testis.
Receptor for extracellular adenine nucleotides such as ADP (PubMed:7779087). 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 (By similarity).
Belongs to the ELO family. ELOVL2 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 polyunsaturated very long chain fatty acid (C20- and C22-PUFA), acting specifically toward polyunsaturated acyl-CoA with the higher activity toward C20:4(n-6) acyl-CoA. May participate in the production of polyunsaturated 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.
Required for the assembly of axonemal inner and outer dynein arms. Involved in preassembly of dyneins into complexes before their transport into cilia (By similarity).
Required for the assembly of axonemal inner and outer dynein arms. Involved in preassembly of dyneins into complexes before their transport into cilia.
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.
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.
Belongs to the phospholipid scramblase family.
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:29171872). Plays an important role in mitochondrial respiratory function, morphology, and apoptotic response (By similarity). Mediates the translocation of cardiolipin from the mitochondrial inner membrane to outer membrane enhancing t-Bid induced cytochrome c release and apoptosis (By similarity). 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 (By similarity). Regulates cardiolipin de novo biosynthesis and its resynthesis (By similarity).
Monomer (By similarity). Forms homooligomers upon binding to Ca(2+), Pb(2+) and Hg(2+) ions (By similarity). Interacts with PDCD6 in a calcium-dependent manner (By similarity). Interacts with PRKCD; interaction is enhanced by UV irradiation (By similarity).
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.
The Proline-rich domain is required for phospholipid scramblase activity.
Co-chaperone that binds to numerous kinases and promotes their interaction with the Hsp90 complex, resulting in stabilization and promotion of their activity. Inhibits HSP90AA1 ATPase activity.
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (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 (By similarity). Forms a complex with Hsp90/HSP90AB1 and CDK6 (By similarity). Interacts with HSP90AA1 (By similarity). Interacts with AR, CDK4, CDK6 and EIF2AK1 (By similarity). Interacts with RB1 (PubMed:8945638). Interacts with KSR1 (By similarity). Interacts with FLCN, FNIP1 and FNIP2 (By similarity).
Belongs to the protein-tyrosine phosphatase family. Receptor class 7 subfamily.
By nerve growth factor; isoform 2 is induced in adrenal tumor cells 2 hours after exposure, levels are down-regulated 24 hours after treatment.
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).
Widely expressed in the brain, most abundant in cerebellum, midbrain, cerebral cortex and hippocampus. Also expressed in heart and skeletal muscle.
Belongs to the eukaryotic ribosomal protein eL34 family.
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. MAEA is required for normal cell proliferation. The CTLH E3 ubiquitin-protein ligase complex is not required for the degradation of enzymes involved in gluconeogenesis, such as FBP1 (By similarity). 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 (By similarity). 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 (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. 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. Interacts with F-actin.
The expected RING-type zinc finger domain is highly divergent and most of the expected Cys residues are not conserved. Still, the protein is required for CTLH complex E3 ubiquitin-protein transferase activity. 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.
O-glycosylated. Probably sulfated on the O-glycans.
Promotes osteogenesis by stimulating the differentiation of mesenchymal progenitors into mature osteoblasts. Important for repair and maintenance of adult bone.
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. Brain. Present in a few pyramidal neurons and mostly in mossy fibers. Colocalizes with PJA2 in dentate granule cells and at postsynaptic sites of primary hippocampal neurons.
Phosphorylated by the activated catalytic chain.
Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
The inactive form of the enzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP produces two active catalytic monomers and a regulatory dimer that binds four cAMP molecules. Interacts with PRKACA and PRKACB. 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.
Homodimer (By similarity). Heterodimer; with NR2C2 which is required for chromatin remodeling and for binding to promoter regions such as globin DR1 repeats (By similarity). Interacts with ESR1; the interaction prevents homodimerization of ESR1 and suppresses its transcriptional activity and cell growth. Interacts with NRIP1 (via its LXXLL motifs); the interaction provides corepressor activity. Interacts with HDAC3 (via the DNA-binding domain); the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation. 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).
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 including ESR1 and RARB. Together with NR2C2, forms the core of the DRED (direct repeat erythroid-definitive) complex that represses embryonic and fetal globin transcription. Binds to hormone response elements (HREs) consisting of two 5'-AGGTCA-3' half site direct repeat consensus sequences. Also activator of OCT4 gene expression. Plays a fundamental role in early embryogenesis and regulates embryonic stem cell proliferation and differentiation. Mediator of retinoic acid-regulated preadipocyte proliferation (By similarity).
Phosphorylated on several serine and threonine residues. Phosphorylation on Thr-210, 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-568 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).
ADP-ribosyltransferase activity is regulated via an allosteric activation mechanism. In absence of activation signal, PARP1 is autoinhibited by the PARP alpha-helical domain (also named HD region), which prevents effective NAD(+)-binding. Activity is highly stimulated by signals, such as DNA strand breaks. Binding to damaged DNA unfolds the PARP alpha-helical domain, relieving autoinhibition. 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. A number of factors (VCP/p97) or post-translational modifications (auto-poly-ADP-ribosylation or ubiquitination) promote PARP1 removal from chromatin.
Homodimer; PARP-type zinc-fingers from separate PARP1 molecules form a dimer module that specifically recognizes DNA strand breaks (By similarity). Heterodimer; heterodimerizes with PARP2 (By similarity). Interacts (via the PARP catalytic domain) with HPF1 (By similarity). Interacts with NMNAT1 (By similarity). Interacts with nucleosomes; with a preference for nucleosomes containing H2A.X. Interacts with APTX (By similarity). Component of a base excision repair (BER) complex, containing at least XRCC1, PARP1, PARP2, POLB and LRIG3 (By similarity). Interacts with SRY (By similarity). The SWAP complex consists of NPM1, NCL, PARP1 and SWAP70. Interacts with TIAM2 (By similarity). Interacts with PARP3; leading to activate PARP1 in absence of DNA. Interacts (when poly-ADP-ribosylated) with CHD1L (via macro domain). Interacts with the DNA polymerase alpha catalytic subunit POLA1; this interaction functions as part of the control of replication fork progression. Interacts with EEF1A1 and TXK (By similarity). Interacts with RNF4 (By similarity). Interacts with RNF146 (By similarity). Interacts with ZNF423 (By similarity). Interacts with APLF (By similarity). Interacts with SNAI1 (via zinc fingers); the interaction requires SNAI1 to be poly-ADP-ribosylated and non-phosphorylated (active) by GSK3B (By similarity). Interacts (when poly-ADP-ribosylated) with PARP9 (By similarity). Interacts with NR4A3; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (PubMed:25625556). 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. Interacts with ZNF365. Interacts with RRP1B. Interacts with TIMELESS; the interaction is direct. Interacts with CGAS; leading to impede the formation of the PARP1-TIMELESS complex. Interacts with KHDC3L, the interaction is increased following the formation of DNA double-strand breaks (By similarity). Interacts (when auto-poly-ADP-ribosylated) with XRCC1; leading to inhibit PARP1 ADP-ribosyltransferase activity. Interacts with SPINDOC; promoting PARP1 ADP-ribosyltransferase activity. Interacts with BANF1; leading to inhibit PARP1 ADP-ribosyltransferase activity in response to oxidative DNA damage. Interacts (when sumoylated and ubiquitinated) with VCP/p97; leading to its extraction from chromatin. Interacts with YARS1; promoting PARP1 ADP-ribosyltransferase activity. Interacts with PACMP micropeptide; Interacts with PACMP micropeptide; interaction (By similarity). 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 (By similarity).
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. Phosphorylated by TXK.
Poly-ADP-ribosylated on serine, glutamate and aspartate residues by autocatalysis. Auto-ADP-ribosylation on serine takes place following interaction with HPF1. Auto poly-ADP-ribosylation on serine residues promotes its dissociation from chromatin. Poly-ADP-ribosylated by PARP2; poly-ADP-ribosylation mediates the recruitment of CHD1L to DNA damage sites (By similarity). Mono-ADP-ribosylated at Lys-521 by SIRT6 in response to oxidative stress, promoting recruitment to double-strand breaks (DSBs) sites (By similarity).
Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (By similarity). 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. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (By similarity). Specificity for the different amino acids is conferred by interacting factors, such as HPF1 and NMNAT1 (By similarity). Following interaction with HPF1, catalyzes serine ADP-ribosylation of target proteins; HPF1 confers serine specificity by completing the PARP1 active site. Also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1 (By similarity). 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. HPF1 initiates serine ADP-ribosylation but restricts the polymerase activity of PARP1 in order to limit the length of poly-ADP-ribose chains. 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. Mediates the poly-ADP-ribosylation of a number of proteins, including itself, APLF, CHFR and NFAT5. 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. Required for PARP9 and DTX3L recruitment to DNA damage sites. PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (By similarity). PARP1-mediated DNA repair in neurons plays a role in sleep: senses DNA damage in neurons and promotes sleep, facilitating efficient DNA repair. In addition to DNA repair, also involved in other processes, such as transcription regulation, programmed cell death, membrane repair, adipogenesis and innate immunity (By similarity). 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. Acts both as a positive and negative regulator of transcription elongation, depending on the context. 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. 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. Involved in replication fork progression following interaction with CARM1: mediates poly-ADP-ribosylation at replication forks, slowing fork progression (By similarity). Poly-ADP-ribose chains generated by PARP1 also play a role in poly-ADP-ribose-dependent cell death, a process named parthanatos. Also acts as a negative regulator of the cGAS-STING pathway. 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. 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. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (By similarity).
Promotes AIFM1-mediated apoptosis. 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.
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.
S-nitrosylated, leading to inhibit transcription regulation activity.
Sumoylated with SUMO1 or SUMO2 by PIAS4 following prolonged residence (trapping) to chromatin. Sumoylation promotes ubiquitination by RNF4 and removal from chromatin by VCP/p97.
The BRCT domain is able to bind intact DNA without activating the poly-ADP-ribosyltransferase activity. The BRCT domain mediates DNA intrastrand transfer (named 'monkey-bar mechanism') that allows rapid movements of PARP1 through the nucleus.
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. Binding to damaged DNA unfolds the PARP alpha-helical domain, relieving autoinhibition.
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. Ubiquitination promotes removal from chromatin by VCP/p97.
Acts as a transcriptional repressor (By similarity). Has mitogenic activity for fibroblasts (By similarity). Heparin-binding protein (By similarity).
Monomer, and domain-swapped homodimer (By similarity). Interacts with nuclear proteins NCL and YBX1/YB1 (By similarity).
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 (By similarity).
The PWWP domain harbors the heparin-binding sites and is responsible for DNA-binding, while the C-terminal region is essentially unstructured.
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.
Expressed in brain and sympathetic ganglia. In brain, expressed in cortex, hippocampus and at much lower levels in cerebellum. In sympathetic ganglia, expressed at approximately equal levels in both superior cervical ganglia and prevertebral ganglia.
Heterotetramer with KCNQ2; form the heterotetrameric M potassium channel. Interacts with calmodulin; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel. Heteromultimer with KCNQ5. May associate with KCNE2. Interacts with IQCJ-SCHIP1 (PubMed:27979964).
KCNQ2/KCNQ3 are ubiquitinated by NEDD4L. Ubiquitination leads to protein degradation. Degradation induced by NEDD4L is inhibited by USP36.
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, ZNF318 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) (By similarity). 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 (By similarity). Interacts with BUD31 (By similarity). Interacts with ARID4A (By similarity). Interacts with ARID4B (By similarity). Interacts (via NR LBD domain) with ZBTB7A; the interaction is direct and androgen-dependent (By similarity). Interacts with NCOR1 (By similarity). Interacts with NCOR2 (By similarity). 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. 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 (By similarity).
Defects in Ar are a cause of androgen insensitivity. Rats with this syndrome are called testicular feminized (TFM).
Highest levels in the seminal vesicle, ventral prostate and coagulating gland with lower levels in the kidney and levator ani muscle.
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 (By similarity).
Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-517 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression (By similarity). Phosphorylation by TNK2 enhances the DNA-binding and transcriptional activity. Phosphorylation at Ser-61 by CDK9 regulates AR promoter selectivity and cell growth. Phosphorylation by PAK6 leads to AR-mediated transcription inhibition (By similarity).
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. 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. Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3 (By similarity).
Sumoylated on Lys-384 (major) and Lys-503 (By similarity). Ubiquitinated. Deubiquitinated by USP26 (By similarity). 'Lys-6' and 'Lys-27'-linked polyubiquitination by RNF6 modulates AR transcriptional activity and specificity (By similarity).
Transcriptional activity is enhanced by binding to RANBP9.
Pulmonary epithelium, testis and oviduct.
Transcription factor specifically required for the formation of motile cilia. 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.
Homodimer. Interacts with UBE2I. Interacts with MDM2. Interacts with CTNNB1. Identified in a complex with CTNNB1 and LEF1 (By similarity).
Phosphorylation at Tyr-114 by SRC is required for induction of apoptosis.
Possesses dinucleoside triphosphate hydrolase activity (By similarity). Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP (By similarity). Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP (By similarity). Exhibits adenylylsulfatase activity, hydrolyzing adenosine 5'-phosphosulfate to yield AMP and sulfate (By similarity). 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 (By similarity). Exhibits adenylylsulfate-ammonia adenylyltransferase, catalyzing the ammonolysis of adenosine 5'-phosphosulfate resulting in the formation of adenosine 5'-phosphoramidate (By similarity). Also catalyzes the ammonolysis of adenosine 5-phosphorofluoridate and diadenosine triphosphate (By similarity). 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 (By similarity). Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways (By similarity). Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis (By similarity). 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 (By similarity) Functions as tumor suppressor (By similarity).
Antiparallel homodimer; disulfide-linked.
Intestinal defense peptide (PubMed:23380721, PubMed:28345637). Has potent antibacterial activity against Gram-negative bacteria E.coli O157:H7, S.typhimurium DT104, and K.pneumoniae; and against Gram-positive bacteria S.aureus, methicillin-resistant S.aureus and L.monocytogenes (PubMed:23380721, PubMed:28345637). Remains active in the presence of NaCl and Mg(2+) (PubMed:23380721). Probably functions by disrupting bacterial membrane integrity (PubMed:28345637). However, does not show cytotoxic activity towards human intestinal cells (PubMed:23380721).
Specifically expressed in small intestine (jejunum and ileum) (PubMed:15494476, PubMed:23380721). Probably expressed by Paneth cells at the base of intestinal crypts (PubMed:23380721). Coexpressed with MMP7 in small intestine (PubMed:23380721).
Predominantly fucosylates the innermost N-acetyl glucosamine (GlcNAc) residue in biantennary N-glycan acceptors.
Predominantly fucosylates the innermost N-acetyl glucosamine (GlcNAc) residue in biantennary N-glycan acceptors. Postulated to generate core alpha(1->3)-fucose epitope within the chitobiose unit of biantennary N-glycans, providing for a recognition signal to reorient aberrantly folded glycoproteins for degradation (By similarity). Involved in biosynthesis of Lewis X-carrying biantennary N-glycans that regulate neuron stem cell self-renewal during brain development (By similarity).
May be involved in the intracellular transport of sterols or other lipids. May bind cholesterol or other sterols.
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. May have a function in liver regeneration and spermatogenesis.
Homodimer; disulfide-linked (PubMed:12717032, PubMed:22948913). Interacts with CHCHD4/MIA40 (By similarity).
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 (By similarity).
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 (By similarity).
Required for proper homologous chromosome pairing and efficient cross-over and intragenic recombination during meiosis.
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 (By similarity). Signals mainly via beta-arrestin pathway. Binding of RARRES2 activates weakly G proteins, calcium mobilization and MAPK1/MAPK3 (ERK1/2) phosphorylation too. 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).
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).
Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway. Involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. Acts as a suppressor of anti-tumor immunity. Limits the growth of intracellular pathogens by depriving tryptophan. Protects the fetus from maternal immune rejection.
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).
May mediate extracellular or intracellular signaling of cortical neurons during forebrain development.
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. Can also catalyze the transfer of xylose from UDP-xylose but less efficiently. Specifically targets extracellular EGF repeats of proteins such as NOTCH1, NOTCH3, FBN1, FBN2 and LTBP1. May regulate the transport of NOTCH1 and NOTCH3 to the plasma membrane and thereby the Notch signaling pathway.
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.
'Lys-6'-linked polyubiquitination at Lys-205 leads to RSAD2 protein degradation.
Acetylated by HAT1. HAT1-mediated acetylation of Lys-196 in turn recruits UBE4A that stimulates RSAD2 polyubiquitination leading to proteasomal degradation.
Belongs to the radical SAM superfamily. RSAD2 family.
Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
By interferon type I, type II and LPS. Interferon alpha induction is rapid and transient, peaks 4-6 hours after stimulation and returns to basal levels 24 hours after stimulation. Interferon gamma elicits a more prolonged response where expression remains elevated 48 hours after stimulation. Induced by infection with Vesicular stomatitis virus and pseudorabies virus, presumably through type I interferon pathway.
Homodimer. Interacts with IRAK1 and TRAF6. Interacts with FPPS. Interacts with HADHB. Interacts (via C-terminus) with VAPA/VAP33 (via C-terminus).
IRAK1 and TRAF6 synergistically activate RSAD2 increasing its activity with CTP as substrate about 10-fold.
In neonatal rat tibia, specifically localized in cells of the periosteum, in osteoblasts lining endosteal and peristeal bone surfaces, to articular surfaces of cartilage and in perichondral cells but not in chondrocytes (at protein level). Expressed predominantly in bone marrow and spleen.
Interferon-inducible antiviral protein which plays a major role in the cell antiviral state induced by type I and type II interferon. Catalyzes the conversion of cytidine triphosphate (CTP) to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) via a SAM-dependent radical mechanism. In turn, ddhCTP acts as a chain terminator for the RNA-dependent RNA polymerases from multiple viruses and directly inhibits viral replication. Therefore, inhibits a wide range of DNA and RNA viruses. 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. 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.
Not detected in undifferentiated primary osteoblasts. Expression increases during differentiation and declines to much reduced levels in mature osteoblasts.
The N-terminal region (1-41) is necessary for its localization to the endoplasmic reticulum membrane and lipid droplet.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.
5' to 3' helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction (By similarity). Specific to 5'-phosphorylated single-stranded guanine-rich sequences (By similarity). May play a role in RNA metabolism, ribosome biogenesis or initiation of translation (By similarity). May play a role in regulation of transcription (PubMed:11106437). Interacts with tRNA-Tyr (By similarity).
Belongs to the DNA2/NAM7 helicase family.
Expressed in liver, skin, muscle, heart, brain, spleen and kidney.
Homooligomer (By similarity). Interacts with RUVBL1 (By similarity). Interacts with RUVBL2 (By similarity). Interacts with GTF3C1 (By similarity). Interacts with ABT1 (By similarity). Interacts with ribosomes (By similarity).
The R3H domain recognizes phosphorylated 5'-ends of single-stranded nucleic acids which promotes binding of nucleic acids and stimulates ATPase activity.
Expressed abundantly in brain, most notably throughout the thalamus, the ventromedial hypothalamus and the caudate nucleus. Isoform 1 is largely predominant in all tissues.
Proxyfan acts as a potent neutral antagonist while thioperamide, ciproxifan and FUB465 act as potent inverse agonists.
The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist).
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. 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. Also mediates the efflux of sphingosine-1-P from cells. Acts as a urate exporter functioning in both renal and extrarenal urate excretion (By similarity). 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 (By similarity). Mediates the secretion of the riboflavin and biotin vitamins into milk. 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. 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 (By similarity). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus. May play a role in early stem cell self-renewal by blocking differentiation (By similarity).
Down-regulated upon ischemia-reperfusion.
Highly expressed in brain capillary, kidney and small intestine. Lower expression in heart. Preferentially expressed (at protein level) on the luminal membrane of brain capillaries, in kidney and small intestine.
Homodimer; disulfide-linked. 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.
N-glycosylated in brain capillary, kidney and small intestine but not in heart.
N-glycosylated. Glycosylation-deficient ABCG2 is normally expressed and functional.
Phosphorylated. Phosphorylation may regulate the localization to the plasma membrane, the homooligomerization and therefore, the activity of the transporter.
The extracellular loop 3 (ECL3) is involved in binding porphyrins and transfer them to other carriers, probably albumin.
May associate with CD21. May regulate the release of Ca(2+) from intracellular stores.
Belongs to the cyclin family. Cyclin L subfamily.
Contains a RS region (arginine-serine dipeptide repeat) within the C-terminal domain which is the hallmark of the SR family of splicing factors. This region probably plays a role in protein-protein interactions (By similarity).
Interacts with CDK11A, CDK11B, CDK12, CDK13 and POLR2A, the hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II. May form a ternary complex with CDK11B and casein kinase II (CKII). Interacts with pre-mRNA-splicing factors, including at least SRSF1, SRSF2 and SRSF7/SLU7.
Involved in pre-mRNA splicing. May induce cell death, possibly by acting on the transcription and RNA processing of apoptosis-related factors.
Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1CC. Interacts with PPP1CA, WDR82 and TOX4 (By similarity).
Expressed in testis, brain and intestine (at protein level). Highly expressed in testis.
Phosphorylated on Thr-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.
High expression in the anterior pituitary and in several brain regions, the atrium, and the ventricle.
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 precursor protein seems to exist in the reticulum endoplasmic as both a monomer and a dimer-sized complex whereas mature form 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.
Detected in a number of tested tissues including pancreas, brain, heart, kidney, liver, thymus and white adipose tissue (at protein level).
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 (By similarity).
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.
Abundantly expressed in heart and liver.
This enzyme metabolizes arachidonic acid predominantly via a NADPH-dependent olefin epoxidation mainly to 14,15-, 11,12-, and 8,9-epoxyeicosatrienoic acids (EET). It also acts as an omega-1-hydroxylase by metabolizing arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-OH-AA).
Belongs to the methylenetetrahydrofolate reductase family.
Heterogenous nuclear ribonucleoprotein (hnRNP) implicated in mRNA processing mechanisms. Component of the CRD-mediated complex that promotes MYC mRNA stability. Is associated in vitro with pre-mRNA, splicing intermediates and mature mRNA protein complexes. Binds to apoB mRNA AU-rich sequences. 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. May be involved in cytoplasmic vesicle-based mRNA transport through interaction with synaptotagmins (By similarity).
Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1. Identified in the spliceosome C complex (By similarity). 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. Component of the APOB mRNA editosome. Interacts with APOBEC1 and A1CF. Part of a complex associated with the FOS mCRD domain and consisting of PABPC1, PAIP1, CSDE1/UNR, HNRPD and SYNCRIP. Interacts with HNRPR, SMN, POLR2A hyperphosphorylated C-terminal domain, minute virus of mice (MVM) NS1 protein and through its C-terminal domain with SYT7, SYT8 and SYT9. The non-phosphorylated and phosphorylated forms are colocalized with PAIP1 in polysomes. Interacts with GTPBP1 (By similarity). Interacts with HABP4 (By similarity).
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.
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 (By similarity).
Expressed in many brain regions, including frontal cortex, brain stem and cerebellum. Associated with neuronal bodies in a punctated matter. Little expression, if any, in oligodendrocytes.
Mediates the Na(+)-independent transport of organic anions such as prostaglandins (PG) E1 and E2, thyroxine (T4), deltorphin II, BQ-123 and vasopressin. Also displays a low transport activity of estrone 3-sulfate. 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. Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions.
Expressed in brain (at protein level) (PubMed:17439943).
Hippocampal neurons with reduced levels of RUFY3 show an increase in formation of additional axons (PubMed:17439943). This effect is suppressed in the presence of the PI3K inhibitor LY294002 and enhanced by overexpression of SHTN1 (PubMed:17439943). Overexpression of RUFY3 suppresses additional axons formed upon overexpression of SHTN1 (PubMed:17439943).
Interacts with PIK3CA and PIK3R1 (PubMed:17439943). Interacts with PAK1 (By similarity). Interacts (via C-terminus) with Ras-related Rab-5 proteins (By similarity). Interacts (via C-terminus) with Ras-related Rap-2 proteins (By similarity). Interacts (via N-terminus) with FSCN1; this interaction induces neuron axon development (By similarity). Interacts with DBN1 (By similarity).
Isoform 1 is partially phosphorylated (PubMed:17439943). Phosphorylated by PAK1 (By similarity).
Low level expression in brain up to 15 dpc, higher level expression from 18 dpc to P14 with highest level around P4 (PubMed:17439943). Low level expression in adult brain (PubMed:17439943). Low level expression in hippocampal neurons up to stage 2 in culture (PubMed:17439943). Higher level from stage 3 with highest level of isoform 1 on day 7 in vitro (DIV7) (PubMed:17439943). Phosphorylated isoform 1 from DIV7 with high level up to DIV28, isoform 2 detectable from stage 3 to DIV7 (PubMed:17439943).
Plays a role in the generation of neuronal polarity formation and axon growth (PubMed:17439943). Implicated in the formation of a single axon by developing neurons (PubMed:17439943). May inhibit the formation of additional axons by inhibition of PI3K in minor neuronal processes (PubMed:17439943). Plays a role in the formation of F-actin-enriched protrusive structures at the cell periphery (By similarity). 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 (By similarity).
Up-regulated during neuronal polarization (PubMed:17439943).
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.
Belongs to the Schlafen family. Subgroup I subfamily.
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. Via its C-terminus binds various phospholipids, most strongly phosphatidylinositol 4-phosphate (PtdIns-(4)P), phosphatidylinositol 5-phosphate (PtdIns-(5)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns-(3,5)P2). Involved in the endosome-to-plasma membrane trafficking and recycling of SNX27-retromer-dependent cargo proteins, such as GLUT1. Required for the association of DNAJC13, ENTR1, ANKRD50 with retromer CSC subunit VPS35. Required for the endosomal recruitment of CCC and retriever complexes subunits COMMD1 and CCDC93 as well as the retrievere complex subunit VPS35L.
Component of the WASH core complex also described as WASH regulatory complex (SHRC) composed of WASHC1, WASHC2, WASHC3, WASHC4 and WASHC5; in the complex interacts (via N-terminus) directly with WASHC1. The WASH core complex associates with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex. Interacts with VPS35; mediates the association with the retromer CSC complex. Interacts with FKBP15. Interacts with CCDC93, CCDC22, VPS35L; indicative for an association of the WASH core complex with the CCC and retriever complexes (By similarity). Directly interacts with TBC1D23 (By similarity).
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.
Belongs to the short-chain dehydrogenases/reductases (SDR) family. ERG27 subfamily.
Bifunctional enzyme involved in steroid-hormone metabolism and cholesterol biosynthesis (PubMed:6946726, PubMed:9658408). Catalyzes the NADP(H)-dependent reduction of estrogens and androgens and regulates the biological potency of these steroids (PubMed:9658408) (By similarity). Converts estrone (E1) to a more potent estrogen, 17beta-estradiol (E2) (PubMed:9658408). Converts dihydrotestosterone (DHT) to an inactive form. Participates also in the post-squalene cholesterol biosynthesis, as a 3-ketosteroid reductase (By similarity).
Binds to the short form of prolactin receptor.
Most abundant in ovaries of pregnant animals.
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 GJB4 (By similarity). Interacts with CNST (PubMed:19864490).
Liver, kidney, intestine, lung, spleen, stomach, testis and brain, but not heart and adult skeletal muscle.
Structural component of gap junctions. 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. Small molecules and ions diffuse from one cell to a neighboring cell via the central pore.
Highest levels in skeletal and cardiac muscle. Also found in comparable amounts in brain, spinal cord and lung. Also detected in testis where it is expressed by Sertoli cells of the seminiferous tubules (at protein level).
Interacts with RABIF and OPTN (By similarity). Interacts with LRRK2; interaction facilitates phosphorylation of Ser-105 (By similarity). Interacts with GDI1, GDI2 and CHM; these interactions are disrupted by phosphorylation on Ser-105 (By similarity). Interacts with RILPL1 and RILPL2; these interactions are dependent on phosphorylation of Ser-105 (By similarity).
Phosphorylation of Ser-105 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM 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). That Rab is activated by DENND3, a guanine exchange factor (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. 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).
This enzyme, isolated from small intestine, specifically inactivates the apo forms of a certain group of intracellular pyridoxal phosphate-requiring enzymes. It has chymotrypsin-like specificity towards small substrates.
Serine hydrolase involved in the detoxification of formaldehyde.
Binds to actin filaments in muscle and non-muscle cells (PubMed:7568216, PubMed:22812662). Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction (PubMed:22812662). Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments. The non-muscle isoform may have a role in agonist-mediated receptor internalization (By similarity).
Homodimer (PubMed:7568216, PubMed:22812662). Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain (PubMed:7568216, PubMed:22812662).
Phosphorylated on Ser-61 by PIK3CG. Phosphorylation on Ser-61 is required for ADRB2 internalization (By similarity).
The molecule is in a coiled coil structure that is formed by 2 polypeptide chains. The sequence exhibits a prominent seven-residues periodicity.
Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily.
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 (By similarity).
Interacts with GIT1. Component of a complex that contains at least FER, CTTN and PTK2/FAK1. Interacts with BMX. Interacts with STEAP4. Interacts with ZFYVE21. Interacts with ESR1. Interacts with PIK3R1 or PIK3R2. Interacts with 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 P53/TP53. Interacts (via first Pro-rich region) with CAS family members (via SH3 domain), including BCAR1, BCAR3, and CASS4. Interacts with NEDD9 (via SH3 domain) (By similarity). Interacts with TGFB1I1. Interacts with SRC, GRB2 and GRB7. Interacts with ARHGEF28. Interacts with SHB. Part of a complex composed of THSD1, PTK2/FAK1, TLN1 and VCL (By similarity). Interacts with PXN and TLN1. Interacts with SORBS1. Interacts with STAT1. Interacts with WASL. Interacts with ARHGAP26 and SHC1. Interacts with RB1CC1; this inhibits PTK2/FAK1 activity and activation of downstream signaling pathways. Interacts with ARHGEF7. Interacts with MDM2 (By similarity). Interacts with PIAS1. Interacts with DCC. Interacts with LPXN (via LD motif 3) (By similarity). Interacts with MISP (By similarity). Interacts with EMP2; regulates PTK2 activation and localization (By similarity). 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 (By similarity).
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 (By similarity). 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.
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-928, 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-928 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 (By similarity). 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 by SRC. Phosphorylation at Tyr-397, Tyr-576 and Tyr-577 is required for maximal kinase activity.
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 first Pro-rich domain interacts with the SH3 domain of CAS family members, such as BCAR1 and NEDD9.
Able to inhibit growth in several cell lines.
Highly expressed in testis, lower levels of expression is seen in skeletal muscle, liver, lung and brain.
Autoproteolytically cleaved into 2 subunits, an extracellular subunit and a seven-transmembrane subunit. This proteolytic processing takes place early in the biosynthetic pathway, either in the endoplasmic reticulum or in the early compartment of the Golgi apparatus.
Calcium-independent receptor of high affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. Receptor probably implicated in the regulation of exocytosis.
Expressed in the brain (at protein level). Brain specific distribution but low levels are also detected in most tissues.
Forms a heterodimer, consisting of a large extracellular region (p120) non-covalently linked to a seven-transmembrane moiety (p85). Interacts with syntaxin and with proteins of the SHANK family via the PDZ domain (PubMed:9208860, PubMed:10958799). Isoform 2 interacts with TENM2 (PubMed:21724987). Interacts (via extracellular domain) with FLRT1, FLRT2 and FLRT3 (via extracellular domain) (By similarity).
Receptor for TENM2 that mediates heterophilic synaptic cell-cell contact and postsynaptic specialization.
The extracellular domain coupled to the a single transmembrane region are sufficient for full responsiveness to alpha-latrotoxin.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily.
Can use both ATP and GTP as phosphoryl donors. Phosphorylation by casein kinase 2 has been estimated to represent up to one quarter of the eukaryotic phosphoproteome.
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 (By similarity). Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection (By similarity). May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response (By similarity). 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 (By similarity). Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation (By similarity). Can also negatively regulate apoptosis (PubMed:12191471). Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3 (PubMed:12191471). Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8 (PubMed:12191471). Phosphorylates YY1, protecting YY1 from cleavage by CASP7 during apoptosis (By similarity). Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV (By similarity). Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, ATF4, SRF, MAX, JUN, FOS, MYC and MYB (By similarity). Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function (By similarity). Mediates sequential phosphorylation of FNIP1, promoting its gradual interaction with Hsp90, leading to activate both kinase and non-kinase client proteins of Hsp90 (By similarity). Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1 (By similarity). Acts as an ectokinase that phosphorylates several extracellular proteins (By similarity). During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV (By similarity). Phosphorylates PML at 'Ser-565' and primes it for ubiquitin-mediated degradation (By similarity). 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 (PubMed:19330005).
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. Interacts with RNPS1, SNAI1, PML and CCAR2 (By similarity).
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 (By similarity).
Antibacterial protein. Putative acid-stable proteinase inhibitor (By similarity).
Belongs to the G-protein coupled receptor 1 family. Bradykinin receptor subfamily. BDKRB2 sub-subfamily.
Diphosphorylation at Ser-365 and Ser-371, at Ser-378 and Ser-380, and at Thr-374 and Ser-380 seem to be correlated pairwise.
Forms a complex with PECAM1 and GNAQ. Interacts with PECAM1 (By similarity).
Forms a complex with PECAM1 and GNAQ. Interacts with PECAM1.
Palmitoylation at Cys-356 and phosphorylation at Tyr-352 seem to be mutually exclusive.
Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Uterus, vas deferens, kidney, ileum, heart, testis, lung and brain.
Carboxylesterases that catalyzes the hydrolysis of pyrethroids pesticides. Hydrolyzes permethrin faster than cypermethrin (By similarity). Hydrolyzes retinyl esters (PubMed:12230550).
Expressed in liver, stomach, small intestine and kidney.
Highly expressed in skeletal muscle and retina. Also detected at lower levels in thyroid gland but not in other endocrine glands such as the adrenal or pituitary glands.
Homodimer (via N-terminus). Can also form higher oligomers. Interacts with OLFM3, FN1, NRCAM, GLDN and NFASC. Interacts (via N-terminus) with MYL2. Interacts with SFRP1, FRZB, FZD7, FZD10, FZD1 and WIF1; regulates Wnt signaling (By similarity). Interacts with SNTA1; regulates muscle hypertrophy. Interacts with ERBB2 and ERBB3; activates ERBB2-ERBB3 signaling pathway. Interacts with SNCG; affects its secretion and its aggregation (By similarity).
Secreted glycoprotein regulating the activation of different signaling pathways in adjacent cells to control different processes including cell adhesion, cell-matrix adhesion, cytoskeleton organization and cell migration. Promotes substrate adhesion, spreading and formation of focal contacts. Negatively regulates cell-matrix adhesion and stress fiber assembly through Rho protein signal transduction. Modulates the organization of actin cytoskeleton by stimulating the formation of stress fibers through interactions with components of Wnt signaling pathways. Promotes cell migration through activation of PTK2 and the downstream phosphatidylinositol 3-kinase signaling. Plays a role in bone formation and promotes osteoblast differentiation in a dose-dependent manner through mitogen-activated protein kinase signaling. Mediates myelination in the peripheral nervous system through ERBB2/ERBB3 signaling. Plays a role as a regulator of muscle hypertrophy through the components of dystrophin-associated protein complex. Involved in positive regulation of mitochondrial depolarization. Plays a role in neurite outgrowth. May participate in the obstruction of fluid outflow in the trabecular meshwork.
Undergoes a calcium-dependent proteolytic cleavage at Gln-225 by CAPN2 in the endoplasmic reticulum. The result is the production of two fragments, one of 35 kDa containing the C-terminal olfactomedin-like domain, and another of 20 kDa containing the N-terminal leucine zipper-like domain (By similarity).
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 and CD74 (By similarity).
Activated by Ca(2+) (PubMed:11580282). Activated by NCALD in a Ca(2+)-dependent fashion (PubMed:11580282).
Functions as an olfactory receptor activated by a urine odorant, uroguanylin (PubMed:18178149). Activated as well by the volatile semiochemicals carbon disulfide (CS2) and carbon dioxide (CO2) (By similarity). Has guanylate cyclase activity upon binding of the ligand (PubMed:18178149). Activation of GUCY2D neurons leads to the cGMP-dependent activation of the CNGA3 channels, membrane depolarization and an increase in action potential frequency. Signaling pathways activated by GUCY2D may trigger social behaviors such as acquisition of food preference (By similarity).
In contrast to mouse, guanylin, a urine odorant, does not stimulate GUCY2D.
Interacts (via the catalytic domain) with NCALD.
Specifically expressed in a subpopulation of olfactory sensory neurons (PubMed:7724600). Expressed in the cilia of the olfactory epithelium (PubMed:11580282).
The nomenclature for members of the GUCY2 gene family is not consistent across species. In mice the GUCY2D gene encodes the protein guanylate cyclase 2D specifically expressed in a subpopulation of olfactory sensory neurons. In rat the official name is GUCY2E for guanylate cyclase 2D. In human this gene is a pseudogene.
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 a 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).
Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling. Modulates the cellular response to ER stress by promoting nuclear translocation of XBP1 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).
Heterodimer of a regulatory subunit PIK3R1 and a p110 catalytic subunit (PIK3CA, PIK3CB or PIK3CD). Interacts (via SH2 domains) with CCDC88A/GIV (tyrosine-phosphorylated form); the interaction enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (By similarity). Interacts with phosphorylated LAT, LAX1, TRAT1 and LIME1 upon TCR and/or activation. Interacts with phosphorylated TOM1L1. Interacts with CBLB. The SH2 domains interact with the YTHM motif of phosphorylated INSR in vitro. Also interacts with tyrosine-phosphorylated IGF1R in vitro. Interacts with CD28 and CD3Z upon T-cell activation. Interacts with NISCH, SOCS7 and HCST. Interacts with RUFY3. Interacts with AXL, FASLG, FER, FGR, HCK, KIT and BCR. Interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated). Interacts with ERBB4 (phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with LYN (via SH3 domain); this enhances enzyme activity. Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with PIK3R2; the interaction is dissociated in an insulin-dependent manner. Interacts with XBP1; the interaction is direct and induces translocation of XBP1 into the nucleus in a ER stress- and/or insulin-dependent but PI3K-independent manner (By similarity). Interacts with FGFR1, FGFR2, FGFR3 and FGFR4 (phosphorylated) (Probable). Interacts with IRS1 and phosphorylated IRS4 (PubMed:8628286). Interacts with PTK2/FAK1 (PubMed:8824286). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with APPL1 and APPL2 (By similarity). Interacts with SRC (By similarity). Interacts with ALOX5; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (By similarity). Interacts with TYK2 (By similarity). Interacts with nephrin NPHN1; the interaction is reduced by high glucose levels (By similarity).
Phosphorylated. Tyrosine phosphorylated in response to signaling by FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylated by CSF1R. Phosphorylated on tyrosine residues by TEK/TIE2. Dephosphorylated by PTPRJ. Phosphorylated by PIK3CA at Ser-608; phosphorylation is stimulated by insulin and PDGF. The relevance of phosphorylation by PIK3CA is however unclear. Phosphorylated in response to KIT and KITLG/SCF. Phosphorylated by FGR and ERBB4 (By similarity).
Polyubiquitinated in T-cells by CBLB; which does not promote proteasomal degradation but impairs association with CD28 and CD3Z upon T-cell activation.
The P85-alpha isoform is widely expressed. Expression of the P55-alpha isoform is highest in brain and skeletal muscle. The P50-alpha isoform is abundant in liver with lower levels in brain and muscle.
The SH3 domain mediates the binding to CBLB.
Homodimer; disulfide-linked (Potential). The relevance of homodimerization is however unsure. May interact with phosphorylated proteins in resting B-cells, including HCK (By similarity).
Inhibited by phenyl beta-GalNAc(4,6-SO(4)).
Sulfotransferase that transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the C-6 hydroxyl group of the GalNAc 4-sulfate residue of chondroitin sulfate A and forms chondroitin sulfate E containing GlcA-GalNAc(4,6-SO(4)) repeating units. It also transfers sulfate to a unique non-reducing terminal sequence, GalNAc(4SO4)-GlcA(2SO4)-GalNAc(6SO4), to yield a highly sulfated structure similar to the structure found in thrombomodulin chondroitin sulfate. May also act as a B-cell receptor involved in BCR ligation-mediated early activation that mediate regulatory signals key to B-cell development and/or regulation of B-cell-specific RAG expression; however such results are unclear in vivo (By similarity).
Carries out a dual function: signal transduction and activation of transcription. Mediates cellular responses to the cytokine KITLG/SCF and other growth factors. Binds to the GAS element and activates PRL-induced transcription. Positively regulates hematopoietic/erythroid differentiation.
Tyrosine phosphorylated in response to signaling via activated KIT, resulting in translocation to the nucleus. Tyrosine phosphorylated in response to signaling via activated FLT3; wild-type FLT3 results in much weaker phosphorylation than constitutively activated mutant FLT3. Alternatively, can be phosphorylated by JAK2. Phosphorylation at Tyr-699 by PTK6 or HCK leads to an increase of its transcriptional activity.
Upon activation, forms a homodimer or a heterodimer with a related family member. Binds NR3C1. Interacts with NCOA1. Interacts with NMI. Interacts with SOCS7. Interacts (via SH2 domain) with INSR. Interacts with CPEB3; this inhibits STAT5B-mediated transcriptional activation.
Probable hormone. Plays a role in pulmonary vascular remodeling (By similarity).
Belongs to the immunoglobulin superfamily. IgLON family.
Expressed mostly by neurons comprising limbic-associated cortical and subcortical regions that function in cognition, emotion, memory, and learning.
First detected at 15 dpc to 16 dpc, at stage 20 dpc it is detected in presumptive cortex, medial limbic areas of the thalamus and hypothalamus. In the adult, it is found in hypothalamus, perirhinal cortex, amygdala and medial thalamic region.
Mediates selective neuronal growth and axon targeting. Contributes to the guidance of developing axons and remodeling of mature circuits in the limbic system. Essential for normal growth of the hippocampal mossy fiber projection.
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 (By similarity). Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
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. Interacts with ECPAS (By similarity). Interacts with KIF26B (By similarity). Interacts with LARP6. Interacts with MCC. Interacts with CFAP95 (By similarity).
Represents a conventional non-muscle myosin. This protein should not be confused with the unconventional myosin-10 (MYO10).
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.
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.
Belongs to the adenosylhomocysteinase family.
Catalyzes the hydrolysis of S-adenosyl-L-homocysteine to form adenosine and homocysteine (PubMed:11927587). Binds copper ions (By similarity).
In fetal glands the majority of the proteins are methylated, whereas in neonatal and adult glands, only 50% are methylated.
Interacts with RIMS1, RIMS2, RPH3A and RPH3AL (By similarity). Interacts with RAB3IP (PubMed:7532276). Interacts with CHM; phosphorylation at Thr-86 disrupts this interaction (By similarity). 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.
Protein transport. Probably involved in regulated exocytosis (By similarity).
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. Has ATP-dependent protein disaggregase activity and is required to maintain the solubility of key mitochondrial proteins. Plays a role in granulocyte differentiation.
Interacts with PHB and PHB2. Interacts with MAVS; the interaction is enhanced by Sendai virus infection.
The ankyrin-repeat region is necessary for ATP-dependent protein disaggregase activity.
Consists mainly of a membrane-spanning beta-barrel formed by 19 beta-strands.
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).
Interacts with ARMC12 in a TBC1D21-dependent manner.
Isoform 1 is widely expressed with strong expression in atrium and ascitic tumor, lower levels in brain and very low levels in liver and kidney. Isoform 2 is also widely expressed with highest levels in brain but no expression in kidney. Also expressed in flagella of epididymal sperm.
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. May play a role in classical or alternative activation of macrophages via its role in arginine transport.
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).
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha 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.
Expressed in the zona fasciculata and medulla of the adrenal gland; expressed in kidney proximal tubules. Basal expression is higher in hypertensive than in normotensive animals.
Interacts (via COMM domain) with COMMD1 (via COMM domain).
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes (By similarity). Negatively regulates cell proliferation. Negatively regulates cell cycle G2/M phase transition probably by transactivating p21/CDKN1A through the p53/TP53-independent signaling pathway (PubMed:12620924). Involved in kidney proximal tubule morphogenesis (PubMed:24515317). Down-regulates activation of NF-kappa-B (By similarity).
Belongs to the Integrator subunit 7 family.
Belongs to the major facilitator superfamily. MFSD6 family.
Belongs to the mitochondrion-specific ribosomal protein mL40 family.
Component of the probable ECS(SPSB2) E3 ubiquitin-protein ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and SPSB2 (By similarity). Interacts with CUL5, RNF7, ELOB and ELOC (By similarity). Interacts with MET (By similarity). Interacts (via B30.2/SPRY domain) with PAWR; this interaction occurs in association with the Elongin BC complex (By similarity). Interacts with NOS2 (By similarity).
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). Negatively regulates nitric oxide (NO) production and limits cellular toxicity in activated macrophages by mediating the ubiquitination and proteasomal degradation of NOS2 (By similarity). Acts as a bridge which links NOS2 with the ECS E3 ubiquitin ligase complex components ELOC and CUL5 (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). Essential for its ability to link NOS2 and the ECS E3 ubiquitin ligase complex components ELOC and CUL5 (By similarity).
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. Hydrolyzes phosphatidylethanolamine, phosphatidylcholine and probably phosphatidylinositol with a possible preference for the former. 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. 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. 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. Therefore, plays an important role in the mobilization of arachidonic acid in response to cellular stimuli and the generation of lipid second messengers. Can also hydrolyze lysophosphatidylcholine. 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.
Binds to the peptide-binding site of MHC class II alpha/beta heterodimers forming an alpha-beta-CLIP complex, thereby preventing the loading of antigenic peptides to the MHC class II complex until its release by HLA-DM in the endosome.
Interacts with the mature form of CTSL; the complex survive in neutral pH environment.
Nonamer composed of three alpha/beta/gamma heterotrimers. Interacts with CD44; this complex is essential for the MIF-induced signaling cascade that results in B cell survival.
Plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to compartments where peptide loading of class II takes place. Enhance also the stimulation of T-cell responses through interaction with CD44.
Stabilizes the conformation of mature CTSL by binding to its active site and serving as a chaperone to help maintain a pool of mature enzyme in endocytic compartments and extracellular space of antigen-presenting cells (APCs).
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination and subsequent activation of the Wnt signaling pathway (By similarity).
Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling (By similarity). Controls dorsoventral patterning via two opposing effects; down-regulates beta-catenin to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway (By similarity). Also facilitates the phosphorylation of APC by GSK3B (By similarity). Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation (By similarity). Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7 (By similarity).
Highly expressed in testis, thymus and lung. Less expression in cerebrum, cerebellum, heart, kidney, skeletal muscle, spleen and liver.
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 AXIN1-HIPK2-TP53 complex (By similarity). Interacts directly in the complex with TP53 and HIPK2 (By similarity). 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 (By similarity). Also binds ANKRD6, PIAS1, PIAS2, PIAS4, MAP3K1, MAP3K4, SUMO1, SMAD6, SMAD7 and RNF111 (By similarity). Interacts with DIXDC1; the interaction prevents interaction with MAP3K1 (By similarity). Interacts with MDFI; the interaction decreases AXIN1-mediated JUN N-terminal kinase (JNK) activation (By similarity). Interacts with MDFIC; the interaction inhibits beta-cateninin-mediated signaling and AXIN1-mediated JUN N-terminal kinase (JNK) activation (By similarity). Interacts with LRP5 (via its phosphorylated PPPSP motifs); the interaction is stimulated by WNT1 and GSK3B and activates beta-catenin signaling (By similarity). Interacts (via the C-terminal) with PPP1CA; the interaction dephosphorylates AXIN1 and regulates interaction with GSK3B (By similarity). Interacts with PPP2CA; the interaction dephosphorylates AXIN1 (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 (By similarity). Interacts with CTNNB1 (via the armadillo repeats 2-7) (By similarity). Interacts with GSK3B; the interaction hyperphosphorylates CTNNB1 leading to its ubiquitination and destruction (PubMed:9482734, PubMed:16815997). Interacts with MACF1 (PubMed:16815997). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (PubMed:16815997). Interacts with TNKS (By similarity). Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction (By similarity). Interacts with WDR26 (By similarity). Interacts with GID8 (By similarity). Interacts with SIAH1 and SIAH2; both probably catalyze AXIN1 ubiquitination and subsequent proteasome-mediated ubiquitin-dependent degradation. Interaction with GSK3B and AXIN1 is competitive (By similarity).
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. Also phosphorylated by CDK2 which regulates interaction with CTNBB1 (By similarity).
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 and subsequent activation of the Wnt signaling pathway. Sumoylation at Lys-858 and Lys-861 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 (By similarity). Ubiquitination by SIAH1 and SIAH2 induces its proteasomal degradation as part of the activation of the Wnt signaling pathway (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein.
Interacts with KCNMA1 (By similarity). Interacts with RAB11FIP1, RAB11FIP2, RAB11FIP3 and RAB11FIP4 (By similarity). May interact with TBC1D14 (By similarity). Interacts with ATP6V1E (By similarity)1. Interacts with PI4KB (By similarity). Interacts with RELCH (By similarity). Interacts (in GTP-bound form) with TBC1D8B (via domain Rab-GAP TBC) (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. 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.
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 (By similarity).
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. Binds TIAM1. Interacts with ATN1, ADGRB1, DIAPH1, EPS8, SHANK1, SHANK2, SHANK3, WASF1 and WASF2. Interacts with ENAH after recruitment of CDC42 (By similarity).
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 (By similarity).
The SH3 domain interacts with ATN1, ADGRB1, WASF1, WASF2, SHANK1, DIAPH1 and ENAH.
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. Uses ATP as an energy source to transport cytosolic Ca(2+) ions across the plasma membrane to the extracellular compartment (By similarity). 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. 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 (By similarity). 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 (By similarity). In lactating mammary gland, allows for the high content of Ca(2+) ions in the milk (By similarity).
Isoforms containing segment B are found in brain, uterus, liver and kidney and in low levels in other tissues. Isoforms containing segment W are found in kidney, uterus, and pancreas. Isoforms containing segment Y are found in pancreas and in low levels in brain and heart. Isoforms containing segment Z are found in brain and heart and isoforms containing segment X are found in low levels in brain. Isoforms containing segment A are found in low levels in heart and small intestine while isoforms containing segment C are found in testis and in low levels in other tissues.
Atypical homeodomain protein which does not bind DNA and is required to modulate cardiac growth and development. Acts via its interaction with SRF, thereby modulating the expression of SRF-dependent cardiac-specific genes and cardiac development. Prevents SRF-dependent transcription either by inhibiting SRF binding to DNA or by recruiting histone deacetylase (HDAC) proteins that prevent transcription by SRF. Overexpression causes cardiac hypertrophy. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and assists in chaperone-mediated protein refolding.
Interacts with serum response factor (SRF). Component of a large complex containing histone deacetylases such as HDAC2. Interacts with the acetylated forms of HSPA1A and HSPA1B. Interacts with HSPA8.
Detected in testis. Detected at the acrosome of round spermatids (at protein level).
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 (By similarity).
May play an important role in formation and fusion of Golgi-derived vesicles during acrosome biogenesis.
Acetylated by ELP3 at Lys-403; acetylation inhibits its homodimerization and enzyme activity. Deacetylated by SIRT2 at Lys-403; deacetylation stimulates its enzyme activity (By similarity).
Belongs to the glucose-6-phosphate dehydrogenase family.
Cytosolic glucose-6-phosphate dehydrogenase that catalyzes the first and rate-limiting step of the oxidative branch within the pentose phosphate pathway/shunt, an alternative route to glycolysis for the dissimilation of carbohydrates and a major source of reducing power and metabolic intermediates for fatty acid and nucleic acid biosynthetic processes.
Has NADP both as cofactor (bound to the N-terminal domain) and as structural element bound to the C-terminal domain.
Homotetramer; dimer of dimers. Interacts with SIRT2; the interaction is enhanced by H(2)O(2) treatment (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.
Weakly expressed in spleen, heart and lung.
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 (By similarity).
It is moderately expressed in the cerebellum on postnatal day 7 in the external granule and Perkinje cells, increases in the second postnatal week and thereafter decreases to an adult level.
Multifunctional protein that is involved in the regulation of many processes including tumor suppression, apoptosis, cell cycle progression or transcription. Promotes apoptosis by favouring the activation of caspase-9/CASP9 and allowing apoptosome formation. 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. Preferentially binds to unmodified histone H3 and sterically inhibiting its acetylation and phosphorylation leading to cell growth inhibition. Participates in other biochemical processes such as regulation of mRNA nuclear-to-cytoplasmic translocation and stability by its association with ELAVL1 (Hu-antigen R). Plays a role in E4F1-mediated transcriptional repression as well as inhibition of protein phosphatase 2A.
Phosphorylated on serine residues, at least in part by casein kinase 2/CK2.
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 distributed in the central nervous system, with an abundant expression in the cerebellum.
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 (By similarity). 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 (By similarity).
Homotrimer. Interacts with SPPL2B (By similarity).
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 (By similarity).
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 (By similarity).
The soluble form is demyristoylated by SIRT6, promoting its secretion.
Expressed in the brain with high levels in the cerebellum, specifically in the Purkinje cell layer, choroid plexus and thalamus (ventral, rhomboid and anterior nuclei). Moderate to high expression in the hippocampus, piriform cortex, olfactory bulb, entorhinal cortex, as well as in geniculate bodies, lamboid septal zone, preoptic area and ventral pallidum (at protein level).
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; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with EIF2S2 (By similarity).
Interacts with MOAP1. Interaction with activated KRAS is still a matter of debate.
Involved in the induction of apoptosis. May act as a Ras effector protein. May suppress the serum-induced basal levels of NF-kappa-B.
Belongs to the tryptophan 2,3-dioxygenase family.
Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine. Catalyzes the oxidative cleavage of the indole moiety.
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 (By similarity).
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.
Expressed in brain, heart, lung and testis.
Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2 (By similarity). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs), such as GRIA1 and GRIA2 (PubMed:19234459, PubMed:19265014).
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 (PubMed:18817736, PubMed:19234459). Shows specificity only for GRIA1 and GRIA2 (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mL37 family.
Broad substrate specificity (S)-2-hydroxy-acid oxidase that preferentially oxidizes glycolate. 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. Can also catalyze the oxidation of glyoxylate, and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate. 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.
By interferon gamma and lipopolysaccharides (LPS).
Homodimer. Interacts with SLC9A3R1. Interacts with GAPDH; induced by oxidatively-modified low-densitity lipoprotein (LDL(ox)). Interacts with S100A8 and S100A9 to form the iNOS-S100A8/9 transnitrosylase complex. Interacts with SPSB1, SPSB2 and SPSB4. Interacts with ELOC and CUL5 in the presence of SPSB1 or SPSB2 or SPSB4. Forms a complex with ASL, ASS1 and HSP90AA1; the complex regulates cell-autonomous L-arginine synthesis and citrulline recycling while channeling extracellular L-arginine to nitric oxide synthesis pathway.
In normal kidney, expressed primarily in the medullary thick ascending limb, with minor amounts in the medullary collecting duct and vasa recta bundle.
Not stimulated by calcium/calmodulin. Aspirin inhibits expression and function of this enzyme and effects may be exerted at the level of translational/post-translational modification and directly on the catalytic activity (By similarity).
Polyubiquitinated; mediated by SPSB1, SPSB2 and SPSB4, leading to proteasomal degradation.
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such PTGS2/COX2. As component of the iNOS-S100A8/9 transnitrosylase complex involved in the selective inflammatory stimulus-dependent S-nitrosylation of GAPDH implicated in regulation of the GAIT complex activity and probably multiple targets including ANXA5, EZR, MSN and VIM. Involved in inflammation, enhances the synthesis of pro-inflammatory mediators such as IL6 and IL8.
sequence Was originally thought to originate from human but appears to be from rat.
Heterodimer with either MAGOH or MAGOHB. Part of the mRNA splicing-dependent exon junction complex (EJC) complex; the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A. Interacts with PYM1; the interaction is direct and dissociates the EJC from spliced mRNAs. Part of a complex that contains the EJC core components CASC3, EIF4A3, MAGOH and RBM8A plus proteins involved in nonsense-mediated mRNA decay, such as UPF1, UPF2, UPF3A and UPF3B. Found in a post-splicing complex with NXF1, MAGOH, UPF1, UPF2, UPF3A, UPF3B and RNPS1. Interacts with DDX39B, MAGOH, DPH1, UPF3B, RNPS1, SRRM1 and ALYREF/THOC4. Interacts with IPO13; the interaction mediates the nuclear import of the MAGOH-RBM8A heterodimer. Identified in the spliceosome C complex. Associates with polysomes.
Required for pre-mRNA splicing as component of the spliceosome (By similarity). 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). Its removal from cytoplasmic mRNAs requires translation initiation from EJC-bearing spliced mRNAs. Associates preferentially with mRNAs produced by splicing. Does not interact with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. Associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs (By similarity).
Acetylated by PCAF/KAT2B, regulating its subcellular localization (By similarity). Deacetylated by SIRT2 (By similarity).
Interacts with DHPS, with SDCBP and DOHH. Found in a complex with Ran and XPO4; the hypusine modification increases the interaction with XPO4.
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. 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. With syntenin SDCBP, functions as a regulator of p53/TP53 and p53/TP53-dependent apoptosis. Regulates also TNF-alpha-mediated apoptosis. Mediates effects of polyamines on neuronal process extension and survival (By similarity). May play an important role in brain development and function, and in skeletal muscle stem cell differentiation (PubMed:18606156, PubMed:19006180).
Interacts with the basal transcription factor GTF2B. Interacts with REXO1 (By similarity).
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.
Heterodimer of CALCRL and RAMP3. 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.
Functional P2XRs are organized as homomeric and heteromeric trimers.
Predominantly expressed in heart but are also present in brain, spinal cord and adrenal gland.
Receptor for ATP that acts as a ligand-gated ion channel.
Hydrolyzes a wide range of dipeptides including the conversion of leukotriene D4 to leukotriene E4. Hydrolyzes cystinyl-bis-glycine (cys-bis-gly) formed during glutathione degradation. Possesses also beta lactamase activity and hydrolytically inactivates beta-lactam antibiotics.
Independently of its dipeptidase activity, acts as an adhesion receptor for neutrophil recruitment from bloodstream into inflamed lungs and liver.
Inhibited by L-penicillamine. Beta-lactamase activity is inhibited by cilastatin.
Interacts with BICDL1; leads to its accumulation in the pericentrosomal region (By similarity). Interacts with BICD2; the interaction is direct (By similarity). Interacts with SCYL1BP1 (By similarity). Interacts with VSP52 (By similarity). Interacts with RABGAP1 (By similarity). Interacts with GCC2 (via its GRIP domain) (By similarity). Interacts with RAB6IP1 (via its RUN 1 domain) (By similarity). Interacts with TMF1 (By similarity). Interacts with PIFO (By similarity). Interacts (GTP-bound) with APBA1/MINT1 isoform 2, also called Mint1_826, but not with isoform 1 (By similarity). Interacts with RIC1; the interaction is direct with a preference for RAB6A-GDP (By similarity). Interacts with RGP1; the interaction is direct with a preference for RAB6A-GDP (By similarity). Interacts with DYNLRB1; the interaction is direct (By similarity). Interacts with BICD1 (By similarity). Interacts with VPS13B (By similarity).
Regulator of membrane traffic from the Golgi apparatus towards the endoplasmic reticulum (ER). Has a low GTPase activity. Involved in COPI-independent retrograde transport from the Golgi to the ER. Recruits VPS13B isoform 2 to the Golgi membrane. Plays a role in neuron projection development.
Belongs to the cytochrome c oxidase subunit 3 family.
By IL-6 (By similarity). By fibronectin.
Expressed on the plasma membrane of hepatocytes and in the narrow apical portions of supporting cells in the vomeronasal sensory epithelium. Detected in the type III alveolar cells of the lung, in the proliferative crypt epithelium of the small intestine and in the older intragemmal cells of the tongue.
Expression first detected in the male gonad at 13.5 dpc, at the onset of testicular differentiation, and at 17 dpc in cell aggregates of the early ovary; then only in some cord cells of the older ovary. Expressed in fetal lung epithelium at 20 dpc. Detected at 13 dpc, sparsely distributed throughout the cytoplasm in the single layer of periderm cells covering the dorsal epithelium of the fetal tongue. Expression increases in the lingual periderm cells at 17 dpc and then disappears at 19 dpc coinciding with the disappearance of the periderm cells at the onset of squamous stratification of the lingual epithelium. Expressed at day 2-3 postnatally in older, elongated taste bud cells and at day 5, uniformly distributed throughout the epithelium of villi, intervillus epithelium and developing crypt buds of the small intestine.
Heterotetramer of two type I and two type II keratins. KRT18 associates with KRT8 (By similarity). Interacts with PNN and mutated CFTR. Interacts with YWHAE, YWHAH and YWHAZ only when phosphorylated. Interacts with DNAJB6, TCHP and TRADD (By similarity). Interacts with the thrombin-antithrombin complex. Interacts with FAM83H (By similarity). Interacts with EPPK1 (By similarity). Interacts with PKP1 and PKP2 (By similarity).
O-GlcNAcylation increases solubility, and decreases stability by inducing proteasomal degradation.
Proteolytically cleaved by caspases during epithelial cell apoptosis. Cleavage occurs at Asp-231 by either caspase-3, caspase-6 or caspase-7 (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 (By similarity). Involved in the uptake of thrombin-antithrombin complexes by hepatic cells.
Belongs to the glutamine synthetase family.
Dodecamer. Interacts with BFSP2 and VIM.
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).
63-kDa precursor undergoes proteolytic processing in two steps, yielding two fragments in the first step (apparent molecular masses of 44 and 18 kDa) (By similarity). 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 (By similarity).
Displays arylsulfatase activity at acidic pH towards the artificial substrate p-nitrocatechol sulfate (By similarity). Catalyzes the hydrolysis of the 3-sulfate groups of the N-sulfo-D-glucosamine 3-O-sulfate units of heparin (By similarity).
Interacts with the C-terminal cytoplasmic domain of giantin/GOLGB1 (By similarity). Interacts with PBR and PKA regulatory subunit RI-alpha. Does not interact with PKA regulatory subunit RI-beta nor PKA regulatory subunit RII-alpha (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B; interactions with PI4KB and with TBC1D22A and TBC1D22B are mutually exclusive. Interacts with C10ORF76 and RAB11B (By similarity).
Involved in the maintenance of Golgi structure by interacting with giantin, affecting protein transport between the endoplasmic reticulum and Golgi. Involved in hormone-induced steroid biosynthesis in testicular Leydig cells. Recruits PI4KB to the Golgi apparatus membrane; enhances the enzyme activity of PI4KB activity via its membrane recruitment thereby increasing the local concentration of the substrate in the vicinity of the kinase.
The GOLD domain is essential for giantin binding.
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.
Predominantly found in brain and, in lower levels, in testis, but was nearly undetectable in spleen, lung, skeletal muscle, kidney and liver.
Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (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 (By similarity). 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:26182372). Dissociates from HSPA1A/HSPA1B and HSP90AA1 in response to arachidonic acid (By similarity). Interacts with CPNE1 (via VWFA domain) (By similarity). Interacts with CDC16, CDC27 (By similarity). Interacts with KLHDC10 (via the 6 Kelch repeats); inhibits the phosphatase activity on MAP3K5 (By similarity). Interacts with ATM and ATR; both interactions are induced by DNA damage and enhance ATM and ATR kinase activity (By similarity). Interacts with RAD17; reduced by DNA damage (By similarity). 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 (By similarity). Interacts with SMAD2 and SMAD3 but not with SMAD1; decreases SMAD3 phosphorylation and protein levels (By similarity). 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:12176367, PubMed:16549782). Interacts with FLCN (By similarity).
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:11523989, PubMed:12176367, PubMed:15546861, PubMed:16892053, PubMed:16549782). 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 (By similarity). 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 (By similarity). Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress (By similarity). Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1 (By similarity). Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E (By similarity). May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels (By similarity). 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 (PubMed:16549782). Dephosphorylate FNIP1, disrupting interaction with HSP90AA1/Hsp90 (By similarity).
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. Interacts with TBC1D31; the interaction is direct and recruits PJA2 to centrosomes.
Has E2-dependent E3 ubiquitin-protein ligase activity. 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. Plays a role in ciliogenesis by ubiquitinating OFD1 (By similarity).
Highly expressed in the brain, in nerve cells but not in glial cells. Abundantly expressed in pyramidal neurons and in the CA3 region of apical dendrites. Colocalizes with PRKAR2B in dentate granule cells and at postsynaptic sites of primary hippocampal neurons.
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.
Expression in brown adipose tissue decreased greatly after birth.
In adult, predominantly expressed in heart, in the cardiac myocytes. Not detected in brain, lung, liver, kidney and white adipose tissue. In embryos, predominantly expressed in the brown adipose tissue.
Plays an important role in the regulation of embryonic development, cell proliferation and cell differentiation, and is required for normal cardiomyocyte proliferation and heart development.
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). Acts also as a general glutamate conjugate and analog transporter that can limit the brain levels of endogenous metabolites, drugs, and toxins. Confers resistance to the antiviral agent PMEA. 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. Acts as a heme transporter required for the translocation of cytosolic heme to the secretory pathway (By similarity). 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. The authors conclude that ABCC5 is a low-affinity cyclic nucleotide transporter and a major function in cGMP excretion is unlikely.
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 (By similarity). Binds ESR1 and ESR2 with bound steroid ligand. Interacts with TBATA (By similarity).
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 (By similarity). Specifically binds the 5'-AACAAT-3' DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis (By similarity). 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 (PubMed:26150426). Not involved in precartilaginous condensation, the first step in chondrogenesis, during which skeletal progenitors differentiate into prechondrocytes (By similarity). 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 (By similarity). 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 (By similarity). Binds to the gene promoter of MBP and acts as a transcriptional repressor (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mS31 family.
Belongs to the succinate/malate CoA ligase alpha subunit family.
Heterodimer of an alpha and a beta subunit. Different beta subunits determine nucleotide specificity. Together with the ATP-specific beta subunit SUCLA2, forms an ADP-forming succinyl-CoA synthetase (A-SCS). Together with the GTP-specific beta subunit SUCLG2 forms a GDP-forming succinyl-CoA synthetase (G-SCS).
Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and specificity for either ATP or GTP is provided by different beta subunits.
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 (PubMed:9660828). 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 (By similarity).
Beta subunit (PAFAH1B1) inhibits the acetylhydrolase activity of the alpha1/alpha1 catalytic homodimer.
During the embryonic stages, high expressed in the brain, spinal cord, sensory ganglia (dorsal root and trigeminal ganglia), and thymus. In brain found throughout the ventricular and marginal zones. Expressed mainly in neural tissues.
Expressed in brain, spleen, lung, liver, kidney and testis. Not expressed in heart and skeletal muscle. Expressed in fetal brain as heterodimer (PubMed:9660828). Not expressed in adult tissues (PubMed:9660828). Expressed exclusively in granule cells (PubMed:9660828).
Forms a catalytic dimer which is either homodimer (alpha1/alpha1 homodimer) or heterodimer with PAFAH1B2 (alpha1/alpha2 heterodimer) (PubMed:9660828). 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).
Originally the subunits of the type I platelet-activating factor (PAF) acetylhydrolase was named alpha (PAFAH1B1), beta (PAFAH1B2) and gamma (PAFAH1B3) (By similarity). Now these subunits have been renamed beta (PAFAH1B1), alpha2 (PAFAH1B2) and alpha1 (PAFAH1B3) respectively (PubMed:9459487).
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.
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. 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. 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 (By similarity).
Homodimer (By similarity). Associates with the spliceosome (By similarity). Found in a complex with RO60 and Y5 RNA (By similarity). Found in a complex with FUBP1 and far upstream element (FUSE) DNA segment (By similarity). Interacts directly with ERCC3 (By similarity). Interacts with CDK7 and GTF2H1 (By similarity). Interacts with SRSF11/P54 (By similarity).
The third RNA recognition motif, called PUMP domain, is atypical and may rather mediate homodimerization and/or protein-protein interactions.
Interacts with SRF. Forms complexes with SRF and SRF cofactors ARID2, MYOCD and NKX2-5. Interacts with the N-terminus of SLC2A4 (By similarity).
May be involved in regulating transcriptional activation of cardiac genes during the aging process. May play a role in biosynthesis and/or processing of SLC2A4 in adipose cells (By similarity).
E3 ubiquitin-protein ligase that regulates cell proliferation. Involved in apoptosis regulation. Mediates ER stress-induced activation of JNK signaling pathway and apoptosis by promoting ERN1 activation and splicing of XBP1 mRNA. Also involved in protein trafficking and localization.
The RING-type zinc finger domain is required for E3 ligase activity and for promoting ER stress-induced JNK activation and apoptosis.
Interacts with RP9, SNW1, SFRS1, SFRS2,U2AF1, RBPJ, SAP30, HDAC2 NKAP and NEK6. Interacts with Epstein-Barr virus RPMS1. Component of the histone deacetylase complex. Component of the Notch corepressor complex. Interacts with NKAPL.
May modulate splice site selection during alternative splicing of pre-mRNAs. Regulates transcription and acts as corepressor for RBPJ. Recruits RBPJ to the Sin3-histone deacetylase complex (HDAC). Required for RBPJ-mediated repression of transcription (By similarity).
Belongs to the cytochrome c oxidase subunit 6B.
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.
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. ENO2 levels in brain increase 10-30 days after birth. Levels continue to accumulate over the following few months (protein only).
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.
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.
In the N-terminal section; belongs to the AlaDH/PNT family.
Expressed in all tissues tested, including liver, heart, lung, skeletal muscle, kidney, stomach, large intestine, small intestine, pancreas, spleen, peritoneal macrophage and thyroid.
Identified in the spliceosome C complex (By similarity). Interacts with PPIA/CYPA (By similarity).
Pre-mRNA binding protein, binds avidly to poly(G) and poly(U) RNA homopolymers. 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.
Highly expressed in photoreceptor cells, oligodendrocytes and throughout the myelinated parts of the central nervous system. Detected in brain, liver, kidney, spleen and trachea.
Homodimer. Interacts (via PH domain) with MYO1C. Interacts (via PH domain) with MYO7A (By similarity). Binds transducins (By similarity).
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.
Belongs to the glycosyltransferase 31 family. Beta3-Gal-T subfamily.
Glycosyltransferase that generates the core 1 O-glycan Gal-beta1-3GalNAc-alpha1-Ser/Thr (T antigen), which is a precursor for many extended O-glycans in glycoproteins. Plays a central role in many processes, such as angiogenesis, thrombopoiesis and kidney homeostasis development.
Homodimer; disulfide-linked. Interacts with the C1GALT1C1 chaperone; required for galactosyltransferase activity (By similarity).
Core component of box C/D small nucleolar ribonucleoprotein (snoRNP) particles; the core proteins SNU13, NOP56, NOP58 and FBL assemble stepwise onto the snoRNA. Interacts with NOLC1/Nopp140. Interacts with NUFIP1, RUVBL1 and RUVBL2; RUVBL1:RUVBL2 seem to bridge the association of NOP58 with NUFIP1. Interacts with PIH1D1 (By similarity).
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 (By similarity).
Sumoylation is essential for high-affinity binding to snoRNAs.
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.
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.
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 (By similarity).
Administration of dexamethasone results in the conversion of the proenzyme to the mature form in thymocytes.
Expressed abundantly in lymphocytes and macrophages of the thymus and spleen, and in the M cells of the intestine. In the brain, expression is limited to reactive microglial cells, the large pyrimidial neurons in the cerebral cortex, the CA1 and CA3 pyrimidial neurons of the hippocampus, the large neurons of the neostriatum, and the Purkinje neurons of the cerebellum.
Expression increases in all brain regions examined with age, and increases markedly in reactive microglial cells amd CA1 pyrimidial neurons following ischemic injury. In the thymus expression increased steadily up to 8 weeks of age before decreasing to a much lower level by 52 weeks. Expression levels in the spleen and stomach do not appear to vary with age.
Glycosylated. The nature of the carbohydrate chain varies between cell types. In brain microglia, the proenzyme contains a high mannose-type oligosaccharide, while the mature enzyme contains a complex-type oligosaccharide. In stomach and spleen, the mature enzyme contains a high mannose-type oligosaccharide. In erythrocyte membranes, the mature enzyme contains a complex-type oligosaccharide.
May have a role in immune function. Probably involved in the processing of antigenic peptides during MHC class II-mediated antigen presentation. May play a role in activation-induced lymphocyte depletion in the thymus, and in neuronal degeneration and glial cell activation in the brain (By similarity).
May interact with NF1/CTF1. Interacts with BCL3. Identified in a complex comprised of PIR, BLC3, NFKB1 and target DNA (By similarity).
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) (By similarity).
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 (By similarity).
Tubulin-folding protein; involved in the early step of the tubulin folding pathway.
Belongs to the sulfotransferase 3 family.
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.
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.
Expression levels increase upon lipid ingestion.
Forms a 1:1 stoichiometric complex with pancreatic lipase.
Readily detectable during gestation, reaches adult levels by 17-20 days gestation, rises markedly at 7 days of age but falls to adult levels by 14 days and remains at that level throughout the suckling-weanling period.
Induces mitochondrial fragmentation, possibly by promoting DNM1L-dependent fission and may play a role in mitochondrial morphogenesis during spermatogenesis.
The N-terminal domain is required for targeting to the mitochondrion.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A11 subfamily.
Brain and retina (PubMed:1400419, PubMed:1497897). Expressed predominantly within neurons (PubMed:1497897). Expressed in the hippocampus (at protein level) (PubMed:8731228).
GABA transport is inhibited by beta-alanine.
Mediates sodium- and chloride-dependent transport of gamma-aminobutyric acid (GABA) (PubMed:1400419, PubMed:1497897). Can also mediate transport of beta-alanine and to a lower extent that of taurine and hypotaurine (By similarity).
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system.
Monomer (By similarity). Interacts with IFRD1/PC4 (By similarity). Interacts (via IBD domain) with POGZ (via IBM motif) and CDCA7L (via IBM motifs) (By similarity). 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 (By similarity). Interacts (via IBD domain) with IWS1 (via IBM motif), MED1 (via IBM motif) and DBF4 (via IBM motifs) (By similarity).
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 (By similarity).
Binding of Ca(2+) triggers a conformation change that is essential for catalytic activity.
Spinal cord, submaxillary gland, cerebrum, cerebellum, and skeletal muscle.
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 (By similarity).
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.
Activating cyclin for the cyclin-associated kinase CDK10.
Associates with CDK10 to promote its kinase activity.
Belongs to the cyclin family. Cyclin-like FAM58 subfamily.
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 (By similarity).
The PH domain is required for localization to the membrane.
Myosin is a hexamer of 2 heavy chains and 4 light chains: interacts with myosin heavy chain MYO19.
Myosin regulatory subunit that plays an important role in regulation of both smooth muscle and nonmuscle cell contractile activity via its phosphorylation. Phosphorylation triggers actin polymerization in vascular smooth muscle. Implicated in cytokinesis, receptor capping, and cell locomotion.
Phosphorylation increases the actin-activated myosin ATPase activity and thereby regulates the contractile activity. It is required to generate the driving force in the migration of the cells but not necessary for localization of myosin-2 at the leading edge. Phosphorylation is reduced following epigallocatechin-3-O-gallate treatment.
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:8071310, PubMed:15485505). Determines cholinergic vesicular quantal size at presynaptic nerve terminals in developing neuro-muscular junctions with an impact on motor neuron differentiation and innervation pattern (PubMed:9182805). Part of forebrain cholinergic system, regulates hippocampal synapse transmissions that underlie spatial memory formation (By similarity). Can transport serotonin.
High expression in all major cholinergic cell groups, including peripheral postganglionic parasympathetic cells, preganglionic sympathetic and parasympathetic cells, ventral spinal cord and brainstem motoneurons, cell groups in the basal forebrain, the habenula and the corpus striatum. Weakly expressed in the cortex and hippocampus.
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. Directly regulates expression of PPARA and UCP1 and is involved in obesity resistance (By similarity).
Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs are known to mediate the association with nuclear receptors.
Reaches a maximum during the meiotic and the postmeiotic stages of germ cell development.
Testis specific. Expressed only in male germ cells.
The JmjC domain and the C6-type zinc-finger are required for the demethylation activity.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. Two pore calcium channel subfamily.
Dimer. Interacts with MTOR; the interaction is required for TPCN1 ATP sensitivity (By similarity). Interacts with STX7, STX8 and STX12 (By similarity). Interacts with JPT2 (By similarity). Found in a complex with LSM12, TPCN1 and TPCN2 (By similarity).
Each of the two internal repeats contains five hydrophobic transmembrane segments (S1, S2, S3, S5, S6) and one positively charged transmembrane segment (S4). S4 segments represent the voltage-sensor and are characterized by a series of positively charged amino acids at every third position.
Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a voltage-gated highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles. Localizes to the early and recycling endosomes membranes where it plays a role in the uptake and processing of proteins and regulates organellar membrane excitability, membrane trafficking and pH homeostasis. Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2. Required for mTOR-dependent nutrient sensing.
Na(+) current is inhibited by ATP in a MTORC-dependent manner. ATP sensitivity is independent of PI(3,5)P2 (By similarity). Probably regulated by Mg(2+) ions, cytosolic Mg(2+) selectively inhibits outward current while lysosomal Mg(2+) modestly inhibits both the outward and inward currents. In the absence of Mg(2+), NAADP readily activates TPCN2, with properties similar to PI(3,5)P2 (By similarity). Both current elicited by PI(3,5)P2 as well as NAADP are inhibited by tetrandrine (By similarity).
Widely expressed. Expressed at relatively high level in kidney, liver and lung, and in the kidney it is expressed at inner medullary collecting ducts.
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. 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.
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.
Catalyzes the reversible hydration of carbon dioxide into bicarbonate and protons and thus is essential to maintaining intracellular and extracellular pH. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.
Present in kidney and lung. Also particularly abundant in brain, muscle, heart and liver. Not detected in skin or spleen.
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.
Homodimer or heterodimer (Potential). Interacts with HOXC8 (By similarity).
May function as a transcriptional regulator.
May result from the retention of an intron.
Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity. The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones. In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides. 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. Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss. In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites (By similarity). 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 (PubMed:23382512).
Defects in Anks6 are the cause of polycystic kidney disease (cy). Heterozygous cy rats are characterized by progressive formation and enlargement of cysts in kidneys.
Homooligomer (PubMed:19324013). 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 (PubMed:19324013). Interacts (via SAM domain) with ANKS3 (via SAM domain) (PubMed:25671767, PubMed:26327442, PubMed:26188091).
Hydroxylated at Asn-129, most probably by HIF1AN. This hydroxylation results in decreased NEK8-binding.
The ankyrin repeats are necessary and sufficient for NEK8-binding.
Widely expressed with moderate level in brain, skeletal muscle and testis. Expressed in renal tubules.
Liver, and to a lesser extent in prostate, kidney, heart and brain.
The G(-) form of this protein is thought to be unexpressed.
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 (PubMed:10393181). Interacts with KCNH2 (By similarity). Associates with ribosomes (PubMed:10393181). 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 (By similarity). Interacts with SERPINA2P/SERPINA2 and with the S and Z variants of SERPINA1 (By similarity). Interacts with PPIB (By similarity). Interacts with ZNRF4 (By similarity). Interacts with SMIM22 (By similarity). Interacts with TMX2 (By similarity). Interacts with TMEM35A/NACHO and CHRNA7 (By similarity). Interacts with reticulophagy regulators RETREG2 and RETREG3 (By similarity).
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 (By similarity).
Phosphorylated at Ser-563 by MAPK3/ERK1. Phosphorylation by MAPK3/ERK1 increases its association with ribosomes.
Ubiquitinated, leading to proteasomal degradation. Probably ubiquitinated by ZNRF4.
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 (By similarity).
Involved in trafficking and recycling of synaptic vesicles.
Protease inhibitor required for egg fertilization. Required to prevent premature zona pellucida hardening before fertilization, probably by inhibiting the protease activity of ASTL, a protease that mediates the cleavage of ZP2 and triggers zona pellucida hardening (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. Interacts with DLAT.
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. May also play a role in glia-glia or glia-neuron interactions in the developing peripheral nervous system.
Detected in brain and on hippocampus neurons, especially at excitatory synapses. Detected in retina (at protein level). Expressed in brain, spinal cord and dorsal root ganglion.
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).
Highly expressed in liver and kidney (at protein level). Expressed at lower levels in testis, lung, cerebellum, skeletal muscle and pancreas (at protein level).
Involved in the regulation of homocysteine metabolism. Converts betaine and homocysteine to dimethylglycine and methionine, respectively. This reaction is also required for the irreversible oxidation of choline.
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. 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. Has anti-apoptotic effects in the cell. Involved in negative control of cell death upon cytokine withdrawal. Promotes development of hematopoietic cells.
Monomer. Interacts with NDOR1. Interacts with CHCHD4.
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.
Belongs to the FAD-binding oxidoreductase/transferase type 4 family.
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.
Kinesin family member that is involved in spindle formation and the movements of chromosomes during mitosis and meiosis. Binds to microtubules and to DNA. Plays a role in congression of laterally attached chromosomes in NDC80-depleted cells.
Heterodimers with GPN1 or GPN3. Binds to RNA polymerase II (RNAPII).
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.
Detected in liver, brain, heart, kidney, colon, aorta, hippocampus, hypothalamus and adrenal fasciculata.
Heteromultimeric cytoplasmic complex with HSP90, HSP70, and FKBP4, in the absence of ligand. After ligand binding, it translocates to the nucleus and binds to DNA as a homodimer and as a heterodimer with NR3C1. Binds the coactivator NCOA2. May interact with HSD11B2 in the absence of ligand. Binds the coactivators NCOA1, TIF1 and NRIP1 (By similarity).
Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.
Very low transactivation activity, not increased by aldosterone.
Belongs to the sulfatase-modifying factor family.
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 (By similarity).
Forms homodimers and heterodimers with PHETA2 (By similarity). Interacts with INPP5B (By similarity) (PubMed:20133602). Interacts with OCRL. Interaction with OCRL may be important for endosomal morphology and function (By similarity) (PubMed:20133602).
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.
Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.
Component of the p62 complex, a complex composed of NUP62, NUP54, and isoform p58 and isoform p45 of NUP58. Isoform p58 interacts with NUTF2. Isoform p58 interacts with SRP1-alpha and Importin p97 proteins when they are together, but not with SRP1-alpha protein alone.
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.
Belongs to the fatty acid desaturase CarF family.
Activated by the substrate 5-phospho-alpha-D-ribosyl-1-pyrophosphate and inhibited by the purine ribonucleotides, the end products of purine biosynthesis.
Catalyzes the formation of phosphoribosylamine from phosphoribosylpyrophosphate (PRPP) and glutamine.
Expressed at a high level in brain, heart, liver and stomach.
In the C-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Appeared in the brain of 16 days-old embryos and was maintained during the subsequent developmental stages.
Expressed exclusively in brain and testis.
Expression increased during the early steps of astrocyte differentiation.
Lysosomal membrane glycoprotein which plays a role in the unfolded protein response (UPR) that contributes to protein degradation and cell survival during proteasomal dysfunction. Plays a role in the process of fusion of the lysosome with the autophagosome, thereby modulating the autophagic process. Promotes hepatocellular lipogenesis through activation of the PI3K/Akt pathway. May also play a role in dendritic cell function and in adaptive immunity.
Autophagy factor required for autophagosome formation. Stabilizes ATG13, protecting it from proteasomal degradation.
Interacts with ATG13. Associates with a complex composed of ATG13, ULK1 and RB1CC1; the association with this complex requires the presence of ATG13.
ATP-dependent serine protease that mediates the selective degradation of misfolded and unassembled polypeptides in the peroxisomal matrix. Necessary for type 2 peroxisome targeting signal (PTS2)-containing protein processing and facilitates peroxisome matrix protein import. May indirectly regulate peroxisomal fatty acid beta-oxidation through degradation of the self-processed forms of TYSND1.
Interacts with PEX5. Interacts with TYSND1 (By similarity). May interact with enzymes involved in beta-oxidation of fatty acids, including ACOX1/AOX (By similarity).
Interacts with PEX5. Interacts with TYSND1.
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.
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family. Glucose transporter subfamily.
Highly expressed in adult and pubertal testis, but not prepubertal testis (PubMed:10821868). Moderate expression in hypothalamus, cerebellum, brainstem, hippocampus, and adrenal gland (PubMed:10821868). Lower amounts present in most other tissues (PubMed:10821868).
Insulin-regulated facilitative hexose transporter that mediates the transport of glucose and fructose (PubMed:10671487). Also able to mediate the transport of dehydroascorbate (PubMed:23396969).
Associates with MYD88 and IRAK2 to form a ternary complex called the Myddosome.
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Pelle subfamily.
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.
Heterodimer with PCLO. Part of a ternary complex involving PCLO and EPAC2. Interacts with RAB3C, RAB3D and RAB26 (By similarity). Binds RAB3A and RAB3B that have been activated by GTP-binding. 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.
Highly expressed in hippocampus, brain cortex, cerebellum and olfactory bulb. Detected at intermediate levels in midbrain, hindbrain and spinal cord, and at low levels in testis.
Rab effector involved in exocytosis. May act as scaffold protein. Plays a role in dendrite formation by melanocytes (By similarity).
Detected in several tissues, most prominent in brain and heart of adults (PubMed:7824279). Expressed in embryonic fibroblasts (PubMed:22659164).
Homodimer (By similarity). Interacts (via C-terminus only or via combined C-terminus and LIM domain, but not LIM domain only) with PTPN13 (via the second or fourth PDZ domains). Found in a complex with PTPN13 and TRIP6 (By similarity). Interacts (via PDZ domain) with ACTN1 and ACTN2 (via C-terminal SDL residues) (PubMed:14729062, PubMed:15456832). Interacts (via PDZ domain) with TRIP6 (via the second LIM domain or via the third LIM domain plus C-terminus) (By similarity). Interacts (via LIM domain) with GRIA1 (via C-terminus); this interaction as well as the interaction with alpha-actinin is required for their colocalization in early endosomes (PubMed:15456832). Interacts with PDLIM1 (PubMed:22659164). Forms (via LIM domain) a heterodimer with PDLIM3 (By similarity). Interacts directly with SRC (via kinase domain and to a lesser extent the SH2 domain) (By similarity).
Phosphorylated on tyrosine residue(s). Can be dephosphorylated by PTPN13.
Suppresses SRC activation by recognizing and binding to active SRC and facilitating PTPN13-mediated dephosphorylation of SRC 'Tyr-419' leading to its inactivation. Inactivated SRC dissociates from this protein allowing the initiation of a new SRC inactivation cycle (By similarity). Involved in reorganization of the actin cytoskeleton. In nonmuscle cells, binds to ACTN1 (alpha-actinin-1), increases the affinity of ACTN1 to F-actin (filamentous actin), and promotes formation of actin stress fibers (PubMed:14729062, PubMed:22659164). Involved in regulation of the synaptic AMPA receptor transport in dendritic spines of hippocampal pyramidal neurons directing the receptors toward an insertion at the postsynaptic membrane. Links endosomal surface-internalized GRIA1-containing AMPA receptors to the alpha-actinin/actin cytoskeleton. Increases AMPA receptor-mediated excitatory postsynaptic currents in neurons (PubMed:15456832).
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.
Inhibits phosphatase activity of protein phosphatase 1 (PP1) complexes.
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.
Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity (By similarity). Important for normal progress through mitosis and normal cytokinesis (By similarity). 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 (By similarity). 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 (By similarity). Required for the up-regulation of atypical chemokine receptor ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation (By similarity). 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 (By similarity). It is a major component of intranuclear and cytoplasmic actin rods (By similarity). Interacts with the subcortical maternal complex (SCMC) via interaction with TLE6 and NLRP5 (By similarity). Interacts with C9orf72 (By similarity).
Inactivated by phosphorylation on Ser-3. Phosphorylated on Ser-3 in resting cells. 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 (By similarity).
Inhibitor of phospholipase A2, also possesses anti-coagulant properties.
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 (By similarity).
Homodimer. Interacts with TNFSF10 and TNFSF11 (By similarity).
Belongs to the actin-binding proteins ADF family. GMF subfamily.
Phosphorylated; stimulated by phorbol ester.
This protein causes differentiation of brain cells, stimulation of neural regeneration, and inhibition of proliferation of tumor cells.
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 (By similarity). Interacts with SCN10A (PubMed:12050667). Interacts with TASOR (By similarity).
Belongs to the Mediator complex subunit 6 family.
In adults it is highly expressed in spleen, followed by kidney and lesser in lung. Not found in liver and skeletal muscle. In newborns it is abundantly expressed in brain and kidney.
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:8631773). 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 (By similarity).
Activated by guanine nucleotide exchange factor RCC1L.
Cleavage at position S2 is mediated by YME1L. Cleavage may occur in the sequence motif Leu-Gln-Gln-Gln-Ile-Gln (LQQQIQ).
Dynamin-related GTPase that is essential for normal mitochondrial morphology by regulating the equilibrium between mitochondrial fusion and mitochondrial fission (PubMed:16778770). Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion. Binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation. The intrinsic GTPase activity is low, and is strongly increased by interaction with lipid membranes (By similarity). 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 (By similarity).
Expressed in brain as well as retinal ganglion, starbust amacrine and horizontal cells of the retina. Absent from nerve fibers and photoreceptor cells of the retina.
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 2 and isoform 3, but not in isoform 1) 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 CHCHD3 and IMMT; these interactions occur preferentially with soluble OPA1 forms. Interacts with RCC1L; this interaction is direct (By similarity). Binds PARL (By similarity). Interacts with PRELID1 (By similarity).
PARL-dependent proteolytic processing releases an antiapoptotic soluble form not required for mitochondrial fusion. Cleaved by OMA1 at position S1 following stress conditions.
Belongs to the PIGG/PIGN/PIGO family. PIGN subfamily.
Ethanolamine phosphate transferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers ethanolamine phosphate to the first alpha-1,4-linked mannose of the glycosylphosphatidylinositol precursor of GPI-anchor.
Belongs to the small membrane AKAP family.
Component of a PRC1-like complex. 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). 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. Interacts with RING1. Interacts with RNF2/RING1B. Interacts with PCGF1, PCGF2, PCGF3, PCGF5 and PCGF6. Interacts (via chromodomain) with histone H3K9Me3 and H3K27me3. Interacts with H3K9Me2 and H4K20Me1. Interacts (via chromodomain) with single-stranded and double-stranded RNA; RNA binding seems to be required for the localization to chromatin (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. Promotes histone H3 trimethylation at 'Lys-9' (H3K9me3). Binds to histone H3 trimethylated 'Lys-9' (H3K9me3) or at 'Lys-27' (H3K27me3). May possibly also bind trimethylated lysine residues in other proteins (in vitro). Binds non-coding, single-stranded and double-stranded RNA. Plays a role in the timely repression of differentiation-specific genes in pluripotent embryonic stem cells to maintain the undifferentiated state. Regulator of cellular lifespan by maintaining the repression of CDKN2A, but not by inducing telomerase activity (By similarity).
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).
Interacts with BAF/BANF1. Interacts with protein phosphatase 2A (PP2A) components PPP2C (PPP2CA or PPP2CB) and PPP2R1A (By similarity).
Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit. 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. May regulate nuclear localization of VRK1 in non-dividing cells. It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex. Involved in brain development.
Belongs to the pseudouridine synthase Pus10 family.
Does not seem to be a disulfide isomerase. Plays an important role in the processing of secretory proteins within the endoplasmic reticulum (ER), possibly by participating in the folding of proteins in the ER.
Homodimer. Part of a large chaperone multiprotein complex comprising CABP1, DNAJB11, HSP90B1, HSPA5, HYOU, PDIA2, PDIA4, PPIB, SDF2L1, UGGT1 and very small amounts of ERP29, but not, or at very low levels, CALR nor CANX (By similarity).
Ubiquitous. Mostly expressed in secretory tissues.
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:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (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: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 (PubMed:9632753, PubMed:10400692). 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 (By similarity). 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 (By similarity). 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 the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1. 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 (By similarity). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (PubMed:12107176). 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 (PubMed:15546921). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (By similarity). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (By similarity). 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. 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. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53. Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility. Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation. Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (By similarity). 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 (By similarity). 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 (By similarity). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (By similarity).
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 (By similarity).
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 (By similarity).
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 (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. 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 TNK2 and CLK2. Interacts with RAF1. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with and phosphorylated by PDPK1 (By similarity). Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts with PA2G4 (PubMed:16832058). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (By similarity). Interacts with WDFY2 (via WD repeats 1-3) (By similarity). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (By similarity). 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 (By similarity). 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 (By similarity). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (By similarity).
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.
Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:10400692). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. 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. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (By similarity). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (By similarity). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase. Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (By similarity).
The AGC-kinase C-terminal mediates interaction with THEM4.
Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation.
Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (By similarity).
Widely expressed. Low levels found in liver with slightly higher levels present in thymus and testis.
Found in testis, brain, heart and at a much lower level in liver.
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 initially identified in the synaptonemal complex (PubMed:1363622). Characterization data from human and mouse indicate the protein is in the endoplasmic reticulum, which agrees with its biological function and the predicted signal sequence.
IGF-binding proteins prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cell culture. They alter the interaction of IGFs with their cell surface receptors. Also exhibits IGF-independent antiproliferative and apoptotic effects mediated by its receptor TMEM219/IGFBP-3R. Promotes testicular germ cell apoptosis (By similarity).
Interacts with XLKD1. Binds IGF2 more than IGF1. Forms a ternary complex of about 140 to 150 kDa with IGF1 or IGF2 and a 85 kDa glycoprotein (ALS). Interacts with TMEM219 (By similarity).
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 types of subunits: alpha and beta.
Single-stranded DNA-dependent ATP-dependent helicase.
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.
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.
Expressed at high level in neuroendocrine tissues.
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 (M), PFKL (L) and PFKP (P). The composition of the PFK tetramer differs according to the tissue type it is present in. 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.
Phosphorylation at Ser-386 promotes interaction with ATG4B.
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).
Homodimer (By similarity). Interacts with the AP-1 complex (By similarity).
Serine peptidase whose precise substrate specificity remains unclear (By similarity). Does not cleave peptides after a arginine or lysine residue (By similarity). Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex (By similarity). May play a role in the regulation of synaptic vesicle exocytosis (By similarity).
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.
Brain-specific, with highest expression in the hippocampal CA3 region (at protein level).
First expressed in the embryonic brain from 18 dpc. Levels increase during brain development until P7 and remain constant until P35. Further increase in adult brain (at protein level).
Phosphorylated by PKG on serine residues. Phosphorylated by PKG on Ser-91.
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).
Abundantly expressed in heart, lung, and kidney. Less evident expression is observed in brain, skeletal muscle, liver and spleen. No expression is detected in testis.
Endothelial orphan receptor that acts as a key regulator of angiogenesis.
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.
Proteolytically cleaved into 2 subunits, an extracellular alpha subunit and a seven-transmembrane subunit.
The transmembrane domain is not required for cleavage, but it is required for dimer formation.
Belongs to the DZIP C2H2-type zinc-finger protein family.
By glucocorticoids (PubMed:18555765). Stimulated by the N-methyl-D-aspartate (NMDA) type glutamate receptor antagonist MK801 (PubMed:18555765). Vitamin D and the Wnt signaling pathway inhibit its expression and activity (PubMed:18555765). Down-regulated during osteoblast mineralization (PubMed:18555765).
Decamer; composed of two pentamers (By similarity). Interacts with PALMD (By similarity). Interacts with RHOJ (By similarity).
Glutamine synthetase activity is inhibited by methionine sulfoximine (MSO).
Glutamine synthetase that catalyzes the ATP-dependent conversion of glutamate and ammonia to glutamine (PubMed:28323). 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. 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. May act as a palmitoyltransferase for RHOJ: able to autopalmitoylate and then transfer the palmitoyl group to RHOJ (By similarity). Plays a role in ribosomal 40S subunit biogenesis (By similarity).
In the adult liver, expression is restricted to a small population of hepatocytes which form only a small rim of one to three hepatocytes around the central veins (PubMed:6138251). Expressed in lung microvascular endothelial cells (PubMed:7638749).
Palmitoylated; undergoes autopalmitoylation.
Activated by forskolin (PubMed:1719547, PubMed:22906005, PubMed:24363043). Is not activated by calmodulin (PubMed:1719547). Inhibited by calcium ions, already at micromolar concentration. Activated by the G protein alpha subunit GNAS (PubMed:1719547, PubMed:7761832, PubMed:21596131). Activated by the G protein beta and gamma subunit complex (PubMed:7761832, PubMed:21596131, PubMed:22906005). Phosphorylation by RAF1 results in its activation (By similarity). Phosphorylation by PKC activates the enzyme (PubMed:22906005).
Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling (PubMed:22906005, PubMed:24363043, PubMed:10427002, PubMed:1719547, PubMed:7761832, PubMed:21596131, PubMed:11087399, PubMed:15591060, PubMed:19243146, PubMed:16766715). Down-stream signaling cascades mediate changes in gene expression patterns and lead to increased IL6 production (PubMed:24363043). Functions in signaling cascades downstream of the muscarinic acetylcholine receptors (PubMed:22906005).
Expressed in brain, olfactory epithelium and lung.
Interacts with RAF1 (By similarity). Interacts with GNAS (PubMed:9417641, PubMed:10427002, PubMed:11087399, PubMed:15591060, PubMed:16766715, PubMed:19243146). Interacts with the G protein beta and gamma subunit complex (PubMed:21596131).
Golgi-localized palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and therefore functions in several unrelated biological processes. 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. 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. 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. In epithelial cells, palmitoylates SCRIB and regulates its localization to the plasma membrane, regulating indirectly cell polarity and differentiation. Also palmitoylates JAM3 and promotes its expression at tight junctions and regulates its function in cell migration (By similarity). Palmitoylates the glucose transporter GLUT4/SLC2A4 and controls the insulin-dependent translocation of GLUT4 to the plasma membrane. In brain, could also palmitoylate SNAP25 and DLG4/PSD95. Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane. Could also palmitoylate NCDN (By similarity). May play a role in follicle stimulation hormone (FSH) activation of testicular Sertoli cells (PubMed:11796495).
Homooligomers. Heterooligomers with ZDHHC3.
Widely expressed. Present in Sertoli cells (at protein level).
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. Seems to contact the mother actin filament.
Belongs to the universal ribosomal protein uL30 family.
Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2) and serotonin (HTR2C) and GABA receptor (GABRA3). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alters their functional activities. Exhibits low-level editing at the GRIA2 Q/R site, but edits efficiently at the R/G site and HOTSPOT1. Does not affect polyomavirus replication but provides protection against virus-induced cytopathic effects. Essential for embryonic development and cell survival and plays a critical role in the maintenance of hematopoietic stem cells (By similarity).
Homodimer. Homodimerization is essential for its catalytic activity. Isoform 5 can form heterodimers with ADARB1/ADAR2. Isoform 1 interacts with ILF2/NF45 and ILF3/NF90. Binding to ILF3/NF90 up-regulates ILF3-mediated gene expression. Isoform 1 and isoform 5 (via DRBM 3 domain) interact with TNPO1. Isoform 5 (via DRBM domains) interacts with XPO5. Isoform 1 and isoform 5 can interact with EIF2AK2/PKR and UPF1.
Sumoylation reduces RNA-editing activity.
The third dsRNA-binding domain (DRBM 3) contains an additional N-terminal alpha-helix that is part of a bi-partite nuclear localization signal, together with the sequence immediately C-terminal to DRBM 3. The presence of DRBM 3 is important to bring together the N-terminal and the C-terminal part of the bi-partite nuclear localization signal for import mediated by TNPO1. RNA binding interferes with nuclear import.
Overexpression causes the formation of large vacuoles that seemed to be derived from the endoplasmic reticulum.
May inhibit NODAL and BMP signaling during neural patterning.
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. Also able to remove the C-terminal phenylalanine residue of alpha-tubulin TUBA8. Recognizes adjacent tubulin dimers along the same protofilament.
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 (By similarity).
Interacts with BCCIP, CREBBP/CBP and RELA/p65.
Widely expressed, with highest levels in liver, kidney, prostate and small intestine. Not detected in endothelial cells.
Cleaves alpha 1,2-, alpha 1,3-, and alpha 1,6-linked mannose residues from glycoproteins (PubMed:2211613). Involved in the degradation of free oligosaccharides in the cytoplasm (By similarity).
Widely expressed. Highest expression in testis, adrenal gland, and kidney.
Epididymis-specific expression (at protein level). Associated with apical membranes of efferent ductule and proximal epididymal duct epithelia (PubMed:12420295).
Orphan receptor. Could be involved in a signal transduction pathway controlling epididymal function and male fertility. May regulate fluid exchange within epididymis.
Component of the outer dense fibers (ODF) of spermatozoa. 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.
First detected in 30-day old rats after which, levels increase during spermatid elongation. Levels decrease at the time of spermatid assembly and disappear just before spermiation.
Interacts (via leucine zipper motif) with TCP11 (By similarity). Interacts with SPAG4 (PubMed:10373309). Interacts with KLC3 (PubMed:12594206).
Testis. Specifically located to the round spermatid layer and to the luminally-oriented cytoplasm of elongated spermatids.
The C-terminal contains many C-X-P repeats.
Belongs to the CoA-transferase III family.
Expressed only in the liver of young adult animals (100 days old) and is absent in the prepubertal male (27 days old), senescent male (800 days old) and female liver.
Induced by androgens and suppressed by estrogens. The expression is under the influence of pituitary growth hormone and thyroid hormone. Is regulated by progesterone in the uterus.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of estradiol and estrone (PubMed:7857871). May play a role in the regulation of estrogen receptor activity by metabolizing free estradiol (By similarity).
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 (By similarity).
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.
Restricted expression in the inner nuclear layer of the retina.
May play a role in the development of the central system.
May induce G2 arrest and apoptosis. May also increase cell sensitivity to apoptotic stimuli.
Belongs to the PI3/PI4-kinase family. ATM subfamily.
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.
Gut, vas deferens, uterus and aorta; barely detectable in liver, kidney, lung, and salivary gland. In the brain, markedly abundant in the cerebellum.
Orphan receptor. May bind to a neuropeptide and may regulate nociceptor function and/or development, including the sensation or modulation of pain (By similarity).
Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways. Binds to EPOR and suppresses EPO-induced STAT5 activation, possibly through a masking effect on STAT5 docking sites in EPOR. Suppresses PDGF-induced mitogenesis (By similarity). Involved in stimulation of glucose uptake by insulin. Involved in coupling from immunoreceptor to Ras signaling. Acts as a negative regulator of cytokine signaling in collaboration with CBL. Induces cytoskeletal reorganization and neurite outgrowth in cultured neurons.
Detected in embryonic brain, spinal cord and cortical neurons.
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 (By similarity). 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.
Phosphorylated on a tyrosine residue by NTRK1, NTRK2, NTRK3 and INSR after stimulation of the receptor by its extracellular ligand. 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 (By similarity).
Detected in kidney, in cortical and the medullary collecting tubules (at protein level) (PubMed:8429910). Detected in kidney medulla and cortex (PubMed:8429910, PubMed:7508187).
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:8429910, PubMed:7508187). Plays an essential role in renal water homeostasis (By similarity).
Ser-256 phosphorylation is necessary and sufficient for expression at the apical membrane. Endocytosis is not phosphorylation-dependent.
Involved in cytokinesis and septation where it has a role in the localization of F-actin.
Mediates electroneutral potassium-chloride cotransport when activated by cell swelling (PubMed:10347194). May contribute to cell volume homeostasis in single cells. May be involved in the regulation of basolateral Cl(-) exit in NaCl absorbing epithelia (Probable).
Phosphorylated, phosphorylation may regulate transporter activity.
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 (By similarity).
Belongs to the SOSS-B family. SOSS-B2 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 (By similarity).
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 (By similarity).
Associates with AP-1 and AP-3 but not with AP-2 complexes (By similarity). Interacts with FURIN (By similarity). Forms a ternary complex with furin and AP-1 (PubMed:9695949). Interacts with PKD2 (via acidic region) (By similarity). Interacts with SORL1 (By similarity).
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.
Constitutively phosphorylated on Ser-352; phosphorylation increases cell internalization and desensitizes the receptor.
Expressed in spleen and brain by neurons and glial cells (at protein level). Expressed in lung, testis and thymus but not in heart, liver or kidney. Expressed in cerebellum, cortex and brainstem.
Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis (By similarity).
Antiporter that mediates the import of reduced folates (PubMed:11600421, PubMed:19243012). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (By similarity). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (By similarity). Also able to mediate the import of antifolate drug methotrexate (PubMed:10827155, PubMed:11600421). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (By similarity).
Expressed in liver, heart, brain, spleen, lung and skeletal muscle.
Proton-selective channel that specifically transports protons into cells. Proton channel activity is only weakly-sensitive to voltage. 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. 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. Probably acts by maintaining the pH appropriate for formation of otoconia. Regulates purinergic control of intracellular calcium in vestibular supporting cells. May be involved in sour taste perception in sour taste cells by mediating entry of protons within the cytosol. Also involved in energy metabolism, by reducing adipose tissue inflammation and protecting from obesity-induced metabolic dysfunction.
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.
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. 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. 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. In cancer cells, however, isoform p19ARF/ARF and TRIP12 are located in different cell compartments, preventing isoform p19ARF/ARF ubiquitination and degradation. Does not mediate ubiquitination of isoform p16-INK4a of CDKN2A. Also catalyzes ubiquitination of NAE1 and SMARCE1, leading to their degradation. 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. 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.
Interacts with MYC; leading to disrupt interaction with isoform p19ARF/ARF of CDKN2A. Interacts with TRADD; leading to disrupt interaction with isoform p19ARF/ARF of CDKN2A. Interacts with SMARCC1; leading to disrupt interaction with SMARCE1.
Channel-forming protein essential for import of protein precursors into mitochondria (PubMed:10980201, PubMed:15347672, PubMed:19401463). Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by forming a complex with BCAP31 and mediating the translocation of Complex I components from the cytosol to the mitochondria (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). Interacts with mitochondrial targeting sequences (PubMed:10980201, PubMed:15347672). Interacts with TIMM29; linking the TIM22 complex to the TOM complex (By similarity). Forms a complex with BCAP31 (via C-terminus) which mediates the translocation of components of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) from the cytosol to the mitochondria (By similarity). Interacts (via N-terminus) with CYP1A1 (via mitochondrial targeting signal); this interaction is required for CYP1A1 translocation across the mitochondrial outer membrane (PubMed:19401463).
Altered in its ability to trans-activate compared to isoform B.
Belongs to the POU transcription factor family. Class-1 subfamily.
Interacts with PITX1. Interacts with LHX3. Interacts with ELK1.
Transcription factor involved in the specification of the lactotrope, somatotrope, and thyrotrope phenotypes in the developing anterior pituitary. Activates growth hormone and prolactin genes. Specifically binds to the consensus sequence 5'-TAAAT-3'.
At the completion of differentiation and migration of granular cells and at the initiation of the formation of synapses in cerebellar neurons.
Interacts with the heterodimer formed by CAPZA1 and CAPZB (By similarity). Interacts with RELA.
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 (By similarity). Promotes dimerization of NF-kappa-B subunits and regulates NF-kappa-B transcription factor activity. Promotes growth of cardiomyocytes, but not cardiomyocyte proliferation. Promotes cardiac muscle hypertrophy.
Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3. Interacts with HSD17B10/MRPP2; forming the MRPP1-MRPP2 subcomplex of the mitochondrial ribonuclease P complex. Interacts with GRSF1.
Mitochondrial tRNA N(1)-methyltransferase involved in mitochondrial tRNA maturation. Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5'-ends. 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. 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. 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. 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. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
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.
Detected in brain, and at much lower levels in liver, skeletal muscle and testis.
Voltage-insensitive potassium channel (PubMed:11374070, PubMed:15677687). Channel opening is triggered by mechanical forces that deform the membrane, and by raising the intracellular pH to basic levels (PubMed:11374070, PubMed:15677687). 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 (PubMed:15677687). 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).
May play a role in the structure and strength of both muscle and bone.
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)) (By similarity). Interacts with BRAWNIN (By similarity).
Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates transcription elongation by RNA polymerase II.
Expression restricted to the thick ascending limb of the loop of Henle (TALH).
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. May serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF. Facilitates neutrophil migration across renal epithelia.
Homodimer that then polymerizes into long filaments. The filaments can additionally assemble laterally to form a sheet. The filaments consist of a zigzag-shaped backbone with laterally protruding arms which interact with bacterial adhesin fimH. Two fimH molecules can bind to a single UMOD monomer.
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. Protects against urinary tract infections by binding to type 1 fimbriated E.coli. 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. Also promotes aggregation of other bacteria including K.pneumoniae, P.aeruginosa and S.mitis and so may also protect against other uropathogens.
In the urine, may contribute to colloid osmotic pressure, retards passage of positively charged electrolytes, prevents urinary tract infection and inhibits formation of liquid containing supersaturated salts and subsequent formation of salt crystals.
Proteolytically cleaved at a conserved C-terminal proteolytic cleavage site to generate the secreted form found in urine. This cleavage is catalyzed by HPN.
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.
Expressed in all tissues tested (at protein level). Longer isoforms are preferentially expressed in brain.
Functions in mitochondrial and peroxisomal division (PubMed:11553726, PubMed:12499366, PubMed:12861026, PubMed:17301055, PubMed:18250306). 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:11553726). The specific recruitment at scission sites is mediated by membrane receptors like MFF, MIEF1 and MIEF2 for mitochondrial membranes (By similarity). 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 (By similarity). Acts downstream of PINK1 to promote mitochondrial fission in a PRKN-dependent manner. Plays an important role in mitochondrial fission during mitosis (By similarity). 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 (By similarity). 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:18250306, 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:18250306, PubMed:23792689). Required for programmed necrosis execution (By similarity). Rhythmic control of its activity following phosphorylation at Ser-656 is essential for the circadian control of mitochondrial ATP production (By similarity).
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 (PubMed:10679301). 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 (PubMed:23792689, PubMed:18250306). Interacts with MFF; the interaction is inhinited by C11orf65/MFI (By similarity). Interacts with FIS1 (PubMed:12861026). Interacts with MIEF2 and MIEF1; GTP-dependent this 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 (By similarity).
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-656.
Phosphorylation/dephosphorylation events on two sites near the GED domain regulate mitochondrial fission (By similarity). Phosphorylation on Ser-656 by CAMK1 and PKA inhibits the GTPase activity, leading to a defect in mitochondrial fission promoting mitochondrial elongation (By similarity). Dephosphorylated on this site by PPP3CA which promotes mitochondrial fission (By similarity). Phosphorylation on Ser-635 by PINK1 activates the GTPase activity and promotes mitochondrial fission (By similarity). Phosphorylation on Ser-635 by CDK1 also promotes mitochondrial fission (PubMed:17301055). Phosphorylated in a circadian manner at Ser-656 (By similarity).
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 (By similarity).
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.
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.
Expressed in testis (PubMed:18651670). Present in Sertoli cells (at protein level) (PubMed:18651670).
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.
Plays an important role in the organization of the cytoskeleton. Binds to and sequesters actin monomers (G actin) and therefore inhibits actin polymerization.
Activated by autocatalytic proteolytical processing upon acidification. N-glycosylation is required for processing and activity (By similarity).
Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus.
Monomer. Interacts with CLN5 (By similarity). Interacts with CLN3 (By similarity).
Belongs to the DNA/RNA non-specific endonuclease 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.
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 (By similarity). Interacts with the phosphorylated form of PJA2 (By similarity). Interacts with MYRIP; his interaction may link PKA to components of the exocytosis machinery, thus facilitating exocytosis, including insulin release. Forms a complex composed of PRKAR2A, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity (By similarity). Interacts with ADCY8; inhibits adenylate cyclase activity through PKA phosphorylation (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.
Interacts with RHOA (PubMed:12900402). Interacts with GTP-bound HRAS, RAP1A, RAP2A, RAP2B and RRAS (By similarity). Interacts with IQGAP1 (PubMed:17086182). Interacts with AVIL (By similarity).
The Ras-GEF domain has a GEF activity towards HRAS and RAP1A. Mediates activation of the mitogen-activated protein kinase pathway (By similarity).
The Ras-associating domain 1 is degenerated and may not bind HRAS (By similarity). The Ras-associating domain 2 mediates interaction with GTP-bound HRAS, RAP1A and probably 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 (By similarity).
Ubiquitously expressed. Detected in glomerular podocytes (at protein level).
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (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 (NADPH--hemoprotein reductase) (By similarity). Exhibits catalytic activity for the formation of hydroxyestrogens from 17beta-estradiol (E2), namely 2- and 4-hydroxy E2 (PubMed:23821647). Metabolizes testosterone and progesterone to B or D ring hydroxylated metabolites (By similarity). May act as a major enzyme for all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (By similarity). Catalyzes the epoxidation of double bonds of certain PUFA. Converts arachidonic acid toward epoxyeicosatrienoic acid (EpETrE) regioisomers, 8,9-, 11,12-, and 14,15- EpETrE, that function as lipid mediators in the vascular system (PubMed:20972997). Additionally, displays dehydratase activity toward oxygenated eicosanoids including hydroperoxyeicosatetraenoates (HpETEs). This activity is independent of cytochrome P450 reductase, NADPH, and O2 (By similarity). Also involved in the oxidative metabolism of xenobiotics, particularly converting polycyclic aromatic hydrocarbons and heterocyclic aryl amines procarcinogens to DNA-damaging products (By similarity). Plays an important role in retinal vascular development. Under ambient/hyperoxic O2 conditions, promotes angiogenesis and capillary morphogenesis of retinal endothelial cells and pericytes, likely by metabolizing the oxygenated products symptomatic of oxidative stress (By similarity). Also, contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression (By similarity).
By polycyclic aromatic hydrocarbons (PAH), beta-naphthoflavone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Up-regulated by diesel exhaust particles (DEP). Decreased by estradiol (at protein level).
Enzyme activity is increased by cytochrome b5 (PubMed:23821647). Enzyme activity is increased by liposomes containing anionic phospholipids, phosphatidic acid and cardiolipin. Inhibited by naringenin with an IC(50) of 5 uM (By similarity).
Is involved in the dynamics of lysosomal membranes associated with microglial activation following brain lesion.
Belongs to the GTP cyclohydrolase I type 2/NIF3 family.
Homodimer (By similarity). Interacts with COPS2 (PubMed:12522100). Interacts with THOC7 (By similarity).
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.
Stimulates prolactin (PRL) release and regulates the expression of prolactin through its receptor GPR10. May stimulate lactotrophs directly to secrete PRL.
Widely expressed, with highest levels in medulla oblongata and hypothalamus.
Belongs to the PtdIns transfer protein family. PI transfer class I subfamily.
Catalyzes the transfer of phosphatidylinositol (PI) and phosphatidylcholine (PC) between membranes (PubMed:7568025, PubMed:18636990). Shows a preference for PI and PC containing shorter saturated or monosaturated acyl chains at the sn-1 and sn-2 positions (By similarity). 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 (By similarity).
Phosphatidylinositol transfer activity is inhibited by N-ethylmaleimide.
Phosphorylated by PKC in a calcium and phosphatidylserine-dependent manner.
Expressed in hair cells of the inner ear.
Protein that plays a role in the inhibition of canonical Wnt signaling pathway (By similarity). May be involved in neuronal migration during development of the cerebral neocortex (PubMed:16278297). Involved in the control of ciliogenesis and ciliary length (By similarity).
Interacts with MTNR1B (By similarity). Interacts with ARRB1 and ARRB2 in a spontaneous and agonist-independent manner; leading to the internalization of GPR135 in the endosomal compartment (By similarity).
Orphan receptor. Has spontaneous activity for beta-arrestin recruitment. Shows a reciprocal regulatory interaction with the melatonin receptor MTNR1B most likely through receptor heteromerization (By similarity).
Expression is under the tight control of the locus control region (LCRs).
Isoform 2 is highly expressed in differentiated arterial smooth muscle cells (ASMC) in the medial layer of the aorta. Weakly detected in brain and testis and to a lesser extent in organs rich in striated muscle or visceral smooth muscle.
Isoform 2 may have a role in regulating the growth and differentiation of arterial smooth muscle cells.
Belongs to the glycosyltransferase 68 family.
Acts as a phosphoinositide 5- and phosphoinositide 6-phosphatase and regulates cellular levels of inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6). Also acts as a 2,3-bisphosphoglycerate 3-phosphatase, by mediating the dephosphorylation of 2,3-bisphosphoglycerate (2,3-BPG) to produce phospho-D-glycerate without formation of 3-phosphoglycerate. May play a role in bone development (endochondral ossification). May play a role in the transition of chondrocytes from proliferation to hypertrophy (By similarity). Through the regulation of intracellular inositol polyphosphates, may control intracellular cation homeostasis, including that of calcium and iron, hence affecting free cation availability required for neural cell signaling (By similarity).
Belongs to the histidine acid phosphatase family. MINPP1 subfamily.
Widely expressed with highest levels in kidney and liver. Expressed in chondrocytes with an elevated expression in hypertrophic chondrocytes.
Down-regulated at high glucose levels of 10 and 25 mmol/liter glucose with highest expression at low glucose levels of 3 mmol/liter.
Facilitates ubiquitin-independent proteasomal degradation of polycomb protein CBX4 (By similarity). Plays a role in inhibiting the activity of glucokinase GCK and both glucose-induced and basal insulin secretion (PubMed:24187134).
Interacts with glucokinase GCK; the interaction occurs preferentially at low glucose levels.
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.
Highly expressed in liver. Moderately expressed in kidney, heart, testis, spleen and lung. Weakly expressed in skeletal muscle (at protein level). Expressed predominantly in liver. Expressed moderately in heart. Expressed weakly in lung, kidney, spleen and skeletal muscle.
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.
The PP1-binding domain is located between residues 59 and 94. The glycogen-binding domain is located between residues 94 and 257. The PYGL-binding site lies in the C-terminal 16 amino acids.
Expressed in kidney; more specifically in renal juxtaglomerular (JG) cells.
Interacts with the C-terminal half of SNRP70/U1-70K, the Arg/Ser-rich domain of AKAP17A as well as with U2AF1 and CLK1.
Splice factor required for alternative splicing of TRA2B/SFRS10 transcripts. May interfere with constitutive 5'-splice site selection (By similarity).
Splice factor required for alternative splicing of TRA2B/SFRS10 transcripts. May interfere with constitutive 5'-splice site selection.
The RanBP2-type zinc fingers mediate binding to RNA.
Belongs to the mitochondrion-specific ribosomal protein mL46 family.
Interacts with RPH3A and RPH3AL (By similarity). Interacts with RIMS1 (PubMed:9252191). Interacts with RIMS2 (PubMed:10748113). The GTP-bound form interacts with GAS8/DRC4 (via coiled-coil domains) (By similarity). Interacts with GDI2, and CHM; phosphorylation at Thr-86 disrupts these interactions (By similarity). Interacts with MADD (via uDENN domain); the GTP-bound form is preferred for interaction (By similarity).
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. Regulates the trafficking of endosomal alpha5beta1 integrin to the plasma membrane and involved in invasive cell migration. In T-cells involved in endosome-to-membrane recycling of receptors including T-cell receptor (TCR), CD28 and ITGAL; proposed to be implicated in T-cell proliferation and effector function. In dendritic cells involved in endosome-to-membrane recycling of major histocompatibility complex (MHC) class II probably involving retromer and subsequently allowing antigen sampling, loading and presentation during T-cell activation. Involved in cytokinesis and following polar body extrusion during oocyte meiotic maturation. Involved in Arp2/3 complex-dependent actin assembly driving Salmonella typhimurium invasion independent of ruffling. Involved in the exocytosis of MMP14 leading to matrix remodeling during invasive migration and implicating late endosome-to-plasma membrane tubular connections and cooperation with the exocyst complex. Involved in negative regulation of autophagy independently from its role in endosomal sorting by inhibiting BECN1 ubiquitination to inactivate PIK3C3/Vps34 activity.
Component of the WASH core complex also described as WASH regulatory complex SHRC composed of WASHC1, WASHC2, WASHC3, WASHC4 and WASHC5. The WASH core complex associates with the F-actin-capping protein dimer (formed by CAPZA1, CAPZA2 or CAPZA3 and CAPZB) in a transient or substoichiometric manner which was initially described as WASH complex. Interacts (via WHD1 region) with WASHC2; the interaction is direct. Interacts with BECN1; WASHC1 and AMBRA1 can competitively interact with BECN1. Interacts with BLOC1S2; may associate with the BLOC-1 complex. Interacts with tubulin gamma chain (TUBG1 or TUBG2). Interacts with TBC1D23 (By similarity).
The VCA (verprolin, cofilin, acidic) domain promotes actin polymerization by the Arp2/3 complex in vitro.
Ubiquitinated at Lys-219 via 'Lys-63'-linked ubiquitin chains by the TRIM27:MAGEL2 E3 ubiquitin ligase complex, leading to promote endosomal F-actin assembly.
From 14.0 dpc, expressed in developing myotomes. Once the muscle is innervated, localized to the neuromuscular junction (NMJ), where its expression is restricted to synaptic nuclei. Expression drops after birth.
Monomer (By similarity). Homodimer (Probable). Interacts with LRP4; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK. Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation. Interacts (via cytoplasmic part) with DOK7 (via IRS-type PTB domain); requires MUSK phosphorylation. Interacts with DVL1 (via DEP domain); the interaction is direct and mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Interacts with PDZRN3; this interaction is enhanced by agrin (By similarity). Interacts with FNTA; the interaction is direct and mediates AGRIN-induced phosphorylation and activation of FNTA (By similarity). Interacts with CSNK2B; mediates regulation by CK2 (By similarity). Interacts (via the cytoplasmic domain) with DNAJA3. Interacts with NSF; may regulate MUSK endocytosis and activity (By similarity). Interacts with CAV3; may regulate MUSK signaling (By similarity). Interacts with RNF31 (By similarity). Interacts with DOK7 (PubMed:23326516).
Phosphorylated (PubMed:23326516). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (PubMed:23326516). Autophosphorylated (By similarity). Autophosphorylation at Tyr-553 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK (By similarity).
Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:23326516). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation.
Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation (By similarity).
Up-regulated upon denervation (at protein level).
May bind filamentous actin. Interacts with the complex composed of DVL2 and Rac. Interacts with AXIN1; competes with MAP3K1. Interacts with MAP3K4 preventing MAP3K4 interaction with AXIN1. Directly interacts (via DIX domain) with DVL2 (via DIX domain). Interacts with gamma-tubulin.
Phosphorylated on tyrosine and serine residues.
Polyubiquitinated, leading to its proteasomal degradation. WNT3A signaling increases DIXDC1 protein levels by inhibiting its ubiquitination and subsequent degradation (By similarity).
Positive effector of the Wnt signaling pathway; activates WNT3A signaling via DVL2. Regulates JNK activation by AXIN1 and DVL2.
The DIX domain mediates interaction with AXIN1 and inhibition of AXIN1-mediated JNK activation through MAP3K1. Mediates interaction with DVL2; this interaction is required for activation of Wnt signaling (By similarity).
The coiled-coil domain mediates interaction with MAP3K4 and inhibition of AXIN1-mediated JNK activation through MAP3K4.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in the antrum and fundus (part of the stomach), duodenum and in gastric endocrine cells.
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.
Monomer. Interacts with GGA1 and GGA2. Binds to clathrin and activated ARFs, such as ARF1, ARF5 and ARF6. Binds RABEP1 and RABGEF1. Interacts with the membrane proteins M6PR/CD-MPR and IGF2R/CI-MPR and the accessory proteins SYNRG, EPN4, NECAP1, NECAP2 and AFTPH/aftiphilin. Interacts with TSG101 and UBC. Interacts with ADRA2B (By similarity). Interacts with NTRK1; the interaction is independent of NTRK1 activation and ubiquitination (PubMed:26446845). Interacts (via VHS domain) with BACE1 (via DXXLL motif) (By similarity).
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. Mediates export of the GPCR receptor ADRA2B to the cell surface. Involved in BACE1 transport and sorting as well as regulation of BACE1 protein levels. Regulates retrograde transport of BACE1 from endosomes to the trans-Golgi network via interaction through the VHS motif and dependent of BACE1 phosphorylation. Modulates BACE1 protein levels independently of the interaction between VHS domain and DXXLL motif through recognition of ubiquitination (By similarity). Key player in a novel DXXLL-mediated endosomal sorting machinery to the recycling pathway that targets NTRK1 to the plasma membrane (PubMed:26446845).
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.
Negatively regulates TSP1 expression at the level of transcription. This down-regulation was shown to reduce taxane-induced apoptosis (By similarity).
Detected in adult testis from age 13 months onwards.
Expressed in testis, specifically in spermatocytes and round spermatids.
Probably inhibits protein phosphatase 1 (PP1) in sperm via binding to catalytic subunit PPP1CC.
This protein is not related to the claudin family.
Homodimer. Interacts with GPIHBP1 with 1:1 stoichiometry (By similarity). Interacts with APOC2; the interaction activates LPL activity in the presence of lipids (By similarity). Interaction with heparan sulfate proteoglycans is required to protect LPL against loss of activity. Associates with lipoprotein particles in blood plasma. Interacts with LMF1 and SEL1L; interaction with SEL1L is required to prevent aggregation of newly synthesized LPL in the endoplasmic reticulum (ER), and for normal export of LPL from the ER to the extracellular space (By similarity). Interacts with SORL1; SORL1 acts as a sorting receptor, promoting LPL localization to endosomes and later to lysosomes, leading to degradation of newly synthesized LPL (By similarity).
Induced by insulin. Inhibited by isoproterenol.
Key enzyme in triglyceride metabolism (By similarity). Catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), and thereby plays an important role in lipid clearance from the blood stream, lipid utilization and storage (By similarity). Although it has both phospholipase and triglyceride lipase activities it is primarily a triglyceride lipase with low but detectable phospholipase activity (By similarity). Mediates margination of triglyceride-rich lipoprotein particles in capillaries (By similarity). Recruited to its site of action on the luminal surface of vascular endothelium by binding to GPIHBP1 and cell surface heparan sulfate proteoglycans (By similarity).
The apolipoprotein APOC2 acts as a coactivator of LPL activity (By similarity). Ca(2+) binding promotes protein stability and formation of the active homodimer. Interaction with GPIHBP1 protects LPL against inactivation by ANGPTL4 (By similarity).
Tyrosine nitration after lipopolysaccharide (LPS) challenge down-regulates the lipase activity.
Expressed in brain, testis, spleen and fibroblasts (at protein level). Not detected in liver, kidney or epithelial cells (at protein level).
Involved in regulating cell migration through association with the actin cytoskeleton. Has an essential role in the maintenance of Z line and sarcomere integrity.
Belongs to the ribose 5-phosphate isomerase family.
Receptor for the hormone galanin, GALP and spexin-1. 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)).
Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts with EPHB6; transphosphorylates EPHB6 to form an active signaling complex. Interacts with PICK1. Interacts (through Tyr-594) with NCK1 (via SH2 domain); activates the JUN cascade to regulate cell adhesion. The ligand-activated form interacts (through Tyr-928) with GRB7 and GRB10 (via SH2 domains). The ligand-activated form interacts (residues within the catalytic domain) with GRB2 (via SH2 domain). Interacts with GRB2, SHC1 and SRC; activates the MAPK/ERK cascade to regulate cell migration. Interacts with CBL; regulates receptor degradation through ubiquitination. Interacts with ACP1 (By similarity).
Phosphorylated. Autophosphorylation is stimulated by the ligand EFNB1. Required for interaction with SH2 domain-containing interactors, for activation of the MAPK/ERK and JUN signaling cascades and for ubiquitination by CBL (By similarity).
Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. In addition to its role in axon guidance also plays an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively (By similarity). Involved in the maintenance of the pool of satellite cells (muscle stem cells) by promoting their self-renewal and reducing their activation and differentiation (By similarity).
Ubiquitinated; (EFNB1)ligand-induced poly- and/or multi-ubiquitination by CBL is regulated by SRC and leads to lysosomal degradation.
Autoinhibited: in the inactive state, the enzymatic TIR domain is held apart by the autoinhibiting ARM repeats. 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. 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. Self-association of TIR domains is facilitated by the octamer of SAM domains.
Homooctamer; forms an octomeric ring via SAM domains. Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF function. Interacts with MAPK10/JNK3 and SDC2 (via cytoplasmic domain).
NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism. 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. 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. Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules. Can activate neuronal cell death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. 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.
Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or MAPK10) enhance the NAD(+) hydrolase (NADase) activity (PubMed:32968873). Phosphorylation at Ser-548 and subsequent activation takes place in response to oxidative stress conditions and inhibits mitochondrial respiration (By similarity). Phosphorylation at Ser-548 increases in response to cerebral ischemia/reperfusion (I/R) injury (PubMed:32968873).
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. 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. As a result, the two following motifs ARM 7 and ARM 8 reverse their directions and lie perpendicularly. Moreover, ARM repeats interact with different domains not only within each protomer but also of the adjacent ones.
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.
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. Enhances ligand-dependent transcriptional activity of nuclear hormone receptors. May play a role in cell differentiation (By similarity).
Detected in adult spleen, thymus, testis, bone marrow, lung and brain. Detected in embryonic brain, liver, lung, intestine, heart, kidney, thymus and spleen (at protein level).
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. Interacts with NANOS2. Directly interacts with ZNF335.
Belongs to the metallo-dependent hydrolases superfamily. TatD-type hydrolase family.
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).
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 (By similarity).
High expression in the spleen, moderate to low levels in several other tissues and cell types, but no detectable expression in skin dendritic cells or CD4(+) T-cells.
Involved in primary cilium formation. Probably acts as a transition zone protein required for localization of PKD1/PC1 and PKD2/PC2 to the ciliary membrane.
Heterochromatin component that specifically recognizes and binds methylated 'Lys-9' of histone H3 (H3K9me) and promotes recruitment of proteins that mediate epigenetic repression. Mediates recruitment of the HUSH complex to H3K9me3 sites: the HUSH complex is recruited to genomic loci rich in H3K9me3 and is required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3, as well as MORC2. Binds H3K9me and promotes DNA methylation by recruiting DNMT3A to target CpG sites; these can be situated within the coding region of the gene. Mediates down-regulation of CDH1 expression. 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. 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.
Homodimer. Interacts (via chromo domain) with histone H3K9me3. Has the highest affinity for H3K9me3, and lesser affinity for H3K9me2 and H3K9me1. Component of the HUSH complex; at least composed of TASOR, PPHLN1 and MPHOSPH8. Interacts with DNMT3, EHMT1 and SETDB1. Interacts with MORC2; the interaction associateS MORC2 with the HUSH complex which recruits MORC2 to heterochromatic loci. Interacts with ZNF638; leading to recruitment of the HUSH complex to unintegrated retroviral DNA (By similarity). Interacts with TASOR (By similarity).
Phosphorylated in M (mitotic) phase. Phosphorylation by CDK1 promotes dissociation from chromatin.
The chromo domain mediates interaction with methylated 'Lys-9' of histone H3 (H3K9me), with the highest affinity for the trimethylated form (H3K9me3).
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.
Glutathione is required for the prostaglandin D synthase activity.
Highly expressed in spleen and bone marrow. Lower levels of expression in small intestine, colon, liver, pancreas and skin. Not detected in brain, heart, lung or kidney (at protein level).
Relaxin is an ovarian hormone that acts with estrogen to produce dilatation of the birth canal in many mammals.
Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-411 is dependent on Thr-406 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation (By similarity).
Homodimer (By similarity). Interacts with DNAJC3 (By similarity). Interacts with STRBP. Forms a complex with FANCA, FANCC, FANCG and HSP70 (By similarity). Interacts with ADAR/ADAR1 (By similarity). The inactive form interacts with NCK1 and GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6, IKBKB/IKKB, IRS1, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). Interacts with DHX9 (via N-terminus) and this interaction is dependent upon activation of the kinase (By similarity).
IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (By similarity). Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (By similarity). Exerts its antiviral activity on a wide range of DNA and RNA viruses (By similarity). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3 and IRS1 (By similarity). In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation (By similarity). Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding pro-inflammatory cytokines and IFNs (By similarity). Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6 (By similarity). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (By similarity). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2) (By similarity). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (By similarity). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity).
Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection. Can also be activated by heparin, pro-inflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR (By similarity).
Component of the 19S proteasome regulatory particle complex (By similarity). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (By similarity). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (By similarity). Component of a complex with USP49 and RUVBL1 (By similarity). Interacts with PRPF19 (By similarity). Interacts with TRIM5 (By similarity). Interacts with NDC80 (By similarity). Interacts with PAAF1 (By similarity). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (PubMed:7776974). Interacts with ERCC6 (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. 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.
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 and EPS15L1. Interacts (via leucine-zipper domain) with CAV1 in a cholesterol-sensitive manner.
Regulates the traffic and/or budding of caveolae. 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). Seems to have an immune potentiation function, especially in the glioma (PubMed:15197346).
The leucine-zipper domain is essential for its localization in the caveolae and for its interaction with CAV1 and EPS15L1.
Up-regulated by 1,2-dithiole-3-thione (D3T).
Probable transcription factor, which may be involved in spermatogenesis and oogenesis.
ATP-binding subunit of the mitochondrial potassium channel located in the mitochondrial inner membrane. 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) (By similarity). Plays a role in mitochondrial iron transport. 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).
Belongs to the ABC transporter superfamily. ABCB family. Multidrug resistance exporter (TC 3.A.1.201) subfamily.
Strong expression is found in the heart, brain and testis (PubMed:16390497). In the testis, expressed both in the somatic Sertoli cells and peritubular cells and in the germline (spermatogonia and pachytene spermatocytes) (PubMed:16390497). Also expressed in the lung, liver, intestine and kidney (PubMed:16390497).
The mitochondrial potassium channel (mitoK(ATP)) is composed of 4 subunits of CCDC51/MITOK and 4 subunits of ABCB8/MITOSUR. Physically interacts with PAAT. Interacts with Neuropilin-1 (NRP1) in mitochondria.
Belongs to the DEAD box helicase family. DDX5/DBP2 subfamily.
Bifunctional enzyme that catalyzes the first two steps in lysine degradation.
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.
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 (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WEE1 subfamily.
Dephosphorylated at Thr-239 by CTDP1 (By similarity). Dephosphorylated at Ser-52 and Ser-123 by the serine/threonine-protein phosphatase 2A preventing its ubiquitin-mediated degradation (By similarity).
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-52 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 (By similarity).
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 (By similarity).
Ubiquitinated and degraded at the onset of G2/M phase.
Heterodimer with other HLH proteins. Interacts with COPS5, IFI204, GATA4, NKX2-5, CLOCK and BMAL1 (By similarity). Isoform Short can form homodimers.
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).
Heterotetramer of 2 alpha/HADHA and 2 beta/HADHB subunits; forms the mitochondrial trifunctional enzyme (By similarity). Also purified as higher order heterooligomers including a 4 alpha/HADHA and 4 beta/HADHB heterooligomer which physiological significance remains unclear (PubMed:1730633). The mitochondrial trifunctional enzyme interacts with MTLN (By similarity).
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. 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. Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids. 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. Independently of the subunit beta, the trifunctional enzyme subunit alpha/HADHA also has a monolysocardiolipin acyltransferase activity. 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. Allows the acylation of monolysocardiolipin with different acyl-CoA substrates including oleoyl-CoA for which it displays the highest activity.
Abundantly expressed in the placenta, with low to moderate levels in the brain, lung, thymus and kidney.
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 (By similarity).
Inhibited by 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA) and guanidinoethylmercaptosuccinic acid (GEMSA). Inhibited by chelating agents such as EDTA and EGTA (By similarity).
AOX genes evolved from a xanthine oxidoreductase ancestral precursor via a series of gene duplication and suppression/deletion events. Different animal species contain a different complement of AOX genes encoding an equivalent number of AOX isoenzymes. In mammals, the two extremes are represented by certain rodents such as mice and rats, which are endowed with 4 AOX genes, and by humans, whose genome is characterized by a single active gene (PubMed:23263164).
Belongs to the xanthine dehydrogenase family.
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and phthalazine, as well as aldehydes, such as benzaldehyde, retinal and pyridoxal. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Is probably involved in the regulation of reactive oxygen species homeostasis. Is a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. Also catalyzes nitric oxide (NO) production; under anaerobic conditions, reduces nitrite to NO with NADH or aldehyde as electron donor, but under aerobic conditions, NADH is the preferred substrate. These reactions may be catalyzed by several isozymes.
The experimental design does not allow to distinguish AOX1 from AOX3 in rat liver as the effector of the superoxide and nitric oxide production (PubMed:17353002 and 19801639).
Highest level of isoform 1 in the brain of newborn rats. Increasing levels of isoforms 2, 3, 4, and 5 in the brain of newborn rats from birth to 6 weeks of postnatal development. Increasing but low level of isoform 6 is expressed in the brain from 2 to 6 weeks of postnatal development.
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. Interacts with MPP2 (via the SH3-Guanylate kinase-like sub-module) (PubMed:27756895).
Part of the postsynaptic scaffold in neuronal cells.
ATP-dependent specificity component of the Clp protease complex. Hydrolyzes ATP. Targets specific substrates for degradation by the Clp complex. 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. 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. Important for efficient erythropoiesis through up-regulation of heme biosynthesis.
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.
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 (By similarity). May provide the octanoyl chain used for lipoic acid biosynthesis, regulating protein lipoylation and mitochondrial respiratory activity particularly in Purkinje cells (By similarity).
Homodimer (By similarity). Isoform 2 interacts with PPARA in the nucleus and increases its activity (PubMed:25031892).
Was originally (PubMed:9795230) thought to be a nuclear protein that interact with nuclear receptor. However, it was shown later to be mitochondrial (PubMed:12654921), a function related to nuclear receptors being unsure.
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 (By similarity).
Belongs to the proteasome subunit p27 family.
Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome (By similarity).
Interacts (via N-terminus) with spn-A/Rad51.
Involved in mitotic DNA repair and meiotic recombination. Functions in the recombinational DNA repair pathway. Essential for interhomolog gene conversion (GC), but may have a less important role in intersister GC than spn-A/Rad51. In the presence of DNA, spn-A/Rad51 enhances the ATPase activity of okr/Rad54.
Activated by phosphorylation of Thr-236. Once activated, activity is stimulated by binding target proteins (By similarity).
Catalytic activity is enhanced by phosphorylation of Thr-236.
Interacts with CIB1 (By similarity). Interacts with NSF; causing NSF dissociation from GRIA2.
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).
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.
Interacts (when phosphorylated at Ser-62) with PPP2R2D. Interacts with SNCA (By similarity).
Phosphorylation at Ser-62 by GWL during mitosis is essential for interaction with PPP2R2D (PR55-delta) and subsequent inactivation of PP2A (By similarity). Phosphorylated by PKA.
Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis. When phosphorylated at Ser-62 during mitosis, specifically interacts with PPP2R2D (PR55-delta) and inhibits its activity, leading to inactivation of PP2A, an essential condition to keep cyclin-B1-CDK1 activity high during M phase (By similarity). May indirectly enhance GAP-43 expression by binding to the NGF-regulatory region of its mRNA.
Up-regulated in denervated skeletal muscle (at protein level).
Whereas isoform ARPP-19 is ubiquitously expressed, isoform ARPP-16 is found only in selected brain neurons.
Heterodimer with IL12B; disulfide-linked. This heterodimer is known as interleukin IL-12. Heterodimer with EBI3/IL27B; not disulfide-linked. This heterodimer is known as interleukin IL-35. Interacts with NBR1; this interaction promotes IL-12 secretion (By similarity).
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 (By similarity). 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. Signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct DNA sites (By similarity).
A germline insertion in Tsc2 is the cause of the Eker rat model of inherited cancer susceptibility. Gives rise to a spectrum of epithelial and nonepithelial neoplasms.
CNS, uterus, heart, skeletal muscle, kidney and spleen.
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 (By similarity). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (By similarity). May also play a role in microtubule-mediated protein transport (PubMed:16707451). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (PubMed:9045618).
Phosphorylation at Ser-1388, Ser-1420 or Ser-1422 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr-1466 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-1800 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 (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 (By similarity). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (By similarity). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (By similarity). 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 (By similarity). Interacts with DAPK1 (By similarity). Interacts with FBXW5 (By similarity). Interacts with NAA10 (via C-terminal domain) (By similarity). Interacts with RRAGA (polyubiquitinated) (By similarity). Interacts with WDR45B (By similarity). Interacts with RPAP3 and URI1 (By similarity). Interacts with YWHAG (By similarity).
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.
Binds GTP saturably and exhibits a low intrinsic rate of GTP hydrolysis.
Component of the chromatin remodeling INO80 complex; specifically part of a complex module associated with the N-terminus of INO80.
Contributes to phagocytic removal of apoptotic cells in many tissues. Plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing. Promotes VEGF-dependent neovascularization (By similarity). 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. Appears to participate in the O-acetylation of GD3 ganglioside sialic acid.
The F5/8 type C 2 domain mediates high-affinity binding to phosphatidylserine-containing membranes.
Belongs to the peptidase S1 family. Tryptase subfamily.
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 (By similarity).
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.
Forms a homodimer or heterodimer. Can form a heterodimer with TSC22D1 (By similarity).
Expressed in the brain and the spinal cord. Expressed in the anterior olfactory nucleus, the olfactory tubercle, the nucleus supraopticus, the nucleus of the lateral olfactory tract, the piriform cortex, the cortico-amygdaloid transition zone, the septofimbrial nucleus and the indusium griseum (at protein level).
Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4. Interacts with LPS-bound LPB. Interacts with LPAR1. Interacts with the TLR2:TLR6 or TLR2:TLR1 heterodimers; upon interaction with ligands such as diacylated lipopeptides and triacylated lipopeptides, respectively. Interacts with MYO18A. Interacts with FSTL1.
Coreceptor for bacterial lipopolysaccharide. 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). Acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. 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. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (By similarity).
Detected in macrophages and peripheral blood monocytes.
The C-terminal leucine-rich repeat (LRR) region is required for responses to smooth LPS.
Up-regulated in Kuppfer cells exposed to bacterial lipopolysaccharide (LPS).
Interacts with ARRDC4 (By similarity). Identified in a complex containing at least ARRDC4, V2R and HGS (By similarity). Interacts with TMEM147 (By similarity).
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:1534150). Involved in renal water reabsorption (By similarity).
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.
Belongs to the methyltransferase superfamily. METTL18 family.
Interacts with GRWD1 and members of the heat shock protein 90 and 70 families; these proteins may possibly be methylation substrates for the enzyme.
Monomethylated at His-144 through automethylation. Automethylation at His-144 positively regulates the methyltransferase activity toward RPL3. Probably methylated on other residues.
Protein-L-histidine N-tele-methyltransferase that specifically monomethylates RPL3, thereby regulating translation elongation. Histidine methylation of RPL3 regulates translation elongation by slowing ribosome traversal on tyrosine codons: slower elongation provides enough time for proper folding of synthesized proteins and prevents cellular aggregation of tyrosine-rich proteins.
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). 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). In the nucleus, binds to the VEGFA core promoter and prevents MYC binding and transcriptional activation by MYC. 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.
Consists of two distinct domains, a catalytic core and a N-terminal extension that is involved in tRNA binding.
Homodimer. The tRNA molecule may bind across the dimer. Interacts with SIRT2. Interacts with METTL6; interaction is required for the tRNA N(3)-methylcytidine methyltransferase activity of METTL6.
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. Positively regulates phosphorylated protein HSF1 nuclear export to the cytoplasm.
Homodimer (By similarity). Heterodimerizes with YWHAZ (By similarity). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm (By similarity). Interacts with ARHGEF28 (By similarity). Interacts with BEX3 (By similarity). Weakly interacts with CDKN1B (By similarity). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (By similarity). Interacts with DENND1A (By similarity). Interacts with GAB2 (By similarity). Interacts with phosphorylated GRB10 (By similarity). Interacts with KSR1 (By similarity). Interacts with NDEL1 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (By similarity). Interacts with the phosphorylated (by AKT1) form of SRPK2 (By similarity). Interacts with TIAM2 (By similarity). Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (PubMed:22827337). Interacts with ZFP36 (via phosphorylated form) (By similarity). Interacts with SLITRK1 (By similarity). Interacts with HSF1 (via phosphorylated form); this interaction promotes HSF1 sequestration in the cytoplasm in a ERK-dependent manner (By similarity). Interacts with RIPOR2 (By similarity). Interacts with KLHL22; required for the nuclear localization of KLHL22 upon amino acid starvation (By similarity). Interacts with CRTC1 (By similarity). Interacts with CRTC2 (probably when phosphorylated at 'Ser-171') (By similarity). Interacts with CRTC3 (probably when phosphorylated at 'Ser-162' and/or 'Ser-273') (By similarity). Interacts with ATP2B1 and ATP2B3; this interaction inhibits calcium-transporting ATPase activity (By similarity). Interacts with MEFV (By similarity).
Present at high levels in the pineal gland early in development and decreased steadily thereafter.
Belongs to the eukaryotic ribosomal protein eL36 family.
Expressed in brain, kidney, liver, lung, spleen and thymus. Not expressed in heart and skeletal muscle.
Involved in the targeting and/or fusion of transport vesicles to their target membrane during transport of proteins from the early endosome to the lysosome. Required for heterotypic fusion of late endosomes with lysosomes and homotypic lysosomal fusion. Required for calcium regulated lysosomal exocytosis. Involved in the export of chylomicrons from the endoplasmic reticulum to the cis Golgi. Required for exocytosis of mediators during eosinophil and neutrophil degranulation, and target cell killing by natural killer cells. Required for focal exocytosis of late endocytic vesicles during phagosome formation.
May interact with STX17 (By similarity). Component of the SNARE complex composed of STX4, SNAP23 and VAMP7 that binds SYT7 during lysosomal exocytosis. Component of the SNARE complex composed of STX7, STX8, VAMP7 and VTI1B that is required for heterotypic fusion of late endosomes with lysosomes. Interacts with PICALM (By similarity). Interacts with RAB21 (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mS26 family.
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.
Plays a key role in regulating maximal capacity for electron transport and oxidative phosphorylation. May be involved in Fe-S cluster shuttling and/or in redox reactions.
Expressed strongly in embryo at 7 dpc. Expressed slightly in embryo at 11, 15 and 17 dpc.
Expressed strongly in testis and liver. Expressed slightly in heart, spleen, lung and kidney.
Interacts with CYTH2. Interacts with KPNA2; the interaction is direct. Does not interacts with ARL4A (By similarity).
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 (By similarity).
Glomerular epithelium cell (podocyte) (at protein level). Detected in liver, bile duct, kidney glomerulus and lung.
Homodimer, and heterodimer with SLC9A3R1. Binds ADRB2, SLC9A3, P2RY1, P2YR2, SRY, RDX, PDZK1 and LPAR2 (By similarity). Found in a complex with EZR, PODXL and SLC9A3R2. Interacts (via the PDZ domains) with PODXL (via the C-terminal PDZ-binding motif DTHL); interaction is detected in glomerular epithelium cells. Interacts with SGK1 and KCNJ1/ROMK1 (By similarity). Interacts (via the PDZ domains) with SLC26A6 (By similarity).
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.
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. May also act as scaffold protein in the nucleus.
Can induce apoptosis in a caspase-dependent manner and plays a role in p53/TP53-dependent apoptosis.
The proline-rich region is required for endoplasmic reticulum localization.
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.
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.
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 Interacts with CACGN8 (By similarity). Interacts with GRIA1.
Brain. Expressed in the neocortex, hippocampal formation, and cerebellum (at protein level).
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.
Abundant in the brain and lower levels in other tissues.
Belongs to the protein kinase superfamily. Tyr protein kinase family. AXL/UFO subfamily.
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 (By similarity).
An intrachain disulfide bond can be formed (PubMed:10601859). The protein structure shows that the relevant Cys residues are in a position that would permit formation of a disulfide bond (PubMed:10873471).
Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
Detected in liver (at protein level) (PubMed:1517209). Expressed in liver (PubMed:2806235).
Homotetramer (MAT-I); dimer of dimers (PubMed:1517209, PubMed:9755242, PubMed:10873471, PubMed:12888348). Homodimer (MAT-III) (PubMed:1517209, PubMed:9755242).
S-nitrosylation of Cys-121 inactivates the enzyme.
Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons (By similarity). Involved in the control of neuronal cell differentiation. Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. Affects also the migration, adhesion, and matrix/bone degradation in macrophages and osteoclasts (By similarity).
Selectively expressed in cortical and hippocampal neurons with prominent expression in the cell bodies and dendrites. Weakly expressed in rat fad pad ECs (RFPECs).
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:11786535, PubMed:15951807). 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:11786535, PubMed:15951807). 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:11786535, PubMed:15951807). 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), 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:11786535). Confers constitutive instability to HIPK2 through proteasomal degradation (By similarity). It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription, spermatogenesis and TNF-alpha signaling (By similarity). Has some overlapping function with SIAH2 (By similarity). 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 (PubMed:15951807). GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins (PubMed:15951807). 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. 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 PEG3 and HIPK2 (By similarity). Interacts with group 1 glutamate receptors GRM1 and GRM5. Interacts with DAB1, which may inhibit its activity. Interacts with UBE2E2. Interacts with SNCAIP. Interacts with HIPK2; the interaction is promoted by DAZAP2 and results in SIAH1-mediated ubiquitination and subsequent proteasomal degradation of HIPK2 (By similarity). Interacts with DAZAP2; the interaction is decreased following phosphorylation of DAZAP2 by HIPK2 (By similarity). Interacts with GAPDH; leading to stabilize SIAH1. Interacts with Bassoon/BSN and Piccolo/PLCO; these interactions negatively regulate SIAH1 E3 ligase activity. Interacts with DCC (By similarity). Interacts with AXIN1; catalyzes AXIN1 ubiquitination and subsequent proteasome-mediated ubiquitin-dependent degradation.
Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal degradation of HIPK2 (By similarity).
The SBD domain (substrate-binding domain) mediates the homodimerization and the interaction with substrate proteins. It is related to the TRAF family.
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.
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. In response to oxidative stress, monoubiquitination at Cys-11 is prevented.
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. Interaction with PEX7 only takes place when PEX7 is associated with cargo proteins containing a PTS2 peroxisomal targeting signal. PEX7 along with PTS2-containing cargo proteins are then translocated through the PEX13-PEX14 docking complex together with PEX5.
Interacts (via WxxxF/Y and LVxEF motifs) with PEX14; promoting translocation through the PEX13-PEX14 docking complex (By similarity). Interacts with PEX12 (By similarity). Interacts (Cys-linked ubiquitinated) with ZFAND6 (By similarity). Interacts (when ubiquitinated at Lys-209) with p62/SQSTM1 (By similarity). Interacts with PEX7, promoting peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal (By similarity).
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. Monoubiquitination at Cys-11 is removed by USP9X in the cytosol, resetting PEX5 for a subsequent import cycle (By similarity). When PEX5 recycling is compromised, polyubiquitinated by PEX10 during its passage through the retrotranslocation channel, leading to its degradation (By similarity). Monoubiquitination at Lys-473 by TRIM37 promotes its stability by preventing its polyubiquitination and degradation by the proteasome. Ubiquitination at Lys-528 is not mediated by the PEX2-PEX10-PEX12 ligase complex and is not related to PEX5 recycling. 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 (By similarity).
Phosphorylated at Ser-140 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). 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. 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.
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. 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.
Heterodimer; disulfide-linked. The heterodimer is composed of the disulfide-linked alpha and beta chains produced by autocatalytic cleavage of the precursor.
Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH (By similarity). 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 (By similarity). Has a higher catalytic efficiency towards C12-ceramides versus other ceramides (By similarity). Also catalyzes the reverse reaction allowing the synthesis of ceramides from fatty acids and sphingosine (By similarity). 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 (By similarity). Has also an N-acylethanolamine hydrolase activity (By similarity). By regulating the levels of ceramides, sphingosine and sphingosine-1-phosphate in the epidermis, mediates the calcium-induced differentiation of epidermal keratinocytes (By similarity). 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 (By similarity).
Proteolytically cleaved into two chains alpha and beta that remain associated via a disulfide bond. 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. The beta chain may undergo an additional C-terminal processing.
Degraded by PCSK6 and other endoproteases including FURIN and PCSK5.
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 (By similarity). 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 (By similarity). This calcium-binding protein also transiently associates with immature PCSK6 and regulates its secretion (By similarity).
Interacts with IKBKE and TBK1 via its coiled coil region. Interaction with TBK1 is disrupted upon viral infection or TLR3 stimulation. Interacts with CDC42BPB.
Physiological suppressor of IKK-epsilon and TBK1 that plays an inhibitory role in virus- and TLR3-triggered IRF3. Inhibits TLR3-mediated activation of interferon-stimulated response elements (ISRE) and the IFN-beta promoter. May act by disrupting the interactions of IKBKE or TBK1 with TICAM1/TRIF, IRF3 and RIGI. Does not inhibit NF-kappa-B activation pathways (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. May promote apoptosis, via its cleavage by caspase-3. Cytoplasm, cytoskeleton.
Proteolytically cleaved by caspase-3 during apoptosis.
The zeta chain is an alpha-type chain of mammalian embryonic hemoglobin.
May play a role in mitochondrial aerobic respiration essentially in the testis. Can also promote mitochondrial fission (By similarity).
Detected in brain and in kidney cortex and medulla, especially at the renal brush border membranes of the proximal convoluted tubules, in distal tubules and on intercalated cells of the collecting duct (PubMed:9843722). Detected cerebellum granule neurons (PubMed:25305496). Detected in astrocytes in hippocampus stratum radiatum (PubMed:19571146). Highly expressed in the stria vascularis in the cochlea (PubMed:12855359). Detected in neurons in Scarpa's ganglion in the inner ear, at nerve terminals in the crista ampullaris, in supporting cells and dark cells, but not in hair cells (PubMed:18838117) (at protein level). Detected in the brain cerebellar granule cell layer, amygdala, thalamus reticular nucleus, habenula, mesencephalic trigeminal neurons, neocortex and piriform cortex, and at lower levels in the olfactory bulb (PubMed:11567039). Detected cerebellum granule neurons (PubMed:23169818, PubMed:25305496). Detected in Scarpa's ganglia and crista ampullaris in the inner ear (PubMed:18838117).
Homodimer; disulfide-linked (PubMed:9843722). 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 (By similarity). 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 (By similarity).
Inhibited by 100 uM quinine. Slightly inhibited by Ba(+) (PubMed:17452494). Activity is first increased and then decreased when the extracellular pH is lowered to 6.0 (PubMed:17452494, PubMed:22948150).
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:17452494, PubMed:19571146). 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:22948150). The homodimer has very low potassium channel activity, when expressed in heterologous systems, and can function as weakly inward rectifying potassium channel. Channel activity is modulated by activation of serotonin receptors (PubMed:17452494). 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. Heterodimeric channels formed by KCNK1 and KCNK9 may contribute to halothane-sensitive currents (By similarity). 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). Contributes to the regulation of the resting membrane potential of pancreatic beta cells (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). The low channel activity of homodimeric KCNK1 may be due to sumoylation. The low channel activity may be due to rapid internalization from the cell membrane and retention in recycling endosomes (By similarity).
Sumoylation is controversial. Sumoylated by UBE2I. Not sumoylated when expressed in xenopus oocytes or mammalian cells. Sumoylation inactivates the channel, but does not interfere with expression at the cell membrane. Sumoylation of a single subunit is sufficient to silence the dimeric channel. Sumoylation of KCNK1 is sufficient to silence heterodimeric channels formed by KCNK1 and KCNK3 or KCNK9. Desumoylated by SENP1; this activates the channel. Desumoylated by SENP1; this strongly increases halothane-mediated activation of heterodimeric channels formed with KCNK9. SENP1 treatment has no effect.
When the external pH is lowered, it takes about 8 minutes till the channel has reached a new, stable state characterized by increased Na(+) permeability. Likewise, when raising the pH back to 7.4, it takes about 12 minutes for the channel to regain its original selectivity for K(+).
Belongs to the centaurin gamma-like family.
Brain. Is expressed in the cerebral cortex, caudate putamen, nucleus accumbens, septal nuclei, thalamus, hippocampus, and habenula. Not detected in cerebellum.
Forms homooligomers and heterooligomers with other GPCRs, such as OPRD1, OPRK1, OPRL1, NPFFR2, ADRA2A, SSTR2, CNR1 and CCR5 (probably in dimeric forms) (PubMed:10842167, PubMed:11896051, PubMed:14645661, PubMed:14729105, PubMed:17384143, PubMed:16682964). 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. Interacts (via C-terminus) with DNAJB4 (via C-terminus). Interacts with calmodulin; the interaction inhibits the constitutive activity of OPRM1; it abolishes basal and attenuates agonist-stimulated G-protein coupling (By similarity). Interacts with FLNA, PLD2, RANBP9 and WLS and GPM6A (PubMed:12519790, PubMed:17548356). Interacts with RTP4 (By similarity). Interacts with SYP and GNAS (PubMed:15857684, PubMed:17005904). Interacts with RGS9, RGS17, RGS20, RGS4, PPP1R9B and HINT1 (By similarity).
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-166 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-375 is involved in G-protein-dependent but not beta-arrestin-dependent activation of the ERK pathway.
Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:15944153, PubMed:16682964, PubMed:1846076, PubMed:21292762, PubMed:7595566, PubMed:7678862, PubMed:8051154, PubMed:8240812, PubMed:8393525, PubMed:9224819, PubMed:9572309, PubMed:11060299, PubMed:17384143, PubMed:18558479, PubMed:17947509). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:15944153, PubMed:16682964, PubMed:1846076, PubMed:21292762, PubMed:7595566, PubMed:7678862, PubMed:8051154, PubMed:8240812, PubMed:8393525, PubMed:9224819, PubMed:9572309, PubMed:11060299, PubMed:17384143, PubMed:18558479, PubMed:17947509). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (PubMed:8624732). 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:9224819, PubMed:16682964). 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:9224819, PubMed:9572309). 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 (PubMed:7595566, PubMed:15944153, PubMed:21292762, PubMed:9572309). Also couples to adenylate cyclase stimulatory G alpha proteins (PubMed:7595566). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (PubMed:11060299, PubMed:17384143, PubMed:18558479, PubMed:17947509). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. 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 (PubMed:11278523, PubMed:11896051, PubMed:15944153). 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. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (PubMed:11060299, PubMed:17384143, PubMed:18558479, PubMed:17947509). Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (PubMed:17384143, PubMed:16682964).
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.
Expressed at all stages examined including 17 dpc, 19 dpc, P2, P10 and P14. Expressed in neocortex, hippocampus and neuroepithelium at 17 dpc and more prominently expressed in striatum, hippocampus and cortex at postnatal days (at protein level).
Inhibited by alpha-(methylamino)isobutyric acid (MeAIB) (PubMed:10660562, PubMed:11692272). Inhibited by lithium, potassium, choline ions, N-methylglucamine (PubMed:11692272). The pH dependence has an allosteric effect on the transport (PubMed:11692272).
N-glycosylation plays an important role in the L-glutamine transport.
Specifically expressed in brain with the highest levels in cerebellum and thalamus (at protein level) (PubMed:10660562). Expressed in glutamatergic, GABAergic and a subset of dopaminergic neurons of the substantia nigra and cholinergic motoneurons (at protein level) (PubMed:12684517). Also expressed by ependymal cells lining the ventricle (at protein level). Expression is also detected in spinal cord, heart, colon and placenta (PubMed:16023720).
Symporter that cotransports short-chain neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane (PubMed:10660562, PubMed:11692272, PubMed:11756489, PubMed:12684517). The transport is elctrogenic, pH dependent and driven by the Na(+) electrochemical gradient (PubMed:11692272, PubMed:11756489, PubMed:12684517). Participates in the astroglia-derived glutamine transport into GABAergic interneurons for neurotransmitter GABA de novo synthesis (PubMed:11756489, PubMed:10660562). May also contributes to amino acid transport in placental trophoblast (By similarity). Regulates synaptic plasticity (By similarity).
Up-regulated by forskolin in astrocytes.
Belongs to the mitochondrion-specific ribosomal protein mL51 family.
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.
In contrast to CACNA2D1 and CACNA2D2, it does not bind gabapentin, an antiepileptic drug.
In heart, it is expressed in atrium but not in ventricle.
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).
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).
Belongs to the Mediator complex subunit 17 family.
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.
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. Interacts with the conotoxin GVIIJ (PubMed:24497506).
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.
Early induced by insulin independently of glucose and by 17-beta-estradiol in liver.
Expressed at high levels in the liver, small intestine and placenta. Not or barely detectable in other tissues, including whole pancreas, adipose tissues, skeletal muscle, kidney, spleen, brain, lung and testis.
Interacts with FZD4 (via FZ domain); competes with WNT2B for binding to FZD4, inhibiting Wnt signaling and repressing peripheral eye development. Interacts with TGFB1; the interaction contributes to regulation of the hair cycle. Interacts with netrin. Interacts with CCN2.
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 eukaryotic initiation factor 4G family.
Cochlea. Expressed at higher level in sesorineural epithelium than in the modiolus region or substantia nigra.
Expressed during embryogenesis. At 14 dpc, not detected in the brain or spinal cord. A striking expression seen in the nerve roots but not in the developing neurons of the dorsal root ganglia. A significant expression also seen around the superior mesentric artery.
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 (By similarity).
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.
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 (By similarity).
ADP-ribosylation prevents ability to form intermediate filaments.
Homomer (By similarity). Interacts with DST (By similarity). Interacts with MTM1 (By similarity). Interacts with EPPK1; interaction is dependent of higher-order structure of intermediate filament (By similarity). Interacts with CRYAB (By similarity). Interacts with NEB (via nebulin repeats 160-164) (By similarity). Interacts (via rod region) with NEBL (via nebulin repeats 1-5) (By similarity). Interacts with PKP1 (By similarity).
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. 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. 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.
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.
Ubiquitination by a SCF-like complex containing ASB2 leads to proteasomal degradation.
Hexamer of two different chains: A and B (A6, A5B, A4B2, A3B3, A2B4, AB5, B6) (By similarity). Interacts with CAPN8 (By similarity). Interacts with AKAP13 (By similarity). Interacts ITGB1BP1 (via C-terminal domain region) (By similarity). 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. Acts as a transcriptional activator of the MYC gene; binds DNA non-specifically. 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). 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. Exhibits histidine protein kinase activity (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX (By similarity). Interacts with TAF1C and SPAG9. Interacts with PARP10. Interacts with KDM5A and KDM5B. Interacts (when phosphorylated at Thr-58 and Ser-62) with FBXW7. Interacts with PIM2. Interacts with RIOX1 (By similarity). The heterodimer MYC:MAX interacts with ABI1; the interaction may enhance MYC:MAX transcriptional activity (PubMed:17304222). Interacts with TRIM6 (By similarity). Interacts with NPM1; the binary complex is recruited to the promoter of MYC target genes and enhances their transcription (By similarity). Interacts with CIP2A; leading to the stabilization of MYC (By similarity).
POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors. When combined, these factors are sufficient to reprogram differentiated cells to an embryonic-like state designated iPS (induced pluripotent stem) cells. iPS cells exhibit the morphology and growth properties of ES cells and express ES cell marker genes.
Phosphorylated by PRKDC (By similarity). Phosphorylation at Ser-329 by PIM2 leads to the stabilization of MYC (By similarity). Phosphorylation at Ser-62 by CDK2 prevents Ras-induced senescence. Phosphorylated at Ser-62 by DYRK2; this primes the protein for subsequent phosphorylation by GSK3B at Thr-58. Phosphorylation at Thr-58 and Ser-62 by GSK3 is required for ubiquitination and degradation by the proteasome. Dephosphorylation at Ser-62 by protein phosphatase 2A (PPP2CA) promotes its degradation; interaction with PPP2CA is enhanced by AMBRA1 (By similarity).
Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3'. Activates the transcription of growth-related genes (PubMed:17304222). Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis (By similarity). Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells. 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 (By similarity).
Ubiquitinated by the SCF(FBXW7) complex when phosphorylated at Thr-58 and Ser-62, leading to its degradation by the proteasome. Ubiquitination is counteracted by USP28 in the nucleoplasm and USP36 in the nucleolus, both interacting with of FBXW7, leading to its deubiquitination and preventing degradation. Also polyubiquitinated by the DCX(TRPC4AP) complex. Ubiquitinated by TRIM6 in a phosphorylation-independent manner.
Belongs to the G-alpha family. G(q) subfamily.
Interacts (via the C-terminal) with MMP2 (via the C-terminal PEX domain); the interaction inhibits the MMP2 activity.
The activity of TIMP2 is dependent on the presence of disulfide bonds.
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.
Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.
Low levels are present in newborn rats and up to day 6. Subsequently, levels increase strongly. Adult levels are detected starting from day 9 in the basal turn of the cochlea, from day 10-11 in the middle turn, and from day 12 in the apical turn.
Motor protein that converts auditory stimuli to length changes in outer hair cells and mediates sound amplification in the mammalian hearing organ. Prestin is a bidirectional voltage-to-force converter, it can operate at microsecond rates. It uses cytoplasmic anions as extrinsic voltage sensors, probably chloride and bicarbonate. After binding to a site with millimolar affinity, these anions are translocated across the membrane in response to changes in the transmembrane voltage. They move towards the extracellular surface following hyperpolarization, and towards the cytoplasmic side in response to depolarization. As a consequence, this translocation triggers conformational changes in the protein that ultimately alter its surface area in the plane of the plasma membrane. The area decreases when the anion is near the cytoplasmic face of the membrane (short state), and increases when the ion has crossed the membrane to the outer surface (long state). So, it acts as an incomplete transporter. It swings anions across the membrane, but does not allow these anions to dissociate and escape to the extracellular space. Salicylate, an inhibitor of outer hair cell motility, acts as competitive antagonist at the prestin anion-binding site (By similarity).
Specifically expressed in outer hair cells. Not detected in other cells of the organ of Corti.
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. The protease responsible for this partial degradation could be calpain II.
Interacts with PKN1. 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.
Binds ROCK1 and ROCK2 (PubMed:8816443). Also binds PKN1/PRK1. Interacts with ARGGEF3. Interacts with RTKN. Interacts with AKAP13. Interacts with RIPOR1 (By similarity).
Expressed at very low levels in quiescent cells but is transiently induced by serum stimulation with levels increasing to a maximum within 30 minutes and declining over the next hour.
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 (By similarity).
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 (By similarity).
May play a role in the formation or function of ciliated cells.
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. Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the HSP90 pathway (By similarity).
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. Binds to the progesterone receptor. Interacts with TERT; the interaction, together with HSP90AA1, is required for correct assembly and stabilization of the telomerase holoenzyme complex. Interacts (via PXLE motif) with EGLN1/PHD2, recruiting EGLN1/PHD2 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation. Interacts with HSP90AA1, FLCN, FNIP1 and FNIP2.
Proteolytically cleaved by caspase-7 (CASP7) in response to apoptosis, leading to its inactivation.
Widely expressed with highest levels in testis.
Heterodimer of a type I and a type II keratin. May associate with KRT17.
Plays a central role in hair and nail formation. Essential component of keratin intermediate filaments in the companion layer of the hair follicle (By similarity).
May modulate NF-kappaB signaling and play a role in cell growth.
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.
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 ATP5MPL (PubMed:17575325). Interacts with PPIF (By similarity). 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 (PubMed:21926988). Interacts with CLN5 and PPT1 (By similarity). Interacts with S100A1; this interaction increases F1-ATPase activity (By similarity). Interacts with MTLN (By similarity). Interacts with TTC5/STRAP; the interaction results in decreased mitochondrial ATP production (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. 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.
Abundantly expressed in testes. Expressed in germ cells, but not in Sertoli or Leydig cells of the adult testis. Localized at the acrosomal region of the round and elongated spermatids at stages VIII-X.
Expressed in lung bronchial epithelium goblet/mucous cells. Also expressed in spleen and testis. Expressed at very low levels in heart muscle, kidney, liver, brain and skeletal muscle.
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 (By similarity).
The MHD1 and MHD2 domains mediate localization on recycling endosomes and lysosome.
Expressed in oligodendrocytes of the postnatal optical nerve up to day 30, then the number of expressing cells decreases.
Expressed specifically in the brain, including the corpus callosum, hippocampal and cerebral white matter. Also detected in cells scattered in gray matter, most probably in oligodendrocytes.
Promotes formation and maturation of oligodendrocytes, especially within the brain. Cooperates with OLIG2 to establish the pMN domain of the embryonic neural tube (By similarity).
Interacts with RAB4A (membrane-bound form); the interaction involves NDRG1 in vesicular recycling of CDH1. Interacts with APOA1, APOA2, PRA1 and RTN1 (By similarity).
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 (By similarity).
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 (By similarity).
May act as a transcription factor. Plays a role in the innate immunity against intracellular pathogens. Required for resistance to M.tuberculosis and L.monocytogenes. Promotes apoptosis of infected cells (By similarity).
Endogenous ligand for GPR171. Neuropeptide involved in the regulation of feeding.
Expressed by 12.5 dpc in essentially all differentiating neurons in the mantle layer of the myelencephalon, metencephalon, diencephalon, spinal cord and several sympathetic ganglia. During later stages of prenatal development, widespread expression continues in post-mitotic neurons of both the CNS and PNS and begins in endocrine cells of the anterior and intermediate pituitary.
Expressed in adult brain (all major structural regions), adrenal gland (medulla) and spinal cord (dorsal and ventral horn). Expressed in pancreatic islands.
Interacts via the C-terminal inhibitory domain with PCSK1 65 kDa form.
May function in the control of the neuroendocrine secretory pathway. Proposed be a specific endogenous inhibitor of PCSK1 (PubMed:10632593, PubMed:10816562). ProSAAS and Big PEN-LEN, both containing the C-terminal inhibitory domain, but not the processed peptides reduce PCSK1 activity in the endoplasmic reticulum and Golgi. It reduces the activity of the 87 kDa form but not the autocatalytically derived 65 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).
ProSAAS(1-180) increases secretion of enzymatically inactive PCSK1.
Proteolytically cleaved in the Golgi. Big SAAS, Little SAAS, PEN and Big LEN are the major processed peptides in proSAAS-overexpressing PC-12 phaeochromocytoma cells (lacking PCSK1 and PCSK2 endopeptidases). Peptides corresponding to PEN and a proSAAS aa 40-59 have been detected in wild-type PC-12 cells.
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.
The four C-terminal amino acids of Big LEN are sufficient to bind and activate GPR171.
Belongs to the complex I subunit 5 family.
Belongs to the WD repeat DCAF13/WDSOF1 family.
Component of the outer dynein arm-docking complex along with ODAD2, ODAD3, ODAD4 and CLXN. Interacts with ODAD3. 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. Interacts with DNAH9. Interacts with MNS1 (By similarity). 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).
Component of the outer dynein arm-docking complex 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).
May mediate cellular response to DNA damage by protecting against ultraviolet C-induced cell death. Can form voltage-gated calcium and potassium channels in vitro.
Identified in a complex composed of RNF43, LGR5 and RSPO1 (By similarity). Also interacts with other R-spondin ligands, including RSPO2, RSPO3 and RSPO4 (By similarity).
Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a stem cell marker of the intestinal epithelium and the hair follicle. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Involved in the development and/or maintenance of the adult intestinal stem cells during postembryonic development (By similarity).
Catalyzes the last step of tRNA splicing, the transfer of the splice junction 2'-phosphate from ligated tRNA to NAD to produce ADP-ribose 1''-2'' cyclic phosphate.
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. 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. 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. 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. Binds cholesterol via its SSD domain.
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). Forms a stable complex 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 (By similarity). Interacts with the SEC23-SEC24 complex in a SAR1-GTP-dependent manner through an ER export signal in its third cytoplasmic loop (By similarity). Binds cholesterol through its SSD domain (By similarity). 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 (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 (By similarity). Interacts with SPRING1 (By similarity).
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 PDZK1. Forms a heterodimer with SLC5A2; this interaction enhances SLC5A2 transporter activity over a hundred-fold.
Forms a heterooligomeric complex with ITAM-containing signaling subunits FCER1G. Interacts (via transmembrane domain) with signaling subunits; this interaction is a prerequisite for receptor complex expression on the cell surface and intracellular signal transduction. Binds the Fc region of antigen-complexed IgG.
Phosphorylated following receptor ligation.
Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Binds with intermediate affinity to both IgG2a and IgG2b. Can bind to IgG2a and IgG2b monomers. Does not display binding to IgG1 or IgG3 (By similarity). Recognizes neutralizing virus-specific IgGs displayed on the cell surface of infected cells and triggers antibody-dependent cellular cytotoxicity (ADCC). Confers protection to lethal influenza virus infection (By similarity). On splenic dendritic cells, uptakes antigen immune complexes and efficiently divert them into MHC class I and II antigen presentation pathways to provide for superior priming of CD4-positive and CD8-positive T cell immune responses (By similarity). Mediates neutrophil activation by IgG complexes redundantly with FCGR2A (By similarity). Plays a role in promoting bone resorption by enhancing osteoclast differentiation following binding to IgG2a (By similarity). Also acts as a receptor for the Fc region of immunoglobulin epsilon (IgE). Binds with low affinity to both the a and b allotypes of IgE. Has also been shown to bind to IgE allotype a only but not to allotype b. Binds aggregated IgE but not the monomeric form and bound monomeric IgG is readily displaced by IgE complexes. Binding to IgE promotes macrophage-mediated phagocytosis, antigen presentation to T cells, production of pro-inflammatory cytokines and the late phase of cutaneous allergic reactions (By similarity). Mediates enhanced ADCC in response to afucosylated IgGs (PubMed:34485821).
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 (By similarity).
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 (By similarity). May play an important role in control of lens epithelial cell proliferation. Can initiate events that lead to a mesangial proliferative glomerulonephritis, including influx of monocytes and macrophages and production of extracellular matrix.
Homodimer; disulfide-linked. Interacts with PDGFRB homodimers, and with heterodimers formed by PDGFRA and PDGFRB (By similarity).
Not detected in the spinal cord at 21 dpc. Expressed weakly at postnatal day 1 (P1) and a strong expression seen at P21 and this continues into adulthood.
Widely expressed. Expressed at high levels in the kidney, adrenal glands, eye and CNS. In the kidney the localization is confined to arterial and arteriolar vascular smooth muscle cells and is also detected at low levels in the glomeruli In the eye in the anterior segment it is localized to the iris and ciliary body. In the retina localizes intensely to the outer plexiform layer, which contains photoreceptor axons and the synaptic layer between photoreceptors and second order neurons. In the spinal cord, prominently expressed in the motorneurons.
Binds 2 magnesium ions, but the ions interact each with only 1 or 2 residues.
Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits; the complex contains two deadenylase subunits, CNOT6 or CNOT6L, and CNOT7 or CNOT8. Interacts with CNOT7 and CNOT8. Interacts with UNR. Interacts with ZFP36L1 (via N-terminus). Interacts with ZNF335.
Poly(A) nuclease with 3'-5' RNase activity. Catalytic component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Involved in mRNA decay mediated by the major-protein-coding determinant of instability (mCRD) of the FOS gene in the cytoplasm. In the presence of ZNF335, enhances ligand-dependent transcriptional activity of nuclear hormone receptors. Mediates cell proliferation and cell survival and prevents cellular senescence.
Binds DNA and may function as a transcriptional repressor.
Interacts with PPP1CA. Interacts with EIF2S1 (By similarity). Interacts with PCNA (By similarity). Interacts with LYN and KMT2A/MLL1. Interacts with PPP1R1A and SMARCB1. Interacts with SMAD7. Interacts with BAG1. Interacts with NOX4 (By similarity).
Phosphorylated at multiple Ser/Thr residues. Phosphorylated on tyrosine by LYN; which impairs its antiproliferative activity. Phosphorylation at Tyr-236 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. Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1. May promote apoptosis by inducing TP53 phosphorylation on 'Ser-15'. Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux.
The sequence described initially (PubMed:9256446) corresponds to a mutant, frameshifted form named PEG-3 that frequently arises during cell transformation and does not seem to exist in normal cells. PEG-3 functions as a dominant negative of GADD34-mediated pro-apoptotic pathway and promotes cancer aggressiveness.
Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MYC or MAD. 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. 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 SPAG9. The heterodimer MYC:MAX interacts with ABI1; the interaction may enhance MYC:MAX transcriptional activity.
Transcription regulator. Forms a sequence-specific DNA-binding protein complex with MYC or MAD which recognizes the core sequence 5'-CAC[GA]TG-3'. The MYC:MAX complex is a transcriptional activator, whereas the MAD:MAX complex is a repressor. May repress transcription via the recruitment of a chromatin remodeling complex containing H3 'Lys-9' histone methyltransferase activity. Represses MYC transcriptional activity from E-box elements (By similarity).
Induced by a ribosomal frameshifting mechanism in response to increased levels of intracellular polyamines.
Interacts with ODC1 and thereby sterically blocks ODC homodimerization. Forms a ternary complex with PSMB4 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with AZIN2; this interaction disrupts the interaction between the antizyme and ODC1. Interacts with FAM171A1 (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 homodimer, and targets the monomers for ubiquitin-independent proteolytic destruction by the 26S proteasome. Triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC. Stabilizes AZIN2 by interfering with its ubiquitination (By similarity). Also inhibits cellular uptake of polyamines by inactivating the polyamine uptake transporter (PubMed:8166639). 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 (By similarity).
Not detectable in newborns. First detected 23 days after birth. Levels increase up to 28 days after birth, and remain constant in adults.
This is a non catalytic metalloprotease-like protein. May play a role in sperm-egg fusion (By similarity).
Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. Synthesizes oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNase L) leading to its dimerization and subsequent activation. Activation of RNase L leads to degradation of cellular as well as viral RNA, resulting in the inhibition of protein synthesis, thus terminating viral replication. Can mediate the antiviral effect via the classical RNase L-dependent pathway or an alternative antiviral pathway independent of RNase L (By similarity).
Produced as a latent enzyme which is activated by dsRNA generated during the course of viral infection. The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated. ssRNA or dsDNA do not act as activators (By similarity).
Belongs to the type I cytokine receptor family. Type 4 subfamily.
Receptor for interleukin-7. Also acts as a receptor for thymic stromal lymphopoietin (TSLP).
The IL7 receptor is a heterodimer of IL7R and IL2RG. The TSLP receptor is a heterodimer of CRLF2 and IL7R.
Expressed at 15 dpc. Expression is maintained until postnatal day 10 and decreases in adults.
Expressed in the kidney, lung, testis, and prostate. Expressed in the brain by sets of neurons, such as the pyramidal cells of the cortex, the Purkinje cells of the cerebellum, and the motoneurons of the brainstem.
Found in a complex with SLC35A2 and SLC35A3.
Mediates the transport of CDP-ribitol (By similarity). Does not exhibit CMP-sialic acid, UDP-galactose and UDP-N-acetylglucosamine transport activity (By similarity).
Belongs to the Mediator complex subunit 14 family.
Hormone involved in different processes, such as regulation of the pH of the duodenal content, food intake and water homeostasis (PubMed:7958688, PubMed:8568688, PubMed:3047699, PubMed:9655680, PubMed:19805236). Exerts its biological effects by binding to secretin receptor (SCTR), a G-protein coupled receptor expressed in the basolateral domain of several cells (PubMed:9506976, PubMed:12403838). Acts as a key gastrointestinal hormone by regulating the pH of the duodenal content (PubMed:7958688, PubMed:8568688, PubMed:3047699, PubMed:9655680). Secreted by S cells of the duodenum in the crypts of Lieberkuehn and regulates the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate (NaHCO(3)) from the ductal cells of the pancreas (PubMed:7958688, PubMed:8568688, PubMed:3047699, PubMed:9655680). Production of bicarbonate is essential to neutralize the pH and ensure no damage is done to the small intestine by the gastric acid (By similarity). In addition to regulating the pH of the duodenal content, plays a central role in diet induced thermogenesis: acts as a non-sympathetic brown fat (BAT) activator mediating prandial thermogenesis, which consequentially induces satiation (By similarity). Mechanistically, secretin released by the gut after a meal binds to secretin receptor (SCTR) in brown adipocytes, activating brown fat thermogenesis by stimulating lipolysis, which is sensed in the brain and promotes satiation (By similarity). Also able to stimulate lipolysis in white adipocytes (By similarity). Also plays an important role in cellular osmoregulation: released into the systemic circulation in response to hyperosmolality and acts at different levels in the hypothalamus, pituitary and kidney to regulate water homeostasis (PubMed:19805236). Also plays a role in the central nervous system, possibly by acting as a neuropeptide hormone: required for hippocampal synaptic function and neural progenitor cells maintenance (By similarity).
In the brain, expressed in the central amygdala, hippocampus, area postrema, nucleus of the tractus solitary and cerebellum (PubMed:15276242). Expressed at higher level in the cerebellum (PubMed:15276242).
Belongs to the class-II aminoacyl-tRNA synthetase family. Phe-tRNA synthetase alpha subunit type 2 subfamily.
Heterotetramer; dimer of two heterodimers formed by FARSA and FARSB.
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 (By similarity).
The effector domain mediates the interaction with RUNDC3A.
Belongs to the ETF beta-subunit/FixA family.
Heterodimer composed of ETFA and ETFB (PubMed:7334008). Identified in a complex that contains ETFA, ETFB and ETFRF1. Interacts with ACADM (By similarity).
Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase (PubMed:7334008). It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase. Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism. ETFB binds an AMP molecule that probably has a purely structural role (By similarity).
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.
Stimulates renal phosphate reabsorption, and could therefore prevent hypercalcemia.
Hypothalamus, anterior pituitary, adrenal medulla, testicular germ cells.
Interacts (via N-terminal extracellular domain) with ADCYAP1.
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.
Belongs to the Mediator complex subunit 29 family.
Belongs to the glutaminyl-peptide cyclotransferase family.
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 (By similarity).
Component of the Fanconi anemia (FA) complex. Interacts with FANCA; interaction is direct. Interacts with REV1 (By similarity).
The UBZ2-type zinc finger binds both 'Lys-48'- and 'Lys-63'-linked polyubiquitin with preference for 'Lys-63'-linked polyubiquitin.
Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RAF1, which prevents dimerization and phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain) with 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). Interacts with LATS1; this interaction is inhibited in the presence of DLG5. Interacts with MARK3 in the presence of DLG5.
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 (By similarity).
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) (By similarity).
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 NKX2-1. Phosphorylates NEK2 and 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 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 (By similarity).
Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization. Plays a role in fetal mononuclear myoblast differentiation by promoting filopodia and myotube formation (By similarity). Maintains naive T lymphocytes in a quiescent state and prevents chemokine-induced T lymphocyte responses, such as cell adhesion, polarization and migration (By similarity). Involved also in the regulation of neutrophil polarization, chemotaxis and adhesion. Required for normal development of inner and outer hair cell stereocilia within the cochlea of the inner ear. Plays a role for maintaining the structural organization of the basal domain of stereocilia. Involved in mechanosensory hair cell function. Required for normal hearing (By similarity).
Expressed in the cochlea (at protein level).
Homooligomer; homooligomerization is regulated by RHOC and leads to the formation of concatemers through the association of N- and C-termini (By similarity). Interacts (phosphorylated form) with 14-3-3 proteins; these interactions occur during myogenic cell differentiation and also induces T cell proliferation arrest (By similarity). Interacts (phosphorylated form) with HDAC6; this interaction occurs during early myogenic differentiation, prevents HDAC6 to deacetylate tubulin and also induces T cell proliferation arrest (By similarity). Interacts with DYSF; this interaction occurs during early myogenic differentiation (By similarity). Interacts with MYOF (By similarity). Interacts (via active GTP- or inactive GDP-bound forms) with RHOA; this interaction is direct, blocks the loading of GTP to RHOA and decreases upon chemokine CCL19 stimulation in primary T lymphocytes. Interacts with RHOC (By similarity). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (By similarity). Interacts with YWHAE (By similarity). Interacts with YWHAQ (By similarity).
Phosphorylated. Chemokine-induced phosphorylation in neutrophils occurs in a PKC- and AKT-dependent manner, resulting in RIPOR2 interaction with YWHAB and stabilization. Phosphorylated by PKCA, AKT1 and MAPKAPK1A; in vitro.
Belongs to the peptidase C19 family. USP10 subfamily.
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. Interacts with IKBKG; this interaction increases in response to DNA damage. Interacts with TANK; this interaction increases in response to DNA damage. Interacts with TRAF6; this interaction increases in response to DNA damage. Interacts with ZC3H12A; this interaction increases in response to DNA damage. Interacts with G3BP1 (via NTF2-like domain) and G3BP2 (via NTF2-like domain). Interacts with p53/TP53, SNX3 and CFTR. Interacts with TBX21.
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. Deubiquitinates TBX21 leading to its stabilization.
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 (By similarity).
Ubiquitinated. Deubiquitinated by USP13 (By similarity).
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.
Interacts with BANP. Interacts with SATB1 (via DNA-binding domains); the interaction inhibits the attachment of both proteins to DNA (By similarity).
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.
Belongs to the chloride channel (TC 2.A.49) family. ClC-5/CLCN5 subfamily.
Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. Important for normal acidification of the endosome lumen. May play an important role in renal tubular function (By similarity). 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.
Detected in brain cortex, hippocampus, thalamus and cerebellum granule cells (at protein level) (PubMed:16123112). Isoform DPPX-S is expressed in brain and some peripheral tissues including kidney, ovary, and testis; in contrast isoform DPPX-L is expressed almost exclusively in brain.
Homodimer (in vitro) (By similarity). Interacts with KCND2 (PubMed:12575952). Identified in a complex with KCND2 and KCNIP2. Forms an octameric complex composed of four DPP6 subunits bound to the KCND2 tetramer.
Promotes cell surface expression of the potassium channel KCND2 (PubMed:12575952). Modulates the activity and gating characteristics of the potassium channel KCND2 (PubMed:12575952, PubMed:16123112, PubMed:19279261, PubMed:19901547). Has no dipeptidyl aminopeptidase activity (By similarity).
Belongs to the iodothyronine deiodinase family.
Highly expressed in the liver, kidney and thyroid gland of adult rats.
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).
Belongs to the zinc-containing alcohol dehydrogenase family.
Binds to DNA motifs with the sequence 5'-GCG(T/G)GGGCG-3' via its C2H2-type zinc fingers. 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.
By growth factors (PubMed:2492104). Rapidly and transiently up-regulated in response to oschemia (PubMed:1859855).
Detected in kidney thick ascending limbs and collecting ducts (at protein level).
Interacts with SNAI1 and SP1 upon 12-O-tetradecanoylphorbol-13-acetate (TPA) induction.
Transcriptional regulator (PubMed:8413279). 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 (By similarity). 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).
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1B subfamily.
Expressed in lung and epididymis (PubMed:30659401). In the caput region of the epididymis, expressed at the luminal and basolateral surfaces of the ducts and in the smooth muscle coat (PubMed:30659401). In the caudal region of the epididymis, expressed along the luminal border but not continuously, in the smooth muscle coat, in the interstitial muscle tissue and in sperm in the caudal lumen (PubMed:30659401).
Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit (PubMed:9118951). An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (By similarity). Interacts with NEDD4 (via WW domains) (PubMed:12654927, PubMed:11323714). Interacts with NEDD4L (via WW domains) (By similarity). Interacts with WWP1 (via WW domains) (By similarity). Interacts with WWP2 (via WW domains) (By similarity). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (By similarity). Interacts (N-glycosylated) with BPIFA1; the interaction is direct and inhibits the proteolytic processing of SCNN1A and SCNN1G and the activation of ENaC (By similarity).
N-glycosylated (PubMed:11773057). N-glycosylation is required for interaction with BPIFA1 (By similarity).
Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride (PubMed:9118951). 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.
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 (By similarity).
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.
Belongs to the opioid neuropeptide precursor family.
Blocks nociceptin action in pain transmission by inhibiting nociceptin-induced hyperalgesia and allodynia.
Expressed predominantly in the spinal cord and brain, being more abundant in the hypothalamus and striatum. Also found in small amounts in ovary.
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.
Specific enzymatic cleavages at paired basic residues probably yield other active peptides besides nociceptin.
The N-terminal domain contains 6 conserved cysteines thought to be involved in disulfide bonding and/or processing.
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. 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. Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with SHMT2 and the other subunits of the BRISC complex.
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. 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. 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. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination.
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.
Guanine nucleotide exchange factor (GEF), which can activate some, but not all, G-alpha proteins by exchanging bound GDP for free GTP.
Interacts with some GDP-bound G alpha proteins. Does not interact with G-alpha proteins when they are in complex with subunits beta and gamma.
Acetylated at Lys-539, Lys-545 and Lys-553 by KAT2B/PCAF (By similarity). Acetylation is promoted by glucose and stabilizes the protein, probably by preventing ubiquitination at the same sites (By similarity). Acetylation promotes de novo lipid synthesis (By similarity). Deacetylated by SIRT2 (By similarity).
Catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, the latter serving as common substrate for de novo cholesterol and fatty acid synthesis.
Expressed in the brain, kidney, mammary gland, lung and liver.
In the C-terminal section; belongs to the succinate/malate CoA ligase alpha subunit family.
In the N-terminal section; belongs to the succinate/malate CoA ligase beta subunit family.
Phosphorylated by PKA and GSK3 in a sequential manner; phosphorylation results in activation of its activity (By similarity). Phosphorylation on Thr-446 and Ser-450 depends on the phosphorylation state of Ser-454 (PubMed:12107176, PubMed:2176822). Phosphorylation on Ser-454 is decreased by prior phosphorylation on the other 2 residues (PubMed:12107176, PubMed:2176822).
Phosphorylation results in activation of its activity (By similarity). Glucose 6-phosphate, fructose 6-phosphate, fructose 2,6-bisphosphate, ribulose 5-phosphate, and fructose 1,6-bisphosphate also act as activators (By similarity).
Ubiquitinated at Lys-539, Lys-545 and Lys-553 by the BCR(KLHL25) E3 ubiquitin ligase complex and UBR4, leading to its degradation (By similarity). Ubiquitination is probably inhibited by acetylation at same site (By similarity). BCR(KLHL25)-mediated degradation of ACLY promotes fatty acid oxidation and is required for differentiation of inducible regulatory T (iTreg) cells (By similarity).
Interacts with 'R7' family proteins RGS6, RGS7, RGS9 and RGS11. Component of some R7-Gbeta5 complex composed of some R7 protein (RGS6, RGS7, RGS9 or RGS11), Gbeta5 (GNB5) and RGS7BP.
Palmitoylated (PubMed:21343290). Undergoes rapid palmitoylation turnover (PubMed:21343290). De novo and turnover palmitoylation are both mediated by ZDHHC2 (PubMed:21343290). Palmitoylation regulates the cell membrane and nuclear shuttling and the regulation of GPCR signaling (By similarity). Upon depalmitoylation, it is targeted from the plasma membrane into the nucleus (By similarity). GPCR signaling inhibits depalmitoylation and promotes localization to the plasma membrane (PubMed:21343290).
Regulator of G protein-coupled receptor (GPCR) signaling. Regulatory subunit of the R7-Gbeta5 complexes that acts by controlling the subcellular location of the R7-Gbeta5 complexes. When palmitoylated, it targets the R7-Gbeta5 complexes to the plasma membrane, leading to inhibit G protein alpha subunits. When it is unpalmitoylated, the R7-Gbeta5 complexes undergo a nuclear/cytoplasmic shuttling. May also act by controlling the proteolytic stability of R7 proteins, probably by protecting them from degradation.
The nuclear localization signal is both required for nuclear localization and palmitoylation.
Belongs to the complex I NDUFS4 subunit family.
Mammalian complex I is composed of 45 different subunits. This is a component of the iron-sulfur (IP) fragment of the enzyme. Interacts with BCAP31 and TOMM40; the interaction mediates its translocation to the mitochondria; the interaction with BCAP31 is direct.
Belongs to the liprin family. Liprin-beta subfamily.
Belongs to the protein kinase superfamily. BUD32 family.
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. Acts as a nucleosome-destabilizing factor that is recruited to genes during transcriptional activation. Recognizes and binds histone H3 without a preference for specific epigenetic markers and also binds DNA. 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. Stimulates the acetylation of 'Lys-56' of nucleosomal histone H3 (H3K56ac) by EP300. With GATA4, co-binds a defined set of heart development genes and coregulates their expression during cardiomyocyte differentiation. Regulates p38 MAP kinase activity by mediating stress activation of MAPK14/p38alpha and specifically regulating MAPK14 signaling. Indirectly promotes phosphorylation of MAPK14 and activation of ATF2. The phosphorylation of MAPK14 requires upstream activity of MAP2K4 and MAP2K6.
Homotetramere. Interacts with MAPK14. Interacts with KDM1B at nucleosomes; this interaction stimulates H3K4me1 and H3K4me2 demethylation. Binds to mononucleosomes. Interacts with GATA4; the interaction is required for a synergistic activation of GATA4 target genes transcription.
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. However, since the active site is not conserved, the dehydrogenase domain seems to serve as a catalytically inert oligomerization module.
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.
The PWWP domain probably mediates the binding to H3K36me3.
Belongs to the nucleobase:cation symporter-2 (NCS2) (TC 2.A.40) family.
Highly expressed in the straight segment of proximal tubules in the kidney, in intestine and liver. Detected in epithelial cells of the bronchiole and epididymis.
Sodium/ascorbate cotransporter (PubMed:10331392). Mediates electrogenic uptake of vitamin C, with a stoichiometry of 2 Na(+) for each ascorbate (By similarity).
Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity (By similarity). Composed of two similar catalytic domains, each possessing a functional active site, with different selectivity for substrates (By similarity). Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin (By similarity). Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response (By similarity). Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins (By similarity). Catalyzes degradation of different enkephalin neuropeptides (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe and possibly Met-enkephalin-Arg-Gly-Leu) (PubMed:20487892). Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe, a strong ligand of Mu-type opioid receptor OPRM1, into Met-enkephalin (By similarity). Met-enkephalin-Arg-Phe cleavage by ACE decreases activation of OPRM1, leading to long-term synaptic potentiation of glutamate release (By similarity). Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) (PubMed:12500972, PubMed:18077343). Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:12500972, PubMed:18077343). Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation (By similarity). Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones (By similarity). Degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) and amyloid-beta proteins is mediated by the N-terminal catalytic domain, while angiotensin I and cholecystokinin cleavage is mediated by the C-terminal catalytic region (By similarity).
Expressed in brain, kidney, lung, skeletal muscle and heart.
Isoform Testis-specific only binds 1 Zn(2+) ion per subunit.
Isoform produced by alternative promoter usage that is specifically expressed in spermatocytes and adult testis, and which is required for male fertility. In contrast to somatic isoforms, only contains one catalytic domain. Acts as a dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of substrates (By similarity). The identity of substrates that are needed for male fertility is unknown. May also have a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety. The GPIase activity was reported to be essential for the egg-binding ability of the sperm. This activity is however unclear and has been challenged by other groups, suggesting that it may be indirect (By similarity).
Monomer and homodimer; homodimerizes following binding to an inhibitor (By similarity). Interacts with calmodulin (CALM1, CALM2 or CALM3); interaction takes place in the cytoplasmic region and regulates phosphorylation and proteolytic cleavage (By similarity).
Phosphorylated by CK2 on Ser-1306; which allows membrane retention (By similarity). Phosphorylated on tyrosine residues on its extracellular part, promoting cleavage by secretase enzymes and formation of the soluble form (Angiotensin-converting enzyme, soluble form) (By similarity).
Produced following proteolytic cleavage by secretase enzymes that cleave the transmembrane form in the juxtamembrane stalk region upstream of the transmembrane region. Cleavage can take place at different sites of the juxtamembrane stalk region.
Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region.
Strongly inhibited by lisinopril and captopril.
Testis-specific isoform is expressed in spermatocytes, adult testis.
The dipeptidyl carboxypeptidase activity is strongly activated by chloride. The dipeptidyl carboxypeptidase activity is specifically inhibited by lisinopril, captopril and enalaprilat.
Up-regulated after myocardial infarction.
Anchoring filament protein which is a component of the basement membrane zone.
Belongs to the CTL (choline transporter-like) family.
Belongs to the adenylate kinase family. AK2 subfamily.
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase activity is critical for regulation of the phosphate utilization and the AMP de novo biosynthesis pathways. Plays a key role in hematopoiesis.
Autopalmitoylated. Autopalmitoylation has a regulatory role in ZDHHC17-mediated Mg(2+) transport.
Belongs to the DHHC palmitoyltransferase family. AKR/ZDHHC17 subfamily.
Interacts (via ANK repeats) with numerous proteins (via the consensus sequence motif [VIAP]-[VIT]-x-x-Q-P). Interacts (via ANK repeats) with CLIP3. Interacts (via ANK repeats) with HTT (By similarity). Interacts (via ANK repeats) with DNAJC5 (via C-terminus) (PubMed:25253725). Interacts (via ANK repeats) with MAP6. Interacts (via ANK repeats) with SNAP23 (By similarity). Interacts (via ANK repeats) with SNAP25(PubMed:25253725, PubMed:26198635). Interacts (via ANK repeats) with EVL (By similarity). Interacts with SPRED1 and SPRED3 (By similarity). Interacts with GPM6A and OPTN (By similarity). 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. 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 (By similarity). Also palmitoylates neuronal protein GPM6A as well as SPRED1 and SPRED3 (By similarity). 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 (By similarity). May play a role in Mg(2+) transport (By similarity). Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane (By similarity). Palmitoylates CASP6, thereby preventing its dimerization and subsequent activation (By similarity).
Identified in a complex that contains SEL1L, OS9, FAF2/UBXD8, UBE2J1/UBC6E and AUP1 (By similarity). Interacts with YOD1 (By similarity). Interacts (via N-terminus) with UBQLN2 (via C-terminus) (By similarity). Interacts with PNPLA2 and UBAC2 (By similarity). Interacts with ZFAND2B; probably through VCP (By similarity). Interacts with LMBR1L (By similarity).
Plays an important role in endoplasmic reticulum-associated degradation (ERAD) that mediates ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway. Involved in inhibition of lipid droplet degradation by binding to phospholipase PNPL2 and inhibiting its activity by promoting dissociation of PNPL2 from its endogenous activator, ABHD5 which inhibits the rate of triacylglycerol hydrolysis.
Belongs to the PPase class C family. Prune subfamily.
Acts as an E3 ubiquitin-protein ligase (By similarity). May have a role during the programmed cell death of hematopoietic cells.
In testis sections, expressed in interstitial tissue and seminiferous tubules. In tubules, expression is mainly in postmeiotic germ cells and to a much lesser extent in Sertoli cells (at protein level). Expressed at high levels in liver, lung, stomach, heart and thymus.
Regulated by lutenising hormone (LH) in Leydig cells but not in germ cells.
Belongs to the transthyretin family. 5-hydroxyisourate hydrolase subfamily.
Belongs to the universal ribosomal protein uS7 family.
Belongs to the pseudouridine synthase RluA family.
Catalyzes uridine to pseudouridine isomerization (pseudouridylation) of different mitochondrial RNA substrates. Acts on position 1397 in 16S mitochondrial ribosomal RNA (16S mt-rRNA). This modification is required for the assembly of 16S mt-rRNA into a functional mitochondrial ribosome. 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. Acts on position 39 in mitochondrial tRNA(Phe). 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. Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing.
Interacts with 16S mt-rRNA, mt-tRNA(Phe) and mt-tRNA(Met). Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA.
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).
Belongs to the eukaryotic/archaeal RNase P protein component 3 family.
Belongs to the myo-inositol oxygenase family.
Abundantly expressed in germ cells, also expressed in testes and seminiferous tubules, with faint expression in Sertoli cells (at protein level).
Forms a ternary complex with PALS1 and CRB1 (By similarity). Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, INADL/PATJ and PARD3/PAR3 (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 (PubMed:22337881). Component of a complex composed of CRB3, PALS1 and PATJ (By similarity). Interacts (via N-terminus) with PALS1/PALS (via PDZ domain) (By similarity). Interacts with TJP3/ZO-3 and CLDN1/claudin-1 (By similarity). Interacts with ASIC3, KCNJ10, KCNJ15, GRIN2A, GRIN2B, GRIN2C, GRIN2D, NLGN2, and HTR2A (By similarity). Interacts with MPP7 (By similarity). Directly interacts with HTR4 (By similarity). Interacts (via PDZ domain 8) with WWC1 (via the ADDV motif) (By similarity). Interacts with SLC6A4 (By similarity). Interacts (via C-terminus) with ARHGEF18 (By similarity). Interacts with NPHP1 (By similarity). Interacts with PARD3/PAR3 (By similarity).
Scaffolding protein that facilitates the localization of proteins to the cell membrane (By similarity). Required for the correct formation of tight junctions and epithelial apico-basal polarity (By similarity). Positively regulates epithelial cell microtubule elongation and cell migration, possibly via facilitating localization of PRKCI/aPKC and PAR3D/PAR3 at the leading edge of migrating cells (By similarity). Plays a role in the correct reorientation of the microtubule-organizing center during epithelial migration (By similarity). May regulate the surface expression and/or function of ASIC3 in sensory neurons (By similarity). May recruit ARHGEF18 to apical cell-cell boundaries (By similarity).
The L27 domain (also called Maguk recruitment domain) is required for interaction with PALS1 and CRB3, and PALS1 localization to tight junctions.
The PDZ domain 6 mediates interaction with the C-terminus of TJP3 and is crucial for localization to the tight junctions (By similarity). The PDZ domain 8 interacts with CLDN1 but is not required for proper localization (By similarity).
Widely expressed in the brain. Highest levels found in the hippocampus and layers v and vi of the neocortex.
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). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol) (PubMed:18719240) (By similarity).
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.
Widely distributed, but in low abundance, throughout the brain. Highest levels detected in the olfactory bulb, nucleus accumbens/olfactory tubercle, prefrontal cortex and other cortical regions, midbrain regions consisting of substantia nigra and ventral tegmentum, cerebellum, and pons/medulla. Among peripheral tissues, highest level observed in the liver, less expression in kidney, gastrointestinal tract, spleen, pancreas, and heart.
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.
May be involved in hepatocellular function and development.
Almost exclusively expressed in the nervous system. Predominantly expressed in neurons.
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).
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 (By similarity).
Catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglyceratea crucial step in glycolysis, by using 2,3-bisphosphoglycerate. Also catalyzes the interconversion of (2R)-2,3-bisphosphoglycerate and (2R)-3-phospho-glyceroyl phosphate.
Heterodimer of PSME1 and PSME2, which forms a hexameric ring.
Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.
Appears on embryonic day 16.5 and is expressed thereafter.
Highly expressed in the lung, in type II alveolar cells. Moderately expressed in kidney followed by small intestine.
Involved in actively transporting phosphate into cells via Na(+) cotransport.
Interacts with subunit of G(i) alpha proteins and regulates the activation of G(i) alpha proteins.
The GoLoco 1 and/or GoLoco 3 domains exhibit GDI activity towards GDP-bound G(i) alpha protein, but not the GoLoco 2 domain.
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, including PTPN6/SHP-1, resulting in the dephosphorylation of the downstream protein kinases SYK and BTK.
Interacts with LYN, PTPN6/SHP-1 and PTPN11/SHP-2.
May act as receptor for class I MHC antigens. Becomes activated upon coligation of LILRB3 and immune receptors, such as FCGR2B and the B-cell receptor. Down-regulates antigen-induced B-cell activation by recruiting phosphatases to its immunoreceptor tyrosine-based inhibitor motifs (ITIM).
May act as receptor for class I MHC antigens. Becomes activated upon coligation with immune receptors, such as FCGR2B and the B-cell receptor. Down-regulates antigen-induced B-cell activation by recruiting phosphatases to its immunoreceptor tyrosine-based inhibitor motifs (ITIM).
Phosphorylated on tyrosine residues by LYN. Phosphorylation at Tyr-697 and Tyr-727 is important for interaction with PTPN6/SHP-1 and PTPN11/SHP-2.
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).
Identified in the spliceosome B complex. Identified in the spliceosome C complex. Associates with the U5 snRNP particle. 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. Interacts with ARAF1. Interacts with AR and NR3C1, but not ESR1, independently of the presence of hormones. Interacts with USH1G.
Involved in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex, one of the building blocks of the spliceosome. Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation.
Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates and be involved in a variety of cellular processes (By similarity). Catalyzes the palmitoylation of KCNMA1, regulating localization of KCNMA1 to the plasma membrane (By similarity). Might also mediate palmitoylation of CNN3 (By similarity).
High levels in pituitary and vas deferens. Lower extent in spinal cord, bladder, brain, adrenal, testis, sensory epithelia from the inner ear.
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 (By similarity).
Expressed in the Purkinje cells and dendrites in the molecular layer of the cerebellum (at protein level). Expressed in the hippocampal neurons (at protein level). Strong expression observed in testis and moderate expression in kidney inner medulla, the submandibular gland, eye, cerebrum and cerebellum.
Mediates electroneutral sodium- and carbonate-dependent chloride-HCO3(-) exchange with a Na(+):HCO3(-) stoichiometry of 2:1 (PubMed:8189393, PubMed:34584093). Plays a major role in pH regulation in neurons (PubMed:8189393). Mediates sodium reabsorption in the renal cortical collecting ducts (By similarity).
Up-regulated in the brain in response to chronic metabolic acidosis.
Chondroitin sulfate-, heparin- and hyaluronan-binding protein (By similarity). May serve to form a basic macromolecular scaffold comprising the insoluble interphotoreceptor matrix (By similarity).
Highly glycosylated (N- and O-linked carbohydrates and sialic acid).
Belongs to the DNA photolyase class-1 family.
Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit.
Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket.
Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with TIMELESS (By similarity). Interacts directly with PER1, PER2 and PER3; interaction with PER2 inhibits its ubiquitination and vice versa (By similarity). Interacts with FBXL21 (By similarity). Interacts with FBXL3 (By similarity). Interacts with CLOCK-BMAL1 independently of PER2 and DNA (By similarity). Interacts with HDAC1, HDAC2 and SIN3B (By similarity). Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent (By similarity). Interacts with PRKDC (By similarity). Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations (By similarity). Interacts with PRMT5 (By similarity). Interacts with EZH2 (By similarity). Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (By similarity). Interacts with PPP5C (via TPR repeats) (PubMed:16790549). Interacts with MAP1LC3B (By similarity). Interacts with CLOCK (By similarity). Interacts with BMAL1 (By similarity). Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with TRIM28, KCTD5 and DDB1 (By similarity). Interacts with FOXO1 (By similarity). Interacts with DTL and DDB1-CUL4A complex (By similarity). Interacts with HNF4A (By similarity). Interacts with PSMD2 in a KDM8-dependent manner (By similarity). Interacts with KDM8 in a FBXL3-dependent manner (By similarity). Interacts with PPARG in a ligand-dependent manner (By similarity). Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity). Interacts with PPARA, NR1I3 and VDR (By similarity).
Expression is regulated by light and circadian rhythms. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12).
Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-570 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC (By similarity).
The LIR motifs (LC3-interacting region) 3 and 5 are required for its interaction with MAP1LC3B and for its autophagy-mediated degradation.
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-BMAL1 independently of PER proteins and is found at CLOCK-BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1, ATF4, MTA1, KLF10 and NAMPT. May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4 (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Plays an essential role in the generation of circadian rhythms in the retina (By similarity). Represses the transcriptional activity of NR1I2 (By similarity).
Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization (By similarity). The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY1 (By similarity). In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex (By similarity). The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues (By similarity). Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex (By similarity). Ubiquitination may be inhibited by PER2 (By similarity). Deubiquitinated by USP7 (By similarity).
Undergoes autophagy-mediated degradation in the liver in a time-dependent manner. Autophagic degradation of CRY1 (an inhibitor of gluconeogenesis) occurs during periods of reduced feeding allowing induction of gluconeogenesis and maintenance of blood glucose levels.
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 (By similarity).
Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1. Interacts with UBE2I. Interacts with NR6A1. Interacts with ESR1 (By similarity). Interacts with TSP57 (By similarity). Interacts with TRAIP (By similarity).
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. Specifically recognizes and binds 'Lys-63'-linked ubiquitin. 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.
Homodimer. Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1.
Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively. Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens. 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.
The N-terminal region is essential for activation of the IFNB promoter activity.
Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (PubMed:12954870). Associated with KCNC4/Kv3.4 is proposed to form the subthreshold voltage-gated potassium channel in skeletal muscle and to establish the resting membrane potential (RMP) in muscle cells (By similarity). Associated with KCNQ1/KCLQT1 may form the intestinal cAMP-stimulated potassium channel involved in chloride secretion that produces a current with nearly instantaneous activation with a linear current-voltage relationship (PubMed:21911611).
Interacts with KCNB1 (PubMed:12954870). Interacts with KCNC2 (PubMed:14679187). Associates with KCNC4/Kv3.4 (By similarity). Interacts with KCNQ1; produces a current with nearly instantaneous activation with a linear current-voltage relationship and alters membrane raft localization (PubMed:21911611).
GTP-binding protein. Can activate phospholipase D with very low efficiency (By similarity). Important for normal function of the Golgi apparatus.
The GTP-bound form interacts with RGPD8 (By similarity). The GTP-bound form directly interacts with ARFIP2; this interaction leads to an increase in the amount of bound GTP at steady state level (By similarity). Binds to SCOC, preferentially in its GTP-bound form. May interact with UNC119 (By similarity). The GTP-bound form interacts with GOLGA1 and GOLGA4.
Serine protease inhibitor selective for kallikreins. Efficiently inhibits KLK4, KLK5, KLK6, KLK7, KLK12, KLK13 and KLK14. Doesn't inhibit KLK8.
Highly expressed in the testis and pituitary cells.
Interacts with IFT88 (By similarity). Interacts with IFT57 (By similarity). Interacts with RABL2/RABL2A; binds preferentially to GDP-bound RABL2 (By similarity). May interact with LHX3 and LHX4; the relevance of such interaction is however unclear in vivo.
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 G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA2B sub-subfamily.
Interacts with RAB26. Interacts with PPP1R9B. Interacts with GGA1, GGA2 and GGA3.
In absence of activation signal, PARP16 is autoinhibited by the PARP alpha-helical domain (also named HD region), which prevents effective NAD(+)-binding. Activity is highly stimulated by signals, which unfold the PARP alpha-helical domain, relieving autoinhibition.
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. 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. Mono-ADP-ribosylation of ribosomal subunits is promoted by NMNAT2. Involved in the unfolded protein response (UPR) by ADP-ribosylating and activating EIF2AK3 and ERN1, two important UPR effectors. May also mediate mono-ADP-ribosylation of karyopherin KPNB1 a nuclear import factor. May not modify proteins on arginine or cysteine residues compared to other mono-ADP-ribosyltransferases.
The PARP alpha-helical domain (also named HD region) is regulatory, it packs against the catalytic domain.
Component of the p62 complex, a complex composed of NUP62, NUP54, and the isoform p58 and isoform p45 of NUP58. Interacts with NUTF2.
Expressed in the heart (at protein level).
Interacts with DSC2 (By similarity). Interacts with JUP (By similarity). Interacts with KRT5/CK5, KRT8/CK8, KRT14/CK14, KRT18/CK18 and VIM (By similarity). Interacts (via N-terminus) with MARK3/C-TAK1 (By similarity). Interacts with DSP (By similarity). Interacts with DSG1, DSG2 and DSG3 (By similarity). Interacts (via N-terminus) with CTNNB1 (By similarity). Interacts with CDH1 (By similarity). Interacts with the RNA polymerase III (Pol III) complex proteins POLR3A/RPC155, POLR3F/RPC39 and POLR3C/RPC82 (By similarity). Interacts with CTNNA3 (By similarity). Interacts (via N-terminus) with SCN5A/Nav1.5 (PubMed:19661460).
Regulates focal adhesion turnover resulting in changes in focal adhesion size, cell adhesion and cell spreading, potentially via transcriptional modulation of beta-integrins (By similarity). Required to maintain gingival epithelial barrier function (By similarity). Required for cardiac sodium current propagation and electrical synchrony in cardiac myocytes (PubMed:19661460). 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 (PubMed:26858265). May play a role in junctional plaques (By similarity).
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.
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 (By similarity).
Forms homodimers and heterodimers with FOXP1 and FOXP4. Dimerization is required for DNA-binding. Interacts with CTBP1 (By similarity). Interacts with FOXP1 (By similarity). Interacts with TBR1 (By similarity). Interacts with ZMYM2 (By similarity).
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 (By similarity). Plays a role in synapse formation by regulating SRPX2 levels.
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 (By similarity).
Auxillary component of the N-terminal acetyltransferase C (NatC) complex which catalyzes acetylation of N-terminal methionine residues.
Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30.
Detected in the olfactory epithelium, the vomeronasal epithelium and, to a lesser extent, the olfactory bulb.
During development, expression in the olfactory epithelium parallels neurogenesis, peaking shortly after birth and declining in the adult.
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. This subunit may have a very specific role in the development and turnover of olfactory and vomeronasal neurons.
Probably involved in cell proliferation and cell-cell interactions.
In the C-terminal section; belongs to the MoaC family.
In the N-terminal section; belongs to the radical SAM superfamily. MoaA family.
Binds DNM1 via its N-terminal SH3 domains (PubMed:14506234). 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. Interacts (via SH3 domain 6) with WASL. Interacts (via SH3 domain 6) interacts with ENAH. Interacts (via C-terminal domain) with TJP1; required for the apical cell-cell junction localization of DNMBP (By similarity).
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 in epithelial cells (By similarity). Participates in the normal lumenogenesis of epithelial cell cysts by regulating spindle orientation (By similarity). Plays a role in ciliogenesis (By similarity). May play a role in membrane trafficking between the cell surface and the Golgi (PubMed:14506234).
Homodimer (PubMed:19646995). 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 (By similarity).
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 (By similarity). Seems to have versatile functions in various biological processes (By similarity). Plays a role in regulating muscle function such as smooth muscle vasorelaxation and cardiac myocyte contractility (By similarity). May regulate myocardial angiogenesis implicating KDR (By similarity). Overexpression mediates cardioprotection and angiogenesis after induced damage (PubMed:15105294). Stabilizes monomeric YWHAZ thereby supporting YWHAZ chaperone-like activity (By similarity).
Widely expressed. High expression in muscle tissues.
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 (By similarity).
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.
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 (By similarity).
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.
Asymmetric arginine dimethylation by PRMT3 occurs at multiple sites in the Arg/Gly-rich region.
Belongs to the universal ribosomal protein uS5 family.
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. Interaction with ZNF277 competes with the binding of RPS2 to protein arginine methyltransferase PRMT3.
Binds DAXX. Interacts with HIPK3. Part of a complex containing HIPK3 and FADD (By similarity). Binds RIPK1 and FAIM2. Interacts with BABAM2 and FEM1B. Interacts with FADD (By similarity). 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 (PubMed:15383280). Interacts with CALM (By similarity). 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 (By similarity).
Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins.
Palmitoylated. Palmitoylation by ZDHHC7 prevents the lysosomal degradation of FAS regulating its expression at the plasma membrane.
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 (By similarity).
Binds DNA as a dimer and can form stable heterodimers with CEBPA and CEBPB (PubMed:1377818). Interacts with ZNF638; this interaction increases transcriptional activation (By similarity).
Transcription factor that binds to the promoter and the enhancer regions of target genes. Binds to the promoter and the enhancer of the alpha-1-fetoprotein gene (PubMed:1377818). Binds to the enhancer element PRE-I (positive regulatory element-I) of the IL-4 gene (By similarity). 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 (By similarity).
Belongs to the glycosyltransferase 16 (GT16) protein family.
Detected in liver (at protein level). Detected in liver, brain, thymus and spleen.
Plays an essential role in protein N-glycosylation. Catalyzes the transfer of N-acetylglucosamine (GlcNAc) onto the free terminal mannose moiety in the core structure of the nascent N-linked glycan chain, giving rise to the second branch in complex glycans.
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:11675392, PubMed:10745007, PubMed:12620235, PubMed:18399557, PubMed:18756270, PubMed:19894725, PubMed:21520375, PubMed:22963166, PubMed:8505342). The Rab GGTase dimer (RGGT) interacts with CHM (component A) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp) (PubMed:12620235). The CHM:RGGT:Rab complex is destabilized by GGpp (PubMed:12620235). Interacts with non-phosphorylated form of RAB8A; phosphorylation of RAB8A at 'Thr-72' disrupts this interaction (By similarity).
Most abundant in the heart, brain, spleen and liver. Less in the lung, muscle, kidney and testis; in these tissues less abundant than the beta subunit.
The enzymatic reaction requires the aid of a Rab escort protein (also called component A), such as CHM.
Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.
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). 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.
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 (By similarity).
Binds to the central extracellular domain of APP and inhibits beta-secretase cleavage of APP.
Cell adhesion protein that promotes the attachment of spinal cord and sensory neuron cells and the outgrowth of neurites in vitro. May contribute to the growth and guidance of axons in both the spinal cord and the PNS.
Expressed at high levels in the floor plate.
Proton-linked monocarboxylate transporter. May catalyze the transport of monocarboxylates across the plasma membrane.
Autophosphorylated and/or phosphorylated at Thr-505, within the activation loop; phosphorylation at Thr-505 is not a prerequisite for enzymatic activity (PubMed:9677322, PubMed:17569658). Autophosphorylated at Ser-299 (By similarity). Upon TNFSF10/TRAIL treatment, phosphorylated at Tyr-155; phosphorylation is required for its translocation to the endoplasmic reticulum and cleavage by caspase-3 (PubMed:17562707). Phosphorylated at Tyr-311, Tyr-332 and Tyr-565; phosphorylation of Tyr-311 and Tyr-565 following thrombin or zymosan stimulation potentiates its kinase activity (PubMed:18550549). Phosphorylated by protein kinase PDPK1; phosphorylation is inhibited by the apoptotic C-terminal cleavage product of PKN2 (By similarity). Phosphorylated at Tyr-311 and Tyr-332 by SRC; phosphorylation leads to enhanced autophosphorylation at Thr-505 (PubMed:18550549). Phosphorylated at Tyr-311 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, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. 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. 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. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. 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. 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). May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. 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. Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin (By similarity). The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion. Phosphorylates ELAVL1 in response to angiotensin-2 treatment (By similarity). Phosphorylates mitochondrial phospholipid scramblase 3 (PLSCR3), resulting in increased cardiolipin expression on the mitochondrial outer membrane which facilitates apoptosis (By similarity). Phosphorylates SMPD1 which induces SMPD1 secretion (By similarity).
Interacts with PDPK1 (via N-terminal region). Interacts with RAD9A (By similarity). Interacts with CDCP1. Interacts with MUC1. Interacts with VASP. Interacts with CAVIN3. 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 (By similarity). Interacts with PLSC3; interaction is enhanced by UV irradiation (By similarity).
Novel PKCs (PRKCD, PRKCE, PRKCH and PRKCQ) are calcium-insensitive, but activated by diacylglycerol (DAG) and phosphatidylserine. Three specific sites; Thr-505 (activation loop of the kinase domain), Ser-643 (turn motif) and Ser-662 (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.
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 (By similarity).
Found at all stages of developing glomeruli and the presumptive proximal tubules in the embryonic kidney. The expression was restricted to the presumptive podocyte.
In kidney, it is found in glomeruli and in the proximal tubules (at protein level).
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 (By similarity).
It may be a useful marker for injured podocytes in puromycin amino-nucleoside nephropathy (PAN) since its expression at the apical surface is altered.
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).
Required for 40S ribosome biogenesis. Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.
Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin-protein ligase complex that controls progression through mitosis and the G1 phase of the cell cycle.
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).
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:10428857, PubMed:11287959, PubMed:27296226, PubMed:28878326). 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:10428857, PubMed:11287959, PubMed:27296226). 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 (By similarity).
Expressed in duodenum, proximal jejunum, cecum, and colon.
Homotetramer (PubMed:27296226, PubMed:29258289, PubMed:28878326). 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 calmodulin. Interacts with BSPRY. Interacts with TCAF1 and TCAF2 (By similarity).
It is uncertain whether Met-1 or Met-41 is the initiator. In human and mouse, initiation starts at a conserved non-canonical ACG threonine codon decoded as Met-1 upstream of the canonical initiation at Met-41.
Phosphorylation at Tyr-201 and Tyr-202 by SRC leads to an increased calcium influx through the channel. Probably dephosphorylated at these sites by PTPN1.
Unusual initiator. The initiator methionine is coded by a non-canonical ACG threonine codon.
Heavily acetylated by KAT2A/GCN5 under conditions of high nutrients, leading to inactivation of PPARGC1A. Deacetylated by SIRT1 in low nutrients/high NAD conditions, leading to its activation.
Homooligomer (By similarity). Interacts with MYBBP1A; inhibits MYBBP1A transcriptional activation. Interacts with PRDM16, LPIN1 and PML. Interacts (via LXXLL motif) with RORA and RORC (via AF-2 motif); activates RORA and RORC transcriptional activation (By similarity). Interacts with LRPPRC (By similarity). Interacts with FOXO1 (By similarity).
Phosphorylation by AMPK in skeletal muscle increases activation of its own promoter. Phosphorylated by CLK2.
Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. 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. 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 (By similarity). Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. Also involved in the integration of the circadian rhythms and energy metabolism. 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.
Up-regulated in brown adipose tissue of diabetic fatty (fa/fa) rats. Exposure of fa/fa rats to cold resulted in a much smaller increase as compared to lean rats in which a 2.6 fold increase was seen. Leptin is required for normal basal and cold-stimulated expression in brown adipose tissue and hyperleptinemia rapidly up-regulates its expression. It is induced not only by cold exposure but also by prolonged low-intensity physical exercise in epitrochlearis muscle.
Coactivator of estrogen receptor-mediated transcription and a corepressor of other nuclear hormone receptors and sequence-specific transcription factors. 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.
Expressed in ovary, uterus, muscle and many regions of brain including hypothalamus, cortex, hippocampus and pituitary. Expressed in neurin and glia cells.
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-estradiol; the interaction increases ESR1 transcriptional activity (By similarity). Interacts with CREBBP and EP300 in a ligand-dependent manner (By similarity). Forms two complexes in the presence of 17-beta-estradiol; one with SRC and ESR1 and another with LCK and ESR1. 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.
The Glu-rich region mediates histones interaction.
The Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs are required for the association with nuclear receptor ESR1.
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.
As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair. Exhibits both DNA polymerase and 3'- to 5'-exonuclease activities. Requires the presence of accessory proteins POLD2, POLD3 and POLD4 for full activity. Depending upon the absence (Pol-delta3) or the presence of POLD4 (Pol-delta4), displays differences in catalytic activity. Most notably, expresses higher proofreading activity in the context of Pol-delta3 compared with that of Pol-delta4. Although both Pol-delta3 and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may 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. Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. Under conditions of DNA replication stress, in the presence of POLD3 and POLD4, may catalyze the repair of broken replication forks through break-induced replication (BIR). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine, 8oxoG or abasic sites.
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 both DNA polymerase and 3' to 5' proofreading exonuclease activities. Within Pol-delta4, directly interacts with POLD2 and POLD4. Following genotoxic stress by DNA-damaging agents, such as ultraviolet light and methyl methanesulfonate, or by replication stress induced by treatment with hydroxyurea or aphidicolin, Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3) by POLD4 degradation. Pol-delta3 is the major form at S phase replication sites and DNA damage sites. POLD1 displays different catalytic properties depending upon the complex it is found in. It exhibits higher proofreading activity and fidelity than Pol-delta4, making it particularly well suited to respond to DNA damage. Directly interacts with PCNA, as do POLD3 and POLD4; this interaction stimulates Pol-delta4 polymerase activity. As POLD2 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. Also observed as a dimeric complex with POLD2 (Pol-delta2). Pol-delta2 is relatively insensitive to the PCNA stimulation (2-5-fold) compared to Pol-delta4 that is stimulated by over 50-fold. The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2. Interacts with CIAO1. Interacts with POLDIP2 (By similarity).
In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.
Regulated by alteration of quaternary structure. Exhibits burst rates of DNA synthesis are about 5 times faster in the presence of POLD4 (Pol-delta4 complex) than in its absence (Pol-delta3 complex), while the affinity of the enzyme for its DNA and dNTP substrates appears unchanged. The Pol-delta3 complex is more likely to proofread DNA synthesis because it cleaves single-stranded DNA twice as fast and transfers mismatched DNA from the polymerase to the exonuclease sites 9 times faster compared to the Pol-delta3 complex. Pol-delta3 also extends mismatched primers 3 times more slowly in the absence of POLD4. The conversion of Pol-delta4 into Pol-delta3 is induced by genotoxic stress or by replication stress leading POLD4 degradation. Stimulated in the presence of PCNA (By similarity). This stimulation is further increased in the presence of KCTD13/PDIP1, most probably via direct interaction between KCTD13 and POLD2 (By similarity).
The CysB motif binds 1 4Fe-4S cluster and is required for the formation of polymerase complexes.
Autophosphorylated (By similarity). Phosphorylated on tyrosine residues in response to KIT signaling (By similarity). Phosphorylation at Tyr-397 is required for optimal activity (By similarity). Phosphorylation at Tyr-508 inhibits kinase activity (By similarity). Phosphorylated at Tyr-508 by CSK (By similarity). Dephosphorylated by PTPRC/CD45 (By similarity). Becomes rapidly phosphorylated upon activation of the B-cell receptor and the immunoglobulin receptor FCGR1A (By similarity). Phosphorylated in response to integrin ITGB1 in B-cells (By similarity).
Detected in spleen (at protein level). Expressed predominantly in B-lymphoid and myeloid cells.
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) (By similarity). This interaction facilitates the phosphorylation of SCIMP 'Tyr-96', 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 (By similarity). Interacts (via SH2 and SH3 domains) with UNC119; leading to LYN activation (By similarity). 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 (By similarity).
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. 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 (By similarity). Phosphorylates LPXN on 'Tyr-72' (By similarity). Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-96'; 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 (By similarity).
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.
The protein kinase domain plays an important role in its localization in the cell membrane.
Ubiquitinated. Ubiquitination is SH3-dependent (By similarity).
Interacts with PRMT5; this interaction is direct. Interacts with GNL2 and RPL23A (By similarity). Interacts with nucleolin/NCL; this interaction is direct (By similarity). Interacts with phosphorylated IRF3; this interaction impairs IRF3 DNA-binding activity (By similarity).
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. Also acts at the level of transcription regulation. Along with PRMT5, binds embryonic globin promoter (By similarity). Represses the expression of embryonic globin Hbb-y gene (By similarity). In neuroblastoma cells, may also repress the expression of oxidative stress genes, including CHAC1, HMOX1, SLC7A11, ULBP1 and that encoding the small nucleolar RNA SNORD41. Preferentially binds to a DNA motif containing 5'-GGTTAT-3' (By similarity). Negatively regulates the antiviral innate immune response by targeting IRF3 and impairing its DNA-binding activity (By similarity). In addition, inhibits NF-kappa-B-mediated expression of pro-inflammatory cytokines (By similarity). Stimulates phagocytosis of photoreceptor outer segments by retinal pigment epithelial cells. Prevents 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.
Enhances the promotion of guanine-nucleotide exchange by PSCD2 on ARF6 in a concentration-dependent manner.
Expressed in brain, spleen, lung, testis and kidney.
Interacts with guanine-nucleotide exchange factors PSCD1, PSCD2, PSCD3 and PSCD4.
Component of the 3M complex, composed of core components CUL7, CCDC8 and OBSL1. Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats); may link the 3M complex to histone deacetylases including HDAC4 and HDAC5.
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. Required for localization of CUL7 to the centrosome.
Despite its name, does not contain a coiled coil domain.
The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2.
By angiotensin II, endothelin-1 and alpha-thrombin. Strongly induced in ovarian granulosa cells by FSH stimulation.
Ligand of the EGF receptor/EGFR and ERBB4. Stimulates EGFR and ERBB4 tyrosine phosphorylation (PubMed:9990076). Contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation (PubMed:24631357).
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.
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.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. PKD subfamily.
Expressed in heart and liver (at protein level).
Isomerization of 3-trans,5-cis-dienoyl-CoA to 2-trans,4-trans-dienoyl-CoA.
Cleaves the alpha-chain at multiple sites and the beta-chain between 'Lys-53' and 'Lys-54' but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly. It does not cleave (activate) prothrombin and plasminogen but converts the inactive single chain urinary plasminogen activator (pro-urokinase) to the active two chain form. Activates coagulation factor VII (By similarity).
Heterodimer; disulfide-linked. Heterodimer of a 50 kDa heavy and a 27 kDa light chain linked by a disulfide bond (By similarity).
Proteolytic cleavage at Gly-23 or Met-27 can give rise to the 50 kDa heavy chain and cleavage at Arg-311 or Lys-317 can give rise to the 27 kDa light chain. The heavy chain can undergo further proteolytic cleavage at Arg-168 or Arg-169 to give rise to two inactive 26 kDa fragments and the light chain can undergo further proteolytic cleavage at Arg-478 to give rise to inactive 17 kDa and 8 kDa fragments (By similarity).
Can form homodimers and heterodimers with IGF2BP1 and IGF2BP3 (By similarity). Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1 (By similarity). Identification in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1 (By similarity). Associates with mRNP complex (By similarity). Interacts with FMR1 (By similarity). Component of a multisubunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1 (By similarity). Interacts through the third and fourth KH domains with PABPC1 in an RNA-independent manner (By similarity). Component of a TAU mRNP complex, at least composed of IGF2BP1, ELAVL4 and G3BP (By similarity). Interacts with ELAVL4 in an RNA-dependent manner (By similarity). Associates with microtubules and polysomes. Interacts with AGO1 and AGO2 (By similarity). Interacts with ELAVL1 and MATR3 (By similarity).
Domains KH3 and KH4 are the major RNA-binding modules, although KH1 and KH2 may also contribute. 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 (By similarity).
Expressed in fetal development and neonatal life, but is undetectable in adult tissues (at protein level). Expressed in embryonic neurons, including in hippocampal (at protein level) and cortical neurons. Also expressed in transformed tissue cultured cell lines derived form adult tissues (at protein level).
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 (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 beta-actin/ACTB (By similarity). May regulate mRNA transport to activated synapses (By similarity). Binds to the 3'-UTR of CD44 mRNA and stabilizes it, hence promotes cell adhesion and invadopodia formation in cancer cells (By similarity). Binds to the oncofetal H19 transcript and to the neuron-specific TAU mRNA and regulates their localization (By similarity). Binds to and stabilizes BTRC/FBW1A mRNA (By similarity). 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 (By similarity). 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 (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 prevents MYC cleavage by endonucleases and possibly microRNA targeting to MYC-CRD (By similarity). Binding to MYC mRNA is enhanced by m6A-modification of the CRD (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). Interacts with GAP43 transcript and transports it to axons. Regulates localized 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. Plays a direct role in the transport and translation of transcripts required for axonal regeneration in adult sensory neurons.
Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity.
A conserved histidine residue in the third TMD (His-115) may play an essential role in the pH sensitivity of SLCO1B2/OATP1B2-mediated substrate transport.
Liver specific. Expression is highest in central perivenous hepatocytes and lowest in the periportal region. Isoform 1 predominates. Not detected in heart, brain, kidney, skeletal muscle, lung, testis or spleen.
Mediates the Na(+)-independent uptake of organic anions such as taurochlate, bromosulfophthalein and steroid conjugates (estrone 3-sulfate, 17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate) (PubMed:19129463). Also transports prostaglandin E2 and L-thyroxine (T4) (PubMed:19129463). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).
A PH-like domain is involved in phosphatidylinositol phosphate binding.
Interacts with the cytoplasmic domain of ITGB1. Could also interact with integrin ITGB2, ITGB3 and/or ITGB5. Interacts (via ANK repeats) with LIMS1 and LIMS2. Interacts with PARVA (via C-terminus) and PARVB; these compete for the same binding site (By similarity). 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 (By similarity). Interacts with FERMT2 (By similarity). Interacts with LIMD2; leading to activate the protein kinase activity. Interacts with PXN/PAXILLIN (via LD motif 4). Interacts with CCDC25 (via cytoplasmic region); initiating the ILK-PARVB cascade to induce cytoskeleton rearrangement and directional migration of cells (By similarity).
Receptor-proximal protein kinase regulating integrin-mediated signal transduction. May act as a mediator of inside-out integrin signaling. Focal adhesion protein part of the complex ILK-PINCH. This complex is considered to be one of the convergence points of integrin- and growth factor-signaling pathway. Could be implicated in mediating cell architecture, adhesion to integrin substrates and anchorage-dependent growth in epithelial cells. Regulates cell motility by forming a complex with PARVB. Phosphorylates beta-1 and beta-3 integrin subunit on serine and threonine residues, but also AKT1 and GSK3B.
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.
Expressed strongly in spleen and at very low levels in thymus.
Interacts with ADAM15. Interacts with FASLG. Interacts with ARRB1 and ARRB2. Interacts with FCGR1A; the interaction may be indirect. Interacts with IL6ST. Interacts (via SH3 domain) with ELMO1. Interacts (via SH3 domain) with TP73. Interacts with YAP1. Interacts with ABL1 and ITGB1, and thereby recruits ABL1 to activated ITGB1. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with CBL. Interacts with VAV1, WAS and RAPGEF1.Interacts (via SH3 domain) with WDCP.
Isoform 2 palmitoylation at position 2 requires prior myristoylation. Palmitoylation at position 3 is required for caveolar localization of isoform 2.
Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS (By similarity).
Phosphorylated on several tyrosine residues. Autophosphorylated. Becomes rapidly phosphorylated upon activation of the immunoglobulin receptors FCGR1A and FCGR2A. Phosphorylation at Tyr-409 increases kinase activity. Phosphorylation at Tyr-520 inhibits kinase activity. Kinase activity is not required for phosphorylation at Tyr-520, suggesting that this site may be a target of other kinases (By similarity).
Subject to autoinhibition, mediated by intramolecular interactions involving the SH2 and SH3 domains. Kinase activity is also regulated by phosphorylation at regulatory tyrosine residues. Phosphorylation at Tyr-409 is required for optimal activity. Phosphorylation at Tyr-520 inhibits kinase activity (By similarity).
Ubiquitinated by CBL, leading to its degradation via the proteasome.
Expression is seen in 11.5 dpc to 14.5 dpc embryos in four distinct regions of the ventricular zone in the developing spinal cord.
Interacts with NOTCH1 (PubMed:28089369). Interacts with NOTCH2 and NOTCH3 (By similarity).
Ligand for multiple Notch receptors and involved in the mediation of Notch signaling. May be involved in cell-fate decisions during hematopoiesis. Enhances fibroblast growth factor-induced angiogenesis (in vitro). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation. May regulate fibroblast growth factor-induced angiogenesis.
Widely expressed in a variety of tissues.
Binds through its N-terminal region to the C-terminus of CD27 and to PXMP2/PMP22. Binds to the C-terminus of TNFRSF18/GITR. Binds to BCL2L1/BCLX isoform Bcl-x(L) but not to BAX (By similarity).
In post-ischemic kidney, found in cells lining the S3 segment of proximal tubules at 12 hours and 1 day post-ischemia. At five and seven days post-ischemia, found in epithelial cells of papillary proliferations in regenerating tubules.
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 (By similarity).
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.
Phosphorylated by ABL2/ARG in response to oxidative stress.
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.
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 (By similarity).
Detected in liver, thymus, spleen and testis.
Identified in the spliceosome C complex. Interacts with AGO1, AGO2, TBP and TXNL4/DIM1 (By similarity).
The N-terminal RRM domains are responsible for recognizing the G-tract of BCL-X RNA.
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. Member of the NMDAR signaling complex in excitatory synapses, it regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission (PubMed:15312654). Regulates dendritic spine development. Also regulates the migration of developing neurons. Phosphorylates the transcription factor FOXO3 to activate its transcriptional activity (By similarity). 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 (By similarity). 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 (By similarity). Interacts with BAALC (PubMed:15659234). Interacts with MPDZ (PubMed:15312654). Interacts with SYN1 (PubMed:1328883). Interacts with CAMK2N2 (PubMed:9724800). Interacts with SYNGAP1 (PubMed:15312654). Interacts with SYNPO2 (PubMed:17923693). Interacts with SHANK3. Interacts with GRIN2B. Interacts with CACNB2. Interacts with LRRC7. Interacts with GRM5 (By similarity). 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+) (PubMed:11182241).
Expressed only in brain (neuropil of cortex, CA1 region hippocampus and molecular layer of cerebellum).
Expression increases from low levels at birth to high levels at 3-4 weeks before dropping slightly in adulthood. Expressed in the cortex and the molecular layer of the cerebellum at postnatal day 7. Isoform 2 expression does not change during development of both cortex and cerebellum. Isoform 4 expression decreases significantly during development of cortex but not cerebellum.
May homomultimerize via its SAM domain. Interacts with the C-terminus of SSTR2 via the PDZ domain. Interacts with SHARPIN, SPTAN1 and DLGAP1/GKAP. Part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts with BAIAP2 (By similarity). Interacts with IGSF9. Interacts with HOMER1 and HOMER3 (PubMed:19345194).
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. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction. Overexpression promotes maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites, and enhances presynaptic function.
Detected in all tissues examined with higher expression in steroidogenic tissues including testis and adrenal gland (at protein level). Highly expressed in liver and testis. Also found in brain, heart, kidney, lung, placenta, skeletal muscle and spleen.
Forms a SNARE complex composed of VAMP8, SNAP29 and STX17 involved in fusion of autophagosome with lysosome (By similarity). May interact with VAMP7 (By similarity). May interact with VTI1B (By similarity). Probably interacts with BET1, SCFD1 and SEC22B (PubMed:10930465). Interacts with PTPN2 and ABL1; involved in STX17 phosphorylation (PubMed:23006999). Interacts with COPB1 (PubMed:21545355). Interacts with TMED9 and TMED10; the interaction is direct (PubMed:21545355). Interacts with RUBCNL/PACER; promoting targeting of RUBCNL/PACER to autophagosome (By similarity). Interacts with VAMP8, SNAP29, VPS39 and VPS41; these interactions are increased in the absence of TMEM39A (By similarity).
Phosphorylated at Tyr-156 probably by ABL1. Dephosphorylation by PTPN2; regulates exit from the endoplasmic reticulum.
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. STX17 is a SNARE of the autophagosome involved in autophagy through the direct control of autophagosome membrane fusion with the lysosome membrane. 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 (By similarity).
Belongs to the glycoprotein hormones subunit beta family.
Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. Interacts with UBTF (By similarity).
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 (By similarity).
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.
Down-regulated in obstructive cholestasis. Up-regulated by treatment with pregnenolone-16 alpha-carbonitrile (PCN) and by overexpression of pregnane X receptor (PXR).
Expressed in kidney, kidney cortex, kidney medulla, liver, intestine and colon. Expressed in proximal tubules in kidney, hepatocytes in liver and enterocytes of villi and crypts in smallintestine. Expressed throughout the liver lobuli. Expressed in hepatocytes surrounding the central veins (at protein level). Expressed in S1, S2 segments of proximal tubules in kidney (at protein level). Highly expressed in kidney and spleen, moderately in skin, and weakly in the gastrointestinal tract, brain, lung, thymus, muscle, and prostate. Weakly expressed in some white matter regions like the corpus callosum and in the granular layer of the cerebellum.
Renal level increases gradually from postnatal day 1 through day 45 in both genders.
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:11502595, PubMed:15640376, PubMed:16142924, PubMed:16272756, PubMed:16581093, PubMed:17567940, PubMed:7990927, PubMed:8955087, PubMed:9195965, PubMed:9776363, PubMed:9808712). Mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (By similarity).
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).
Component of the asymmetric unit membrane (AUM); a highly specialized biomembrane elaborated by terminally differentiated urothelial cells. May play an important role in normal bladder epithelial physiology, possibly in regulating membrane permeability of superficial umbrella cells or in stabilizing the apical membrane through AUM/cytoskeletal interactions (By similarity).
Heterodimer with uroplakin-3A (UPK3A) or uroplakin-3B (UPK3B).
N-glycosylated with high-mannose oligosaccharides.
Highly expressed in ovary, where it is restricted to undifferentiated granulosa cells. Expressed in hypothalamus, pituitary gland, testis and uterus.
Putative transcriptional activator involved in the hypothalamo-pituitary-gonadal system.
Belongs to the helicase family. PIF1 subfamily.
DNA-dependent ATPase and 5'-3' DNA helicase required for the maintenance of both mitochondrial and nuclear genome stability. Efficiently unwinds G-quadruplex (G4) DNA structures and forked RNA-DNA hybrids. Resolves G4 structures, preventing replication pausing and double-strand breaks (DSBs) at G4 motifs. Involved in the maintenance of telomeric DNA. Inhibits telomere elongation, de novo telomere formation and telomere addition to DSBs via catalytic inhibition of telomerase. Reduces the processivity of telomerase by displacing active telomerase from DNA ends. Releases telomerase by unwinding the short telomerase RNA/telomeric DNA hybrid that is the intermediate in the telomerase reaction. Possesses an intrinsic strand annealing activity.
The PIF1 N-terminal (PINT) domain enhances the interaction with ssDNA through intrinsic binding activity, it also harbors DNA strand-annealing activity.
Belongs to the Mediator complex subunit 27 family.
Associates with the organic matrix of bone and cartilage. Thought to act as an inhibitor of bone formation.
Belongs to the osteocalcin/matrix Gla protein family.
Requires vitamin K-dependent gamma-carboxylation for its function.
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 (By similarity).
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. Interacts with TCF3 and with polycomb proteins, such as PCH2 and BMI1/PCGF4 (By similarity).
Phosphorylated and activated by MAPK1/ERK2 and MAPK3/ERK1. Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-203, Ser-253 and Thr-315.
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 (By similarity).
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 (By similarity).
Homodimer. Interacts with lamin-associated polypeptides IA, IB and 2. Interacts with SPAG4 and SEPT12 (By similarity).
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.
Highest expression in bone marrow and to a much lesser extent in small intestine.
Template-independent DNA polymerase which catalyzes the random addition of deoxynucleoside 5'-triphosphate to the 3'-end of a DNA initiator.
(Microbial infection) Interacts with C.botulinum neurotoxin type A1 and type A2 (BoNT/A, botA) (PubMed:16543415, PubMed:21632541, PubMed:21483489). Interaction is improved by glycosylation of SV2 (PubMed:29649119).
(Microbial infection) Interacts with C.botulinum neurotoxin type D (BoNT/D, botD).
(Microbial infection) Interacts with C.botulinum neurotoxin type E (BoNT/E) (PubMed:18815274, PubMed:19476346, PubMed:19650874). Interaction requires glycosylation of SV2 proteins (PubMed:19476346).
(Microbial infection) Interacts with C.botulinum neurotoxin type F (BoNT/F) (PubMed:19650874). Interaction requires glycosylation of SV2 proteins (PubMed:19650874).
(Microbial infection) Possible receptor for C.botulinum neurotoxin type D (BoNT/D, botD); BoNT/D does not bind to extracellular loop 4 as do BoNT/A and BoNT/E (PubMed:21483489). Another group does not find a convincing interaction with SV2 (PubMed:21632541).
(Microbial infection) Receptor for C.botulinum neurotoxin type A (BoNT/A, botA); the toxin binds via extracellular loop 4 (PubMed:16543415). Restores uptake of BoNT/A in mouse and rat cells that are deleted for SV2 receptor (PubMed:16543415, PubMed:18815274). Glycosylation of SV2B is not essential for receptor activity, but enhances the interaction (PubMed:18815274, PubMed:19650874). Also serves as a receptor for the closely related C.botulinum neurotoxin type A2; glycosylation is not essential but enhances the interaction (PubMed:29649119).
(Microbial infection) Receptor for C.botulinum neurotoxin type E (BoNT/E); the toxin probably binds via extracellular loop 4 (PubMed:18815274). Restores uptake of BoNT/E in mouse cells that are deleted for SV2 receptor (PubMed:18815274). Glycosylation of SV2B is not essential for receptor activity, but enhances the interaction (PubMed:19650874).
(Microbial infection) Receptor for C.botulinum neurotoxin type F (BoNT/F); binding requires glycosylation of this protein (PubMed:19476346, PubMed:19650874).
Interacts with SYT1 in a calcium-independent manner. Forms a complex with SYT1, syntaxin-1 and SNAP25 (By similarity).
Probably plays a role in the control of regulated secretion in neural and endocrine cells.
The N-terminal cytoplasmic domain is phosphorylated by CK1.
Widely expressed throughout the brain. Specifically expressed by pinealocytes in the pineal gland. Also detected in testis (at protein level). Specifically expressed in neural tissues. Expressed in the spinal cord and in all brain regions with a stronger expression in hippocampus and cortex.
May modify the assembly dynamics of microtubules, such that microtubules are slightly longer, but more dynamic.
Belongs to the proton-activated chloride channel family.
Proton-activated chloride channel that mediates import of chloride ion in response to extracellular acidic pH. Involved in acidosis-induced cell death by mediating chloride influx and subsequent cell swelling.
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.
Can bind 1 iron ion per dimer. Iron binding seems to decrease LDLR degradation activity.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.
Expressed in developing and adult brain, hippocampus, cerebellum, cerebral cortex, thalamus and substantia nigra. Predominantly found in neurons.
Homodimer. Interacts with the E2 ubiquitin-conjugating enzyme, UBE2D1 (via RING-type zinc finger). Interacts with myosin regulatory light chain (MRLC) and TMEM4.
The FERM domain binds phospholipids and mediates lipoprotein receptors recognition at the plasma membrane through their cytoplasmic tails.
The RING domain mediates ubiquitination and the neurite outgrowth inhibitory activity.
The RING-type zinc finger mediates the interaction with UBE2D E2 enzymes.
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.
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.
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. 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. May play a role in meiosis.
Interacts with WDR81; involved in early to late endosome cargo transport. Interacts with BECN1; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes.
Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. The binding of Met-tRNA(I) occurs after the AUG codon finds its position in the P-site of 40S ribosomes, the situation that takes place during initiation complex formation on some specific RNAs. Its activity in tRNA binding with 40S subunits does not require the presence of the aminoacyl moiety. Possesses the unique ability to deliver non-Met (elongator) tRNAs into the P-site of the 40S subunit. In addition to its role in initiation, can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits (By similarity).
Translation initiation factor that is able to deliver tRNA to the P-site of the eukaryotic ribosome in a GTP-independent manner. The binding of Met-tRNA(I) occurs after the AUG codon finds its position in the P-site of 40S ribosomes, the situation that takes place during initiation complex formation on some specific RNAs. Its activity in tRNA binding with 40S subunits does not require the presence of the aminoacyl moiety. Possesses the unique ability to deliver non-Met (elongator) tRNAs into the P-site of the 40S subunit. In addition to its role in initiation, can promote release of deacylated tRNA and mRNA from recycled 40S subunits following ABCE1-mediated dissociation of post-termination ribosomal complexes into subunits.
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 (By similarity).
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. Interacts with CD59, SEC24A, SEC24B, SEC24C, SEC24D and ATL1. Interacts with KDELR1; the interaction is decreased by KDEL ligand. 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. Found in a complex composed at least of SURF4, TMED2 and TMED10 (By similarity).
Detected on postnatal day 7 in cerebellum. Follows a caudorostral progression according to the myelination process. Appears to redistribute from the internode to the paranodal region during myelin compaction and maturation (PubMed:9396755). Expression reaches maximal levels between days 14 and 18 and remains at the same levels until adulthood.
Interacts with CNTN1/contactin in cis form.
Predominantly expressed in brain. In myelinated nerve fibers of the CNS predominantly found in paranodal axoglial junctions. In unmyelinated nerve fibers of the CNS diffusely distributed along the entire surface. Weak expression is detected in ovary, pancreas, colon, lung, heart, intestine and testis.
Required, with CNTNAP2, 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 paranodal region of the axo-glial junction. In association with contactin involved in the signaling between axons and myelinating glial cells.
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:1350383, PubMed:8428958, PubMed:28126851). 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:1350383, PubMed:8428958, 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 (PubMed:7569905, PubMed:9647694). 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 (By similarity).
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. Interacts with UBXN6. Interacts with SERPINA1/alpha1-antitrypsin (By similarity).
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 (By similarity).
The FF ER export motif at the C-terminus is not sufficient to support endoplasmic reticulum exit, and needs assistance of Gln-508 for proper recognition of COPII coat components.
Interacts with components of the ASC-1 complex TRIP4, ASCC1, ASCC2 and ASCC3. Interact with AHCYL1 and AHCYL2. Interact with YTHDC2.
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. N6-methylation of adenine(4220) in 28S rRNA is required for translation.
Belongs to the glycosyltransferase 43 family.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.3/KCNH7 sub-subfamily.
Detected in total brain, in superior cervical, mesenteric and celiac ganglia, and at very low levels in retina. Found in pituitary.
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 PMA/ionomycin and concanavalin/interleukin-2.
Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells (PubMed:7505205). Involved in cytotoxic T-cell-mediated apoptosis, natural killer cell-mediated apoptosis and in T-cell development (PubMed:7505205). 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 (By similarity).
Cytoplasmic form induces gene transcription inhibition.
Expressed in activated splenocytes and thymocytes. Moderate or weak expression found in small intestines, kidney and lung.
Homotrimer. 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. Can induce apoptosis but does not appear to be essential for this process.
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.
Brain specific. Broadly expressed in neurons of most regions of the brain.
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.
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.
Acetyltransferase activity increases in presence of the kinase substrate, sphingosine (By similarity). In Purkinje cells, kinase activity on sphingosine increases in presence of VEGFA (By similarity). In neurons, kinase activity increases during the first 24h in presence of Amyloid-beta protein 42 to decrease after 96h (PubMed:26334640).
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 (Probable) (PubMed:16118219). In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis (By similarity). 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:28284343). In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES induction through p38 MAPK signaling pathway. 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. In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA (By similarity).
Expressed in microglia (at protein level).
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.
In neurons, expression increases during the first 24h in presence of Amyloid-beta protein 42 to decrease after 96h.
Interacts with ACY1 (By similarity). Binds to calmodulin. Interacts with SPHKAP (By similarity). Interacts with CIB1, the interaction occurs in a calcium-dependent manner. Interacts with TRAF2 (By similarity). Interacts with EEF1A1; the interaction enhances SPHK1 kinase activity (By similarity).
Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC2 sub-subfamily.
Expressed exclusively in vomeronasal organ neurons (sensory microvilli).
Thought to form a receptor-activated calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Is not activated by intracellular calcium store depletion.
Heterotrimer. Interacts with PAX1 and ARHGEF6 (or ARHGEF7) (By similarity).
Highly expressed in brain especially in hippocampus, thalamus and midbrain and to a lower extent in heart and spinal cord. Weakly expressed in testis. A very slow signal is also observed in heart, kidney and liver.
Protein phosphatase that inactivates multifunctional CaM kinases such as CAMK4 and CAMK2. Dephosphorylates and inactivates PAK. May play a role in the inhibition of actin fiber stress breakdown and in morphological changes driven by TNK2/CDC42. Inactivates multifunctional CaM kinases. Dephosphorylates PRKAA2 (By similarity).
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. Binds to double-stranded RNA or DNA without sequence specificity. Involved in development of the eye and of primordial germ cells.
Interacts with PARP1 (via catalytic domain).
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. HIPK subfamily.
Protein kinase that phosphorylates TP53, and thus induces TP53 repression of BIRC5 promoter (By similarity). May act as a corepressor of transcription factors (Potential).
Interacts with CDC42 and RHOQ, 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 (By similarity).
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).
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).
Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.
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. 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. Class-III ADH is remarkably ineffective in oxidizing ethanol. Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.
Exclusively expressed in neurons of the habenular complex. The expression is particularly prominent in the medial habenular nucleus, whereas the lateral habenular nucleus exhibited a lower level of expression.
Normal cells and cells transformed by human papillomavirus type 16 E6E7 and polyomavirus large T. Suppressed in cells transformed by oncogenes such as V-SRC, V-ABL, V-FPS, V-MOS, V-SIS, V-K-RAS, and polyomavirus middle T.
Cleaved by caspases at the onset of apoptosis.
Extended rod-like protein with long coiled-coil domains.
Homodimer, may assemble into homohexamers (By similarity). Homotetramer; forms a parallel homotetramer with a flexible rod-like structure that can give rise to I- and Y-shaped conformations (PubMed:25787021). Interacts with GORASP1/GRASP65 (PubMed:11739401, PubMed:25787021, PubMed:9346242, PubMed:9628863). The homooligomer forms a complex with GORASP1 with a 1:1 stoichiometry (PubMed:25787021). Interacts with RAB1B that has been activated by GTP-binding (PubMed:18167358). Interacts with p115/USO1; interaction with p115/USO1 inhibits interaction with STX5 and/or RAB1B (PubMed:9150144, PubMed:9753325, PubMed:10744704, PubMed:10769027, PubMed:18167358). Interacts with STX5 (PubMed:18167358). Interacts with ZFPL1 (By similarity). Interacts with AKAP450/AKAP9; leading to recruit AKAP450/AKAP9 to the cis-Golgi (By similarity).
Methylation by PRMT5 is required for Golgi ribbon formation.
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 (PubMed:9150144, PubMed:20197635). 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 (PubMed:10679020, PubMed:11035033, PubMed:18167358). 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 (PubMed:9753325). 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 (By similarity). Regulates the meiotic spindle pole assembly, probably via the same mechanism (By similarity). Also regulates the centrosome organization (By similarity). Also required for the Golgi ribbon formation and glycosylation of membrane and secretory proteins (By similarity).
Phosphorylated at Ser-37 by CDK1 at the onset of mitosis, inhibiting the interaction with p115/USO1 and triggering Golgi disassembly (PubMed:9150144, PubMed:9753325). A report however suggests that Golgi disassembly is independent of phosphorylation at Ser-37 (PubMed:20699666). 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 (PubMed:10769027).
The nuclear localization signal (cNLS) mediates interaction with importin-alpha, recruiting importin-alpha to the Golgi membrane and liberating TPX2.
Brain. Detected in several other tissues.
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration.
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration. During cytokinesis, forms a complex with YWHAB, which is crucial for daughter cell separation, and facilitates abscission by a mechanism which may implicate the regulation of RHOA. In cardiac myocytes, regulates myofilament function and excitation coupling at the Z-lines, where it is indirectly associated with F-actin via interaction with COPB1. During endothelin-induced cardiomyocyte hypertrophy, mediates activation of PTK2/FAK, which is critical for cardiomyocyte survival and regulation of sarcomere length. Plays a role in the pathogenesis of dilated cardiomyopathy via persistent phosphorylation of troponin I (TNNI3). Involved in nerve growth factor (NFG)-induced neurite outgrowth and neuron morphological change independently of its kinase activity, by inhibition of RHOA pathway, activation of CDC42 and cytoskeletal rearrangement. May be involved in presynaptic facilitation by mediating phorbol ester-induced synaptic potentiation. Phosphorylates gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), which reduces the response of GABA receptors to ethanol and benzodiazepines and may mediate acute tolerance to the intoxicating effects of ethanol. Upon PMA treatment, phosphorylates the capsaicin- and heat-activated cation channel TRPV1, which is required for bradykinin-induced sensitization of the heat response in nociceptive neurons. Is able to form a complex with PDLIM5 and N-type calcium channel, and may enhance channel activities and potentiates fast synaptic transmission by phosphorylating the pore-forming alpha subunit CACNA1B (CaV2.2). Downstream of TLR4, plays an important role in the lipopolysaccharide (LPS)-induced immune response by phosphorylating and activating TICAM2/TRAM, which in turn activates the transcription factor IRF3 and subsequent cytokines production. In differentiating erythroid progenitors, is regulated by EPO and controls the protection against the TNFSF10/TRAIL-mediated apoptosis, via BCL2. May be involved in the regulation of the insulin-induced phosphorylation and activation of AKT1. Phosphorylates NLRP5/MATER and may thereby modulate AKT pathway activation in cumulus cells (By similarity).
Forms a ternary complex with TRIM63 and RACK1/GN2BL1 (PubMed:15596539). Can form a complex with PDLIM5 and N-type calcium channel (PubMed:12665800). Interacts with COPB1 (PubMed:9360998). Interacts with DGKQ (By similarity). Interacts with STAT3 (By similarity). Interacts with YWHAB (By similarity). Interacts with HSP90AB1; promotes functional activation in a heat shock-dependent manner (By similarity). Interacts (via phorbol-ester/DAG-type 2 domain) with PRPH and VIM (By similarity). Interacts with NLRP5/MATER (By similarity).
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-566 (activation loop of the kinase domain), Thr-710 (turn motif) and Ser-729 (hydrophobic region), need to be phosphorylated for its full activation.
Phosphorylation on Thr-566 by PDPK1 triggers autophosphorylation on Ser-729. Phosphorylation in the hinge domain at Ser-350 by MAPK11 or MAPK14, Ser-346 by GSK3B and Ser-368 by autophosphorylation is required for interaction with YWHAB (By similarity).
Abundant in heart, brain, aorta, vena cava, vas deferens, submaxillary gland, lung, and kidney. Found at lower levels in prostate, parotid gland and skeletal muscle.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA1A sub-subfamily.
Homo- and heterooligomer. Heterooligomerizes with ADRA1B homooligomers in cardiac myocytes. Interacts with CAVIN4.
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 (By similarity).
Highly expressed during early stages of development at 17 dpc and postnatal day 10 (P10) but significantly reduced in the adult brain.
In brain, expressed in both excitatory and inhibitory neurons but not expressed by glial cells.
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates (By similarity). 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 IGF2R and SORT1, promoting their partitioning to an endosomal membrane subdomain where they can interact with the retromer cargo-selective complex (By similarity). Thereby, regulates retrograde transport from endosomes to the Golgi apparatus of these lysosomal sorting receptors and plays a role in trafficking of lysosomal proteins (By similarity). In the nervous system, catalyzes the palmitoylation of DLG4/PSD95 and regulates its synaptic clustering and function in synaptogenesis (PubMed:31189538). Could be involved in the differentiation of dopaminergic neurons and the development of the diencephalon (By similarity). Could also catalyze the palmitoylation of GAP43 (By similarity). Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane (By similarity). Could also palmitoylate FYN as shown in vitro (By similarity).
This is a receptor for calcitonin. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin.
May be involved in cell cycle regulation.
Ubiquitinated; mediated by UHRF2 and leading to its subsequent proteasomal degradation.
Cell surface proteoglycan that bears heparan sulfate.
Cell surface proteoglycan that bears heparan sulfate. May act as a catalyst in increasing the rate of conversion of prion protein PRPN(C) to PRNP(Sc) via associating (via the heparan sulfate side chains) with both forms of PRPN, targeting them to lipid rafts and facilitating their interaction. Required for proper skeletal muscle differentiation by sequestering FGF2 in lipid rafts preventing its binding to receptors (FGFRs) and inhibiting the FGF-mediated signaling. Binds Cu(2+) or Zn(2+) ions (By similarity). Binds, via the heparan sulfate side chains, alpha-4 (V) collagen and participates in Schwann cell myelination.
N- and O-glycosylated. N-glycosylation is mainly of the complex type containing sialic acid. O-glycosylated with heparan sulfate. The heparan sulfate chains can be cleaved either by the action of heparanase or, degraded by a deaminative process that uses nitric oxide (NO) released from the S-nitrosylated cysteines. This process is triggered by ascorbate, or by some other reducing agent, in a Cu(2+)- or Zn(2+) dependent manner. Cu(2+) ions are provided by ceruloproteins such as APP, PRNP or CP which associate with GCP1 in intracellular compartments or lipid rafts.
S-nitrosylated in a Cu(2+)-dependent manner. Nitric acid (NO) is released from the nitrosylated cysteines by ascorbate or by some other reducing agent, in a Cu(2+) or Zn(2+) dependent manner. This free nitric oxide is then capable of cleaving the heparan sulfate side chains.
This cell-associated glypican is further processed to give rise to a medium-released species.
Belongs to the MICOS complex subunit Mic60 family.
Component of the MICOS complex, a large protein complex of the mitochondrial inner membrane that plays crucial roles in the maintenance of crista junctions, inner membrane architecture, and formation of contact sites to the outer membrane. Plays an important role in the maintenance of the MICOS complex stability and the mitochondrial cristae morphology.
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 (By similarity). 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 (By similarity). 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 (By similarity). Interacts with HSPA1A/HSPA1B and OPA1, preferentially with the soluble OPA1 form (By similarity). Interacts with MICOS13/MIC13, MICOS10/MIC10, CHCHD3/MIC19, CHCHD6/MIC25, SAMM50 and TMEM11 (By similarity). Interacts with APOO/MIC23/MIC26 and APOOL/MIC27 (By similarity). Interacts with ARMC1 (By similarity). Interacts with ARMC12 (By similarity).
Detected in the first branchial arch of embryonic day 11 (11 dpc) embryo, and subsequently in the myotomes and the dorsal root ganglia in developing somites from 11.5 dpc through 13.5 dpc, but not in the brain. However, at 15 dpc, 18, dpc, 21 dpc and P0, highly expressed in the brain.
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.
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. The native outer hair cell receptor may be composed of CHRNA9-CHRNA10 heterooligomers. Interacts with the alpha-conotoxin RgIA (PubMed:25740413).
Detected in the nasal epithelium, in the outer hair cells of the cochlea, in the pars tuberalis of the hypophysis, and in the developing muscle of the tongue. Also expressed in the neurons of dorsal root ganglia.
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. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this leads 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.
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.
Homodimer. Binds actin monomers (By similarity).
Expressed in liver, brain, spleen and testis.
Transcriptional activator. Binds the consensus sequence 5'-DHWATTGAYTWWD-3' on a variety of gene promoters such as those of HNF3B and TTR. Important for liver genes transcription. The affinity of HNF-6-alpha and HNF-6-beta for DNA differs depending on the target sequence.
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 (By similarity). 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).
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.
Belongs to the thiamine pyrophosphokinase family.
Appears to be stable component of the Pol II(G) complex form of RNA polymerase II. Pol II synthesizes mRNA precursors and many functional non-coding RNAs and is the central component of the basal RNA polymerase II transcription machinery. May play a role in Mediator-dependent regulation of transcription activation. In vitro, acts as negative regulator of transcriptional activation; this repression is relieved by the Mediator complex, which restores Pol II(G) activator-dependent transcription to a level equivalent to that of Pol II (By similarity).
Component of the Pol II(G) complex, which contains the RNA polymerase II (Pol II) core complex subunits and Polr2m and appears to be an abundant form of Pol II.
Belongs to the chloride channel (TC 2.A.49) family. ClC-1/CLCN1 subfamily.
Predominantly expressed in skeletal muscles.
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 (By similarity).
Voltage-gated chloride channel (PubMed:1659664). Plays an important role in membrane repolarization in skeletal muscle cells after muscle contraction (By similarity).
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. 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). Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains.
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.
Acetylation at Lys-338 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. Binds to the core DNA motif of NPPA promoter.
Monomer. Homodimer (via the T-box); binds DNA as homodimer. Interacts (via the T-box) with NKX2-5 (via the homeobox); this complex binds DNA. Interacts with GATA4. Interacts with KAT2A and KAT2B.
The T-Box domain binds to double-stranded DNA.
Component of heteromultimeric potassium channels. Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). The KCND2-KCNIP2 channel complex contains four KCND2 and four KCNIP2 subunits (By similarity). Probably part of a complex consisting of KCNIP1, KCNIP2 isoform 3 and KCND2. At least isoform 2 and isoform 3 can self-associate to form homodimers and homotetramers. Isoform 3 interacts with KCNIP1 in a calcium-dependent manner (By similarity). Interacts with KCND2 (PubMed:16820361). Isoform 1 and isoform 3 interact with KCND3 isoform 1.
Expressed in heart, brain and lung. In brain, abundantly expressed in striatum, hippocampus and olfactory bulb, moderately expressed in cerebral cortex and lowly expressed in thalamus and hypothalamus. Isoform 1 is predominant in cerebral cortex, striatum and hippocampus. Isoform 1, isoform 2 and isoform 3 are equally expressed in olfactory bulb. Iisoform 3 is expressed at high levels and isoform 1 at low levels in heart (in PubMed:11263977).
Palmitoylated. Palmitoylation enhances association with the plasma membrane.
Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. Modulates channel density, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner (PubMed:16820361). In vitro, modulates KCND2/Kv4.2 and KCND3/Kv4.3 currents. Involved in KCND2 and KCND3 trafficking to the cell surface. Essential for the expression of I(To) currents in the heart (By similarity). Required for normal protein levels of KCND2 in the heart ventricle (By similarity).
Belongs to the AB hydrolase superfamily.
Lipase that preferentially hydrolysis medium-chain saturated monoacylglycerols including 2-arachidonoylglycerol (By similarity). Through 2-arachidonoylglycerol degradation may regulate endocannabinoid signaling pathways. 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. 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 (By similarity).
Belongs to the potassium channel family. B (Shab) (TC 1.A.1.2) subfamily. Kv2.2/KCNB2 sub-subfamily.
Interacts with MAGI3 and NDP. Component of a complex, at least composed of TSPAN12, FZD4 and norrin (NDP). Interacts (via FZ domain) with TSKU; TSKU competes with WNT2B for binding to FZD4, inhibiting Wnt signaling and repressing peripheral eye development. Interacts with glypican GPC3.
Receptor for Wnt proteins (By similarity). Most of 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 (By similarity). 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 both activated by Wnt protein-binding, but also by a 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 (By similarity). Both pathways seem to involve interactions with G-proteins (By similarity). May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (By similarity).
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. Stimulates the Ras signaling pathway via RAPGEF2.
Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site (By similarity). Interacts with CRY1; the interaction may block GPCR-mediated regulation of cAMP concentrations. Interacts with ADCY6 and stimulates its adenylyl cyclase activity (By similarity). Interacts with ADCY2 and ADCY5 (By similarity). Stimulates the ADCY5 adenylyl cyclase activity (By similarity). Interaction with SASH1 (By similarity). Interacts with GASL2L2 (By similarity).
Isoform Gnas-3 is abundant in brain with intermediate levels in skeletal muscle and very low levels in other tissues.
May be proteolytically processed to give rise to a number of active peptides.
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.
This protein is produced by a bicistronic gene which also produces the ALEX protein from an overlapping reading frame.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. STKL subfamily.
Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6. Interacts with STAT3 and JAKs (By similarity).
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 the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs.
Folds into a two seven-bladed beta-propeller structure which is required for elongator complex assembly.
Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma (By similarity).
Most abundant in heart, lung, kidney, and aortic endothelial cells.
This inhibitor contains three inhibitory domains. The first domain interacts with VIIa and TF, the second one with Xa (By similarity).
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 CSNK2B (By similarity). Interacts with PCNA.
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 (By similarity). May enhance the PCNA-dependent DNA polymerase delta activity.
Belongs to the NUP186/NUP192/NUP205 family.
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. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the complex, interacts directly with UIMC1/RAP80, BRCC3/BRCC36 and BABAM2. Homodimer. Interacts directly (when phosphorylated at Ser-402) with BRCA1. The phosphorylated homodimer can interact directly 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-402 of the pSXXF motif by ATM or ATR constitutes a specific recognition motif for the BRCT domain of BRCA1.
Associates with RNA polymerase II, the TCR-specific proteins CKN1/CSA and ERCC6/CSB, and XPA. Identified in the spliceosome C complex. Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE. 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. The IB complex does not contain PRPF19.
Involved in pre-mRNA splicing as component of the spliceosome. Involved in transcription-coupled repair (TCR), transcription and pre-mRNA splicing.
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 (By similarity).
Homomultimers or heteromultimers (Potential). Forms heterodimer with calmodulin. When activated by calmodulin and calcium, interacts with the BH4 domain of BCL2 and weakly with BCLX isoform Bcl-X(L). Does not bind and inhibit calcineurin. Interacts with ZFYVE27; may negatively regulate ZFYVE27 phosphorylation (By similarity).
This protein was previously referred to as T2R7 but is now considered to be the ortholog of human TAS2R13.
Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes. Part of a mRNA decay activation complex at least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 and XRN1 and mRNA-decapping enzymes DCP1A and DCP2. Associates with the RNA exosome complex. Interacts (via phosphorylated form) with 14-3-3 proteins; these interactions promote exclusion of ZFP36 from cytoplasmic stress granules in response to arsenite treatment in a MAPKAPK2-dependent manner and does not prevent CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner. Interacts with AGO2 and AGO4. Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation. Interacts (via N-terminus) with CNOT6. Interacts with CNOT6L. Interacts (via C-terminus) with CNOT7; this interaction occurs in a RNA-independent manner, induces mRNA deadenylation and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts with EDC3. Interacts (via N-terminus) with EXOSC2. Interacts with heat shock 70 kDa proteins. Interacts with KHSRP; this interaction increases upon cytokine-induced treatment. Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85. Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation. Interacts with NCL. Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation. Interacts with PABPC1; this interaction occurs in a RNA-dependent manner. Interacts (via hypophosphorylated form) with PABPN1 (via RRM domain and C-terminal arginine-rich region); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38 MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis. Interacts with PAN2. Interacts (via C3H1-type zinc finger domains) with PKM. Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase. Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay. Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress. Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner. Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-59 and Ser-86 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF-alpha mRNA decay. Interacts with XRN1. Interacts (via C-terminus and Ser-179 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-179 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs. Interacts (via phosphorylated form) with YWHAE. Interacts (via C-terminus) with YWHAG; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAH; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAQ; this interaction occurs in a phosphorylation-dependent manner. Interacts with (via C-terminus) YWHAZ; this interaction occurs in a phosphorylation-dependent manner. Does not interact with SH3KBP1. Interacts (via P-P-P-P-G repeats) with GIGYF2; the interaction is direct (By similarity).
Associates with the cytoplasmic CCR4-NOT deadenylase complex to trigger ARE-containing mRNA deadenylation and decay processes.
Phosphorylated. Phosphorylation at serine and/or threonine residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner. Phosphorylated by MAPKAPK2 at Ser-53 and Ser-179; phosphorylation increases its stability and cytoplasmic localization, promotes binding to 14-3-3 adapter proteins and inhibits the recruitment of cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the mRNA decay machinery, thereby inhibiting ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Phosphorylation by MAPKAPK2 does not impair ARE-containing RNA-binding. Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon skeletal muscle satellite cell activation; this phosphorylation inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes MYOD1 mRNA. Phosphorylated by MAPK1 upon mitogen stimulation. Phosphorylated at Ser-59 and Ser-86; these phosphorylations increase in a SH3KBP1-dependent manner. Phosphorylated at serine and threonine residues in a pyruvate kinase PKM- and p38 MAPK-dependent manner. Phosphorylation at Ser-53 may participate in the PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner. Dephosphorylated by serine/threonine phosphatase 2A at Ser-179.
The C3H1-type zinc finger domains are necessary for ARE-binding activity.
Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination leads to proteasomal degradation through a p38 MAPK signaling pathway.
Zinc-finger RNA-binding protein that destabilizes numerous 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:27193233). Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA (By similarity). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:27193233). Binds also to ARE of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages. Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (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.
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. Might play a general role in vesicular transport.
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 (By similarity). 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.
Was initially reported to localize in the nucleus (PubMed:11525638). However, it was later shown to localize in the endoplasmic reticulum lumen.
Highly abundant in kidney and lung. Found in a lesser extent in spleen, colon, and thymus. Also expressed in uterine myometrium and endometrium.
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 (By similarity). Implicated the smooth muscle contractile response to PGE2 in various tissues. Isoform 1 and isoform 2 have identical ligand binding properties, but isoform 2 lacks coupling to calcium mobilization and may therefore attenuate the action of PGE2 on tissues.
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 brain, spinal cord and dorsal root ganglion (DRG). Expressed by a subset of sensory neurons in the DRG. Expressed by granule cells in the cerebellar cortex. In hippocampus, expression is detected in dentate gyrus granule cells, in pyramidal cells of CA1-CA3 subfields and in interneurons of the striatum oriens and radiatum of all subfields. In cerebral cortex expressed in small, medium and large pyramidal cells in layers 2, 3 and 5 respectively. Also expressed in striatum, globus pallidus, inferior and superior calliculi, amygdala, magnocellular preoptic nucleus, islands of Calleja and large neurons of olfactory tubercules.
Highly expressed in newborn spinal cord but hardly detected in the cerebellum compared to adult. Expressed at postnatal day 1 in ependymal cells lining the central canal of spinal cord and in motor neurons. In adult, expression decreases in ependymal cells and increases in motor neurons. The number of positive interneurons decreases but the individual interneuron expression increases in adult spinal cord compared to newborn.
In vitro, has no proton-gated channel activity.
Probable cation channel with high affinity for sodium.
2-oxoglutarate dehydrogenase (E1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHC) (PubMed:18783430). 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 (Probable). 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) (Probable). 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 (By similarity). Can catalyze the decarboxylation of 2-oxoadipate in vitro, but at a much lower rate than 2-oxoglutarate (By similarity). Mainly active in the mitochondrion. 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 (By similarity).
Calcium ions and ADP stimulate, whereas ATP and NADH reduce catalytic activity.
The OGDH-containing OGDHC complex is present in the brain and in the heart.
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).
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. Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Interacts with CLOCK and CRY1.
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 (By similarity).
Binds activated protein C. Enhances protein C activation by the thrombin-thrombomodulin complex; plays a role in the protein C pathway controlling blood coagulation (By similarity).
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 (By similarity).
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) (By similarity).
In vitro phosphorylation at Thr-117 by AURKB prevents interaction with INCENP and localization to mitotic chromosomes. Phosphorylation at Thr-48 by CK2 is critical for its mitotic and anti-apoptotic activities. Phosphorylation at Thr-34 by CDK15 is critical for its anti-apoptotic activity.
Monomer or homodimer. Exists as a homodimer in the apo state and as a monomer in the CPC-bound state. The monomer protects cells against apoptosis more efficiently than the dimer. Only the dimeric form is capable of enhancing tubulin stability in cells. When phosphorylated, interacts with LAMTOR5/HBXIP; the resulting complex binds pro-CASP9, as well as active CASP9, but much less efficiently. 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 CDCA8. Interacts with JTB. Interacts (via BIR domain) with histone H3 phosphorylated at 'Thr-3' (H3pT3). Interacts with EVI5. Interacts with GTP-bound RAN in both the S and M phases of the cell cycle. Interacts with USP9X. Interacts with tubulin. Interacts with BIRC2/c-IAP1. The monomeric form interacts with XIAP/BIRC4. Both the dimeric and monomeric form can interact with DIABLO/SMAC. Interacts with BIRC6/bruce. Interacts with FBXL7; this interaction facilitates the polyubiquitination and subsequent proteasomal degradation of BIRC5 by the SCF(FBXL7) E3 ubiquitin-protein ligase complex (By similarity).
Multitasking protein that has dual roles in promoting cell proliferation and preventing apoptosis (By similarity). Component of a chromosome passage protein complex (CPC) which is essential for chromosome alignment and segregation during mitosis and cytokinesis (By similarity). Acts as an important regulator of the localization of this complex; directs CPC movement to different locations from the inner centromere during prometaphase to midbody during cytokinesis and participates in the organization of the center spindle by associating with polymerized microtubules (By similarity). Involved in the recruitment of CPC to centromeres during early mitosis via association with histone H3 phosphorylated at 'Thr-3' (H3pT3) during mitosis (By similarity). The complex with RAN plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules (By similarity). May counteract a default induction of apoptosis in G2/M phase (By similarity). The acetylated form represses STAT3 transactivation of target gene promoters (By similarity). May play a role in neoplasia. Inhibitor of CASP3 and CASP7 (By similarity). Essential for the maintenance of mitochondrial integrity and function (By similarity).
The BIR repeat is necessary and sufficient for LAMTOR5 binding.
Ubiquitinated by the Cul9-RING ubiquitin-protein ligase complex, leading to its degradation. Ubiquitination is required for centrosomal targeting.
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 (By similarity). Interacts with SDC2 (By similarity).
Core component of the TRAPP complexes which has a function of guanine nucleotide exchange factor activity for Rab1 GTPase. Plays a role in vesicular transport from endoplasmic reticulum to Golgi and autophagy (By similarity). May play a role in dendrite postsynaptic membrane trafficking (By similarity).
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.
Skin, placenta, also detectable in ovary and adrenal gland.
Detected in the granule and pyramidal cell layer in the hippocampus.
Homodimer. The homodimer interacts with a single NTRK1 chain. The homodimer interacts with a single NGFR chain (By similarity). The NGF dimer interacts with a single SORCS2 chain (via extracellular domain). 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). 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 (By similarity).
Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems. Extracellular ligand for the NTRK1 and NGFR receptors, activates cellular signaling cascades to regulate neuronal proliferation, differentiation and survival (By similarity). 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 (By similarity). 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).
Interacts with DENND1A and DENND1B; in a nucleotide-dependent manner. Interacts with DENND1C; weak interaction which is nucleotide-independent (By similarity). Interacts (GTP-bound form) with ACAP2 and MICALL1; the interaction is direct and probably recruits ACAP2 and MICALL1 to membranes (PubMed:23572513). Interacts with EHD1; the interaction is indirect through MICALL1 and probably recruits EHD1 to membranes (By similarity). Interacts with GDI1, GDI2 and CHM; phosphorylation at Thr-72 disrupts these interactions (By similarity).
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 is activated by the guanine exchange factors DENND1A, DENND1B and DENND1C (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 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 (By similarity).
Homopentamer. Forms a complex with GCH1 where a GCH1 homodecamer is sandwiched by two GFRP homopentamers. Interacts with GCH1.
Liver and kidney. Somewhat lower level in testis, heart, brain and lung.
Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine.
Highly expressed in neural, neuroendocrine, exocrine and endothelial tissues and in osteoblasts. Detected in neurons throughout the central nervous system, in meninges and choroid plexus, in the anterior pituitary, the intermediate lobe, in pancreas, adrenal cortex, gastric glands, and in the inner nuclear layer of the retina.
Acts as an inhibitor of serine/threonine-protein phosphatase 2A (PP2A) activity. Potentiates ubiquitin-mediated proteasomal degradation of serine/threonine-protein phosphatase 2A catalytic subunit alpha (PPP2CA) (By similarity). Inhibits PP2A-mediated dephosphorylation of WEE1, promoting ubiquitin-mediated proteolysis of WEE1, thereby releasing G2/M checkpoint (By similarity).
CHEK1-mediated phosphorylation at Ser-36 negatively regulates its ability to inhibit serine/threonine-protein phosphatase 2A (PP2A) activity. Phosphorylation leads to its release from the PP2A complex and its sequestration by 14-3-3 proteins in the cytoplasm resulting in its inability to translocate to the nucleus, where it otherwise inhibits PP2A.
Interacts with PPP2CA, PPP2R2A and PPP2R1A (By similarity). The CHEK1-mediated Ser-36 phosphorylated form interacts with 14-3-3 proteins (By similarity).
By cAMP, glucocorticoids, phorbol esters and insulin.
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 (By similarity).
Activated at the onset of neuronal differentiation.
Expressed at high levels in the embryonic brain in the period related to neuroblast proliferation and differentiation.
Probably participates in neurogenesis. Could play a role in regulating gene activity in the proliferative and/or differentiative pathways induced by NGF.
Expressed in the foot process layer of podocytes in the kidney glomerulus and in tubules (at protein level).
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 (By similarity).
Phosphorylation of Tyr-1176 decreases sensitivity to cleavage by calpain in vitro.
Expressed in all tissues tested, including brain, liver, spleen and heart. In the brain, restricted to epithelial cells of the choroid plexus. Isoform alpha is the more abundant form.
Forms heterodimers with the anti-apoptotic proteins, Bcl-X(L), Bcl-2 and Bcl-W. Also binds protein S100A10. The Ser-113/Ser-137 phosphorylated form binds 14-3-3 proteins. Interacts with AKT1 and PIM3 (By similarity). Interacts with HIF3A (via C-terminus domain); the interaction reduces the binding between BAD and BAX (By similarity). Interacts (via BH3 domain) with NOL3 (via CARD domain); preventing the association of BAD with BCL2 (PubMed:17998337). Interacts with GIMAP3/IAN4 and GIMAP5/IAN5 (By similarity).
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.
Methylation at Arg-132 and Arg-134 by PRMT1 inhibits Akt-mediated phosphorylation at Ser-137.
Phosphorylated at one or more of Ser-113, Ser-137, Ser-156 and Ser-171 in response to survival stimuli, which blocks its pro-apoptotic activity. Phosphorylation on Ser-137 or Ser-113 promotes heterodimerization with 14-3-3 proteins. This interaction then facilitates the phosphorylation at Ser-156, a site within the BH3 motif, leading to the release of Bcl-X(L) and the promotion of cell survival. Ser-137 is the major site of AKT/PKB phosphorylation, Ser-156 the major site of protein kinase A (CAPK) phosphorylation.
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.
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.
By isoprenaline. Prolongend stimulation does not change the percentages of secreted forms (with gliadoralin A 1-90 as predominant form).
Found in saliva (at protein level). Secreted from the submandibular gland.
May play a role in the formation of the protective mucosal protein pellicle involved in the reinforcement and protection of oral mucosal epithelial surface.
Predominantly proteolytically processed at its C-terminus before secretion to produce the major form gliadoralin A 1-90. Further proteloytically processed after secretion to produce minor forms. Potential substrate of transglutaminase.
Cell adhesion protein that participates in lymphocyte recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion. Has a monoamine oxidase activity. May play a role in adipogenesis (By similarity).
Highly expressed in adipocytes, aorta and lung. Expressed at lower levels in heart, kidney, large intestine, liver, small intestine and stomach.
Homodimer; disulfide-linked (By similarity). Forms a heterodimer with AOC2 (By similarity).
Binds phosphatidylserine (PS) in a calcium-independent manner. PS-binding is inhibited by phosphotidic acid and phosphatidylinositol. Does not bind phosphatidylcholine (By similarity).
Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN. Interacts with CAVIN4; this augments the transactivation of NPPA by CAVIN4 (By similarity). Binds to PRKCA in the presence of phosphatidylserine (PubMed:9566962). Interacts with CAVIN1 and CAV3 (By similarity).
Plays an important role in caveolar biogenesis and morphology. Regulates caveolae morphology by inducing membrane curvature within caveolae. 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 (By similarity). May play a role in targeting PRKCA to caveolae (PubMed:9566962).
The leucine-zipper domain is essential for its localization in the caveolae.
Component of the BCR(KBTBD8) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD8 and RBX1.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of neural crest specification. 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.
Expressed predominantly in the acinar cells of the submandibular gland and to lesser extent in the prostate.
SMR1 mRNA is about 1000 times more abundant in the submandibular gland of male than female.
Several O-linked glycosylation sites might be present in the C-terminal part.
Sialorphin is an endogenous inhibitor of neprilysin. Inhibits the breakdown of Met-enkephalin and substance P in isolated tissue from the dorsal zone of the rat spinal cord. Has an analgesic effect when administered to rats by intravenous injection.
Sialorphin may be involved in the modulation of mineral balance between at least four systems: kidney, bone, tooth and circulation.
Submandibular gland peptide T is able to directly or indirectly down-regulate cardiovascular depression induced by septic shock (endotoxin stimuli), or anaphylactic challenge (nematode antigen sensitization).
Brainstem-restricted receptor for GDF15 which regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses (Probable). Upon interaction with its ligand, GDF15, interacts with RET and induces cellular signaling through activation of MAPK- and AKT- signaling pathways (By similarity).
Expressed in the brainstem, restricted to cells in the area postrema and the immediately adjacent region of the nucleus tractus solitarius (PubMed:28846097, PubMed:28846099). Detected at low levels in testis (PubMed:28846099).
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 (By similarity).
Homodimer; disulfide-linked. Can also form heterodimer with VEGF (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 (By similarity).
RNA-binding protein required for the maturation of box H/ACA snoRNPs complex and ribosome biogenesis. During assembly of the H/ACA snoRNPs complex, it associates with the complex and disappears during maturation of the complex and is replaced by NOLA1/GAR1 to yield mature H/ACA snoRNPs complex. Probably competes with NOLA1/GAR1 for binding with DKC1/NOLA4 (By similarity).
Does not associate with known Na,K-ATPase alpha-subunits (By similarity). Associates with a SMAD7-transcriptional complex. Interacts with SNW1 and TOR1AIP1.
Expressed in perinatal myocytes (at protein level). Expressed during postnatal development in skeletal muscle and heart.
May act as a transcriptional coregulator during muscle development through its interaction with SNW1. Has lost its ancestral function as a Na,K-ATPase beta-subunit (By similarity).
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.
Essential for the degradation of glycogen in lysosomes. Has highest activity on alpha-1,4-linked glycosidic linkages, but can also hydrolyze alpha-1,6-linked glucans.
Belongs to the uracil-DNA glycosylase (UDG) superfamily. SMUG1 family.
Recognizes base lesions in the genome and initiates base excision DNA repair. Acts as a monofunctional DNA glycosylase specific for uracil (U) residues in DNA with a preference for single-stranded DNA substrates. The activity is greater toward mismatches (U/G) compared to matches (U/A). Excises uracil (U), 5-formyluracil (fU) and uracil derivatives bearing an oxidized group at C5 [5-hydroxyuracil (hoU) and 5-hydroxymethyluracil (hmU)] in ssDNA and dsDNA, but not analogous cytosine derivatives (5-hydroxycytosine and 5-formylcytosine), nor other oxidized bases. The activity is damage-specific and salt-dependent. The substrate preference is the following: ssDNA > dsDNA (G pair) = dsDNA (A pair) at low salt concentration, and dsDNA (G pair) > dsDNA (A pair) > ssDNA at high salt concentration.
Interacts with BCL2 and BCL2L1. Interacts with C1QBP (By similarity).
The BH3 motif is required for the induction of cell death.
Interacts with MAS1 (By similarity). Interacts with ARRB1 (PubMed:11579203). Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA (By similarity).
Is expressed in the liver, kidney, aorta, lung, uterus, ovary, spleen, heart, adrenal gland, and vascular smooth muscle cell.
Receptor for angiotensin II, a vasoconstricting peptide, which acts as a key regulator of blood pressure and sodium retention by the kidney (PubMed:2041570, PubMed:10747880). The activated receptor in turn couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15) and thus activates phospholipase C and increases the cytosolic Ca(2+) concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C (PubMed:10747880).
Detected in testis, small intestine, parotid gland, lung and brain. Small amounts are detected in heart, kidney and spleen (PubMed:10926847). Expressed in skeletal muscle (PubMed:9632638).
Interacts with BSG; interaction mediates SLC16A3 targeting to the plasma membrane.
Proton-dependent transporter of monocarboxylates such as L-lactate and pyruvate (PubMed:9632638, PubMed:10926847) (By similarity). Plays a predominant role in the L-lactate efflux from highly glycolytic cells (PubMed:9632638, PubMed:10926847).
Two basolateral sorting signals (BSS) in its C-terminal cytoplasmic tail are required to direct SLC16A3 to the basolateral membrane.
Was initially assigned as monocarboxylate transporter 3 (MCT3) (PubMed:9632638). However, it was later shown that it corresponds to monocarboxylate transporter 4 (MCT4).
Was initially thought to be considered to be a low affinity lactate transporter with negligible affinity for pyruvate (By similarity). However, it was later shown that SLC16A3 is a high affinity lactate transporter with physiologically relevant affinity for pyruvate (By similarity).
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.
Arf-GAP domain interacts with G domain and may regulate its GTPase activity.
G domain binds GTP and has GTPase activity.
GAP activity is stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and, to a lesser extent, by phosphatidylinositol 3,4,5-trisphosphate (PIP3). Phosphatidic acid potentiates PIP2 stimulation (By similarity).
GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. Aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase.
Interacts with EPB41L1, PLCG1, NF2, HOMER1 and HOMER2.
PH domain binds phospholipids and is required for nuclear targeting.
Present in cortex, hippocampus and olfactory bulb but absent in cerebellum (at protein level).
Associates with the V0 complex of the vacuolar ATPase (V-ATPase).
Required for the assembly of the V0 complex of the vacuolar ATPase (V-ATPase) in the endoplasmic reticulum.
Belongs to the NFYC/HAP5 subunit family.
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 (By similarity).
May be involved in the regulation of spermatogenesis and sperm maturation.
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 (By similarity).
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 (By similarity).
Enhances the tyrosine carboxypeptidase activity of VASH1 and VASH2, thereby promoting the removal of the C-terminal tyrosine residue of alpha-tubulin. Also required to enhance the solubility and secretion of VASH1 and VASH2. Plays a role in axon and excitatory synapse formation (PubMed:30607023).
Heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter.
Molecular chaperone; assists the folding of proteins upon ATP hydrolysis. Known to play a role, in vitro, in the folding of actin and tubulin.
Interacts with tubulin. Interacts with BORCS5; recruits ARL8B to lysosomes. Interacts with VPS41; the interaction mediates the recruitment of the HOPS complex to lysosomes. Interacts (GTP-bound form) with PLEKHM2 (via RUN domain); the interaction is required to recruit the motor protein kinesin-1 on lysosomes. 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. PLEKHM1 and PLEKHM2 compete for interaction with ARL8B.
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 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. 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. 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 (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). Also acts as a regulator of endosome to lysosome trafficking pathways of special significance for host defense. 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. 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 (By similarity). 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 (By similarity).
Ubiquitinated at Lys-141 by RNF167, leading to its degradation.
Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1. 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. Connects PAF1C with the RNF20/40 E3 ubiquitin-protein ligase complex. Involved in polyadenylation of mRNA precursors (By similarity).
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (By similarity). The PAF1 complex interacts with PHF5A (By similarity). Interacts with POLR2A, TCEA1, SKIC3, KMT2A/MLL1, SUPT5H, RNF20 and RNF40. Interacts with UBE2E1 (By similarity).
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.
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 (PubMed:10541966). 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 (By similarity) (PubMed:10541966).
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. Interacts with PARP1; this interaction functions as part of the control of replication fork progression. Interacts with MCM10 and WDHD1; these interactions recruit the polymerase alpha complex to the pre-replicative complex bound to DNA. Interacts with RPA1; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (By similarity).
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 (By similarity).
Interacts with ITGAV/ITGB3 in an RGD-dependent manner, increasing endothelial cell's motility.
Regulates vascular tubulogenesis in vivo. Inhibits platelet-derived growth factor (PDGF)-BB-induced smooth muscle cell migration and promotes endothelial cell adhesion to the extracellular matrix and angiogenesis (By similarity).
Activated by arachadonic acid, mechanical stretching and intracellular acidification.
Does not display channel activity but reduces the channel activity of isoform 1, isoform 2 and isoform 4 and reduces cell surface expression of isoform 2.
Expressed in cardiomyocytes (at protein level). Expressed in various brain regions including the lateral olfactory tract, piriform cortex of the forebrain, paraventricular and anteromedial thalamic nuclei, brainstem, caudate putamen, nucleus accumbens, neocortex and interpeduncular nucleus. Isoform 5 is expressed in brain and kidney.
Homodimer; disulfide-linked (By similarity). Heterodimer with KCNK1; disulfide-linked (By similarity). Interacts with BVES; the interaction enhances KCNK2 surface expression and is inhibited by cAMP (By similarity).
Ion channel that contributes to passive transmembrane potassium transport. 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).
Phosphorylation at Ser-348 controls the reversible conversion from a leak channel to a voltage-dependent channel.
The C-terminal region of isoform 5 mediates its intracellular retention.
Mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway.
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.
Binds phospholipids via a region that includes the 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 (By similarity).
Interacts with HTR6. Interacts with SPRED2.
Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity (By similarity).
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.
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-323 (By similarity).
Component of a multi subunit autoregulatory ribonucleoprotein complex (ARC), at least composed of IGF2BP1, PABPC1 and CSDE1. Interacts with STRAP. Part of a complex associated with the FOS mCRD domain and consisting of PABPC1, PAIP1, HNRPD and SYNCRIP. The interaction with PABPC1 is direct and RNA-independent. Interacts with EIF4ENIF1/4E-T.
RNA-binding protein 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. Required for efficient formation of stress granules.
Electrogenic proton/amino acid symporter with a high selectivity for the small side chains amino acids glycine, alanine and proline, where both L- and D-enantiomers are transported. Extension of the backbone length, as in beta-alanine and 4-aminobutanoate or methylation of the amino group, as in sarcosine and N,N-dimethylglycine, are also tolerated but decrease transport efficiency. A free carboxyl group is preferred.
Expressed in lung and spleen, and to a lower extent in brain, heart, kidney and skeletal muscle.
Inhibited by L- and D-pipecolic acid, nipecotic acid, isonipecotic acid, L- and D-cycloserine, and L-2-azetidine-carboxylate.
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 (By similarity). May interact with DAZAP2, FAM168A, PRDX6, RBM6, TMTC1 and YPEL2 (By similarity). Interacts with CDC27 (PubMed:20716133).
Functions as a cell adhesion molecule through homophilic interaction. Stimulates cell growth (By similarity).
Binds to DAXX. Interacts via its N-terminus with SRFBP1 (By similarity). Interacts with NDUFA9 (PubMed:16396496). Interacts with TRARG1; the interaction is required for proper SLC2A4 recycling after insulin stimulation (By similarity).
Expressed in skeletal and cardiac muscles (PubMed:2649883). Expressed in brown and white adipose tissues (PubMed:2649883).
Insulin-regulated facilitative glucose transporter, which plays a key role in removal of glucose from circulation (PubMed:2649253, PubMed:2645527, PubMed:2211693). 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 (PubMed:2649253, PubMed:2645527, PubMed:2211693). Upon insulin stimulation, translocates from these compartments to the cell surface where it transports glucose from the extracellular milieu into the cell (PubMed:2649253, PubMed:2645527, PubMed:2211693).
Insulin-stimulated phosphorylation of TBC1D4 is required for GLUT4 translocation.
It is a candidate for certain post-receptor defects in non-insulin-dependent diabetes mellitus.
Palmitoylated. Palmitoylation by ZDHHC7 controls the insulin-dependent translocation of GLUT4 to the plasma membrane.
The dileucine internalization motif is critical for intracellular sequestration.
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.
Auto-ubiquitinated as part of the enzymatic reaction.
Directly interacts with ITGA2B and, as a result, with integrin ITGA2B/ITGB3. There is no evidence that integrin ITGA2B/ITGB3 is an endogenous substrate for RNF181-directed ubiquitination.
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. Catalyzes monoubiquitination of 26S proteasome subunit PSMC2/RPT1.
DNA-binding protein that seems to act as a transcription factor (By similarity). Involved in the regulation of neuronal differentiation, acts upon JNK-signaling pathway activation and plays a role in neurite outgrowth in hippocampal cells (PubMed:17156131). May mediate with FIBP FGF-signaling in the establishment of laterality in the embryo (By similarity). Promotes cell motility, seems to stimulate tumor metastasis (By similarity).
Induced by basic fibroblast growth factor (bFGF).
Catalyzes the conversion of 25-hydroxyvitamin D3 (25(OH)D3) to 1-alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)(2)D3), and of 24,25-dihydroxyvitamin D3 (24,25(OH)(2)D3) to 1-alpha,24,25-trihydroxyvitamin D3 (1alpha,24,25(OH)(3)D3). Is also active with 25-hydroxy-24-oxo-vitamin D3. Plays an important role in normal bone growth, calcium metabolism, and tissue differentiation.
Acts as a specific nuclear import carrier for HSP70 proteins following heat-shock stress: acts by mediating the nucleoporin-dependent translocation of ATP-bound HSP70 proteins into the nucleus. HSP70 proteins import is required to protect cells from heat shock damages. Does not translocate ADP-bound HSP70 proteins into the nucleus (By similarity).
Forms an asymmetric homodimer; required for binding and nuclear import of HSP70 proteins. Interacts with ATP-bound HSP70 proteins. Interacts with NUP62 and NUP153 (via F-X-F-G repeats). Interacts with HSPA8.
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. 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).
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in the duodenum, antrum and fundus (part of the stomach).
Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis. Acts in collaboration with MRRF. GTP hydrolysis follows the ribosome disassembly and probably occurs on the ribosome large subunit. Not involved in the GTP-dependent ribosomal translocation step during translation elongation.
Detected at age 28 days and was most abundant at age 63 days. No expression at 21 days, seems therefore to be expressed in spermatids and not in spermatocytes or spermatogonia of the germ cells.
May play a role in fertility regulation.
Testis-specific and age-dependent (at protein level). Highly expressed. Expressed in round spermatids located in the inner half-layer of the seminiferous epithelium as well as in early elongated spermatids having cytoplasmic protrusions into the tubular lumen.
Highest activity in liver, kidney and heart. Low activity in muscle and brain.
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 (By similarity).
Belongs to the riboflavin transporter family.
Highly expressed in the placenta and small intestine, moderately in the kidney, colon, lung, prostate, uterus, and thymus, and weakly in all 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. May also act as a receptor for 4-hydroxybutyrate.
Riboflavin transport is Na(+)-independent but moderately pH-sensitive (By similarity). Activity is strongly inhibited by riboflavin analogs, such as lumiflavin (By similarity). Weakly inhibited by flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (By similarity).
Up-regulated during postnatal lung development.
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. Interacts with DAB2IP. Interacts directly with NOL3 (via CARD domain); inhibits TNF-signaling pathway. Interacts with SH3RF2, TRADD and RIPK1. SH3RF2 facilitates the recruitment of RIPK1 and TRADD to TNFRSF1A in a TNF-alpha-dependent process. Interacts with PGLYRP1; this interaction is important for cell death induction. Interacts (via death domain) with MADD (via death domain) (By similarity).
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 (By similarity).
Expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain.
Inhibited by emetine, quinidine and verapamil. The IC(50) of emetine is 4.2 uM. Not inhibited by valproic acid. Transport of (R)-carnitine is stimulated by cholesterol in the plasma membrane.
Sodium-ion dependent, high affinity carnitine transporter. Involved in the active cellular uptake of carnitine. Transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Also relative uptake activity ratio of carnitine to TEA is 11.3.
Heterodimer of an alpha and a beta subunit (By similarity). Interacts with FLNB. Interacts with HAX1. ITGAV:ITGB6 interacts with FBN1 (By similarity). ITGAV:ITGB6 interacts with TGFB1 (By similarity).
Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin (By similarity). It recognizes the sequence R-G-D in its ligands (By similarity). ITGAV:ITGB6 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (By similarity). 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 (By similarity).
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.
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:22898811). Transports an electroneutral complex composed of a divalent metal cation and two bicarbonate anions or alternatively a bicarbonate and a selenite anion (PubMed:22898811). Thereby, it also contributes to the cellular uptake of selenium, an essential trace metal and micronutrient (PubMed:22898811). Also imports cadmium a non-essential metal which is cytotoxic and carcinogenic (PubMed:22898811). 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. Also indirectly regulates the expression of proteins involved in cell morphology and cytoskeleton organization. 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. Protects, for instance, cells from injury and death at the onset of inflammation (By similarity). 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. Also participates in manganese reabsorption in the proximal tubule of the kidney. 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. With manganese cellular uptake also participates in mitochondrial proper function (By similarity). 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 (By similarity).
N-glycosylated. N-glycosylation is not required for proper iron and zinc transport.
Up-regulation upon iron or zinc loading increases expression at the plasma membrane (at protein level).
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 (By similarity). Represses NF-kappa-B transcriptional activity by inhibiting phosphorylation of RELA at 'Ser- 536' (By similarity). May be involved in early neuronal development (By similarity).
Inhibited by divalent copper and zinc ions, but not by nickel or cobalt. Inhibited by its prosegment, but not smaller fragments. Inhibited by 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor.
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. 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. Catalyzes the first step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2. Also mediates the first step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B). Mediates the protein cleavage of GNPTAB into subunit alpha and beta, thereby participating in biogenesis of lysosomes. 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. Involved in the regulation of M6P-dependent Golgi-to-lysosome trafficking of lysosomal enzymes. It is required for the activation of CREB3L2/BBF2H7, a transcriptional activator of MIA3/TANGO and other genes controlling mega vesicle formation. Therefore, it plays a key role in the regulation of mega vesicle-mediated collagen trafficking.
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. The propeptide is autocatalytically removed through an intramolecular cleavage after Leu-186. Further cleavage generates 14, 10, and 8 kDa intermediates.
Widely expressed (PubMed:9990022). In adult rat, highly expressed in anterior pituitary, thyroid and adrenal glands and in liver (PubMed:9990022). In 2-day old rat, detected in developing skin, striated muscles, cardiac muscles, bones, teeth and internal organs (PubMed:9990022). Highly expressed in retina, cerebellum, pituitary, submaxillary, thyroid and adrenal glands, molars, thymus, kidney and intestine (PubMed:9990022).
Binds 3 calcium ions via the second, third and fourth EF-hand. EF-2 and EF-3 bind both magnesium and calcium, while EF-4 binds only calcium. At the resting state, magnesium is bound to EF-2 and EF-3 and upon activation, both sites bind calcium simultaneously while EF-4 is the last one to be occupied.
Fourfold reduction in calcium affinity for NCS1/FREQ in the presence of magnesium.
Monomer (PubMed:25979333). Interacts with KCND2 (By similarity). Interacts in a calcium-independent manner with PI4KB, but only if myristoylated (PubMed:11526106). This binding competes with CALN2/CABP7 binding to PI4KB (PubMed:11526106). Interacts in a calcium-dependent manner with PICK1 (via AH domain) (PubMed:19109914). Interacts with ARF1, ARF3, ARF5 and ARF6 (By similarity). Interacts with IL1RAPL1 (By similarity).
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. Stimulates PI4KB kinase activity. Involved in long-term synaptic plasticity through its interaction with PICK1. May also play a role in neuron differentiation through inhibition of the activity of N-type voltage-gated calcium channel.
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. Regulates autophagy, inflammasome mediated IL1B and IL18 processing, and pyroptosis, but not apoptosis.
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-344. Interacts with PRMT2 (By similarity). Isoform A interacts with NCOR2. Isoform B (but not isoform A) interacts with NCOA2 and NCOA1 (By similarity). Isoform B (but not isoform A) interacts with KLF9. Interacts with GTF2B (By similarity).
Isoform A and isoform B are expressed in the pituitary.
Ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity including repression of its isoform B, MR and ER. Transrepressional activity may involve recruitment of corepressor NCOR2.
Phosphorylated on multiple serine sites. Several of these sites are hormone-dependent. Phosphorylation on Ser-293 is highly hormone-dependent and modulates ubiquitination and sumoylation on Lys-387. Phosphorylation on Ser-344 also requires induction by hormone. Basal phosphorylation on Ser-82, Ser-190 and Ser-399 is increased in response to progesterone and can be phosphorylated in vitro by the CDK2-A1 complex. Increased levels of phosphorylation on Ser-399 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-293, but not at Ser-190, is impaired during the G(2)/M phase of the cell cycle. Phosphorylation on Ser-344 by ERK1/2 MAPK is required for interaction with SP1 (By similarity).
Steroid hormone receptor involved in the regulation of eukaryotic gene expression which affects cellular proliferation and differentiation in target tissues.
Sumoylation is hormone-dependent and represses transcriptional activity. Sumoylation on all three sites is enhanced by PIAS3. Desumoylated by SENP1. Sumoylation on Lys-387, the main site of sumoylation, is repressed by ubiquitination on the same site, and modulated by phosphorylation at Ser-293 (By similarity).
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 (By similarity).
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-293 (By similarity).
Monomer (By similarity). Homodimer (By similarity). Interacts with EP300 (By similarity). Interacts with MYD88 (By similarity). Interacts with PIAS3 (By similarity).
Phosphorylated by CK2 and this positively regulates its activity.
Sumoylation represses the transcriptional activity and displays enhanced resistance to protein degradation (By similarity). Sumolyated by UBE2I/UBC9 and SUMO1 (By similarity). Inactivates the tumor suppressor activity (By similarity). Elevated levels in tumor cells (By similarity). Major site is Lys-276 (By similarity). Sumoylation is enhanced by PIAS3 (By similarity). Desumoylated by SENP1 in tumor cells and appears to compete with ubiquitination on C-terminal sites (By similarity).
Transcriptional regulator which displays a remarkable functional diversity in the regulation of cellular responses (By similarity). Regulates transcription of IFN and IFN-inducible genes, host response to viral and bacterial infections, regulation of many genes expressed during hematopoiesis, inflammation, immune responses and cell proliferation and differentiation, regulation of the cell cycle and induction of growth arrest and programmed cell death following DNA damage (By similarity). Stimulates both innate and acquired immune responses through the activation of specific target genes and can act as a transcriptional activator and repressor regulating target genes by binding to an interferon-stimulated response element (ISRE) in their promoters (By similarity). Binds to a consensus sequence in gene promoters (By similarity). Its target genes for transcriptional activation activity include: genes involved in anti-viral response, such as IFN-alpha/beta, RIGI, TNFSF10/TRAIL, ZBP1, OAS1/2, PIAS1/GBP, EIF2AK2/PKR and RSAD2/viperin; antibacterial response, such as NOS2/INOS; anti-proliferative response, such as p53/TP53, LOX and CDKN1A; apoptosis, such as BBC3/PUMA, CASP1, CASP7 and CASP8; immune response, such as IL7, IL12A/B and IL15, PTGS2/COX2 and CYBB; DNA damage responses and DNA repair, such as POLQ/POLH; MHC class I expression, such as TAP1, PSMB9/LMP2, PSME1/PA28A, PSME2/PA28B and B2M and MHC class II expression, such as CIITA; metabolic enzymes, such as ACOD1/IRG1 (By similarity). Represses genes involved in anti-proliferative response, such as BIRC5/survivin, CCNB1, CCNE1, CDK1, CDK2 and CDK4 and in immune response, such as FOXP3, IL4, ANXA2 and TLR4 (By similarity). Stimulates p53/TP53-dependent transcription through enhanced recruitment of EP300 leading to increased acetylation of p53/TP53 (By similarity). Plays an important role in immune response directly affecting NK maturation and activity, macrophage production of IL12, Th1 development and maturation of CD8+ T-cells (By similarity). Also implicated in the differentiation and maturation of dendritic cells and in the suppression of regulatory T (Treg) cells development (By similarity). Acts as a tumor suppressor and plays a role not only in antagonism of tumor cell growth but also in stimulating an immune response against tumor cells (By similarity).
Ubiquitinated. Appears to compete with sumoylation on C-terminal sites (By similarity).
No icosapeptide-like peptide is cleaved from the C-terminal.
Pancreatic hormone is synthesized in pancreatic islets of Langerhans and acts as a regulator of pancreatic and gastrointestinal functions.
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.
Belongs to the nucleoporin Nup85 family.
Component of the nuclear pore complex (NPC). Component of the NPC Nup107-160 subcomplex, consisting of at least NUP107, NUP98/Nup96, NUP160, NUP133, NUP85, NUP37, NUP43 and SEC13. Interacts with NUP160, NUP133 and SEC13. Interacts with NUP37, NUP107 and NUP43. Interacts with CCR2.
Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance. As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus. The Nup107-160 complex seems to be required for spindle assembly during mitosis. NUP85 is required for membrane clustering of CCL2-activated CCR2. Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade. Involved in nephrogenesis.
Detected in insulin-secreting 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).
Detected in mast cells and platelets (at protein level).
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 (By similarity).
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.
Increased expression in embryonal tissues.
Interacts with TIMP1 and ITGB1 and recruits TIMP1 to ITGB1. Interacts with CD9. Identified in a complex with CD9 and ITGB3. Interacts with PMEL. Interacts with KDR/VEGFR2; identified in a complex with ITGB1 and KDR/VEGFR2 and is required to recruit KDR to ITGB1 complexes. Interacts with SYT7 (By similarity).
Palmitoylated at a low, basal level in unstimulated platelets. The level of palmitoylation increases when platelets are activated by thrombin (in vitro) (By similarity).
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.
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. Predominant kallikrein protein in the kidney.
Kidney and submandibular gland. Not expressed in liver, pancreas, spleen, parotid, testis, cortex, prostate, ovary and pituitary.
The N-terminal C2 domain associates with lipid membranes upon calcium binding.
Each of the eight TSP type-3 repeats binds two calcium ions. The TSP C-terminal domain binds three calcium ions.
Pentamer; disulfide-linked. Exists in a more compact conformation in the presence of calcium and shows a more extended conformation in the absence of calcium. 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+). Interacts with MATN1, MATN3, MATN4 and ACAN. Binds heparin, heparan sulfate and chondroitin sulfate. EDTA dimishes significantly its binding to ACAN and abolishes its binding to MATN3, MATN4 and chondroitin sulfate. Interacts with collagen I, II and IX, and interaction with these collagens is dependent on the presence of zinc ions. Interacts with ADAMTS12 (By similarity). Interacts with ITGA7 (PubMed:20019333).
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. Could play a role in the pathogenesis of osteoarthritis. 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) (By similarity). 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 (PubMed:20019333).
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.
Belongs to the eukaryotic GSH synthase family.
Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner (PubMed:7862666). Glutathione (gamma-glutamylcysteinylglycine, GSH) is the most abundant intracellular thiol in living aerobic cells and is required for numerous processes including the protection of cells against oxidative damage, amino acid transport, the detoxification of foreign compounds, the maintenance of protein sulfhydryl groups in a reduced state and acts as a cofactor for a number of enzymes (PubMed:7862666). Participates in ophthalmate biosynthesis in hepatocytes (By similarity).
Both SDE2-UBL and the mature SDE2 are polyubiquitinated.
Inhibits translesion DNA synthesis by preventing monoubiquitination of PCNA, this is necessary to counteract damage due to ultraviolet light-induced replication stress (By similarity). SDE2 is cleaved following PCNA binding, and its complete degradation is necessary to allow S-phase progression following DNA damage (By similarity).
Interacts (via PIP-box) with PCNA; the interaction is direct and prevents ultraviolet light induced monoubiquitination of PCNA (By similarity). Interacts with FBL/fibrillarin (By similarity). Interacts with CACTIN (By similarity). Interacts with SF3B1 (By similarity). Interacts with U2AF1 (By similarity).
Plays a role in pre-mRNA splicing by facilitating excision of relatively short introns featuring weak 3'-splice sites (ss) and high GC content (By similarity). May recruit CACTIN to the spliceosome (By similarity).
Plays a role in ribosome biogenesis by enabling SNORD3- and SNORD118-dependent cleavage of the 47S rRNA precursor (By similarity). Binds ncRNA (non-coding RNA) including the snoRNAs SNORD3 and SNORD118 (By similarity).
The PIP-box (PCNA interacting peptide) motif mediates both the interaction with PCNA and cleavage of the SDE2 precursor by a deubiquitinating enzyme.
The SAP domain is necessary for specific binding to DNA.
The propeptide displays a ubiquitin-like fold.
Upon binding to PCNA, the N-terminal UBL (ubiquitin-like) propeptide is cleaved at Gly-77 by an unidentified deubiquitinating enzyme; the resulting mature SDE2 is degraded by the DCX(DTL) complex in a cell cycle- and DNA damage dependent manner.
Interacts with FANCL, GGNBP1 and ZNF403/GGNBP2.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.7/SCN9A subfamily.
Expressed at high level in the dorsal root ganglion and at much lower levels in the brain, sciatic nerve, nodose ganglia, heart, thyroid and adrenal glands and Schwann cells, but not in the cardiac and skeletal muscles, brain and liver.
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. It is a tetrodotoxin-sensitive Na(+) channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain.
Phosphorylation at Ser-1488 by PKC in a highly conserved cytoplasmic loop increases peak sodium currents.
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) (By similarity). SCN1B and SCN3B are non-covalently associated with SCN2A. SCN2B and SCN4B are disulfide-linked to SCN2A (By similarity). Interacts with NEDD4 and NEDD4L (By similarity). Interacts with the conotoxin GVIIJ (PubMed:24497506).
Ubiquitinated by NEDD4L; which may promote its endocytosis. Does not seem to be ubiquitinated by NEDD4.
Binds MYO5A, MYO7A and F-actin. Binds RAB27A that has been activated by GTP-binding via its N-terminus (By similarity). Interacts with PRKAR2A. Interacts with components of the exocyst complex, including EXOC3 and EXOC4.
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 (By similarity). 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 estrogen, tamoxifen and growth hormone. Repressed by progesterone and by the antiestrogen ICI 182780.
Expressed predominantly in epithelium of uterus and oviduct.
In uterus, strongly expressed at proestrus, declines at estrus and disappears at diestrus. In oviduct, strongly expressed at both proestrus and estrus but declines significantly at diestrus. In uterus, highly expressed on day 1 of pregnancy but declines dramatically on day 2 and is not detected between days 3 and 7. In oviduct, highly expressed on days 1 and 2 of pregnancy but declines significantly on days 3 and 4.
Localized to zymogen granules, where it functions in trypsinogen activation (By similarity). May indirectly regulate cell motility, cell-cell and cell/extracellular matrix interactions (By similarity).
Transports the calcitonin gene-related peptide type 1 receptor (CALCRL) to the plasma membrane. Acts as a receptor for adrenomedullin (AM) together with CALCRL.
Detected in brain cortex, hippocampus and cerebellar granule cell layer.
Enhances the incorporation of serine into phosphatidylserine and sphingolipids.
Up-regulated by kainate treatment in neuronal cell layers of the hippocampus.
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.
Predominantly expressed in small intestine. Highly expressed in jejunum and ileum. Also expressed in testis and at lower level in lung, kidney, stomach and colon.
Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide-exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Nucleotide release is mediated via its binding to the nucleotide-binding domain (NBD) of HSPA8/HSC70 where as the substrate release is mediated via its binding to the substrate-binding domain (SBD) of HSPA8/HSC70. Inhibits the pro-apoptotic function of PPP1R15A, and has anti-apoptotic activity. Markedly increases the anti-cell death function of BCL2 induced by various stimuli.
Homodimer. Forms a heteromeric complex with HSP70/HSC70. Binds to the ATPase domain of HSP/HSC70 chaperones. Interacts with NR3C1. Interacts with the N-terminal region of STK19. Interacts with PPP1R15A. Interacts with BCL2 in an ATP-dependent manner. Interacts with SIAH1, SIAH2, HSPA8 (via NBD), HSPA1A (via NBD) and HSPA1B (via NBD).
Belongs to the ZP domain family. ZPB subfamily.
Expressed in cardiomyocytes (at protein level).
Homodimer. Interacts with COL17A1 (via cytoplasmic region) (By similarity). Interacts with DSC2 (By similarity). Interacts with PKP1 (By similarity). Interacts with PKP2 (By similarity). Interacts weakly with TMEM65 (By similarity).
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 (PubMed:26858265).
The N-terminal region is required for localization to the desmosomal plaque and interacts with the N-terminal region of PKP1.
Belongs to the glycosyl hydrolase 18 family.
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.
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 (By similarity).
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), WASHC1, WASHC2, WASHC3, WASHC4 and WASHC5. Interacts with RCSD1/CAPZIP (By similarity). Directly interacts with CRACD; this interaction decreases binding to actin (By similarity).
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. Interacts via (C-terminus) with PRIM1. 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 (By similarity). Within the complex, POLA1 directly interacts with PRIM2 (By similarity).
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 (By similarity). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (By similarity). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. 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 (By similarity). Binds RNA:DNA duplex and coordinates the catalytic activities of PRIM1 and POLA2 during primase-to-polymerase switch.
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. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands.
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.
Na(+)/Mg(2+) ion exchanger that acts as a predominant Mg(2+) efflux system at the mitochondrial inner membrane.
Possible morphogenetic cytoskeletal element in spermiogenic differentiation.
Expressed in the gustatory cells of the circumvallate papillae. Not detected in non-sensory lingual epithelium, brain, parotid gland, liver, uterus, lung, heart, adrenal gland, ovary, spleen, pancreas, intestine, thymus, kidney or muscle.
Interacts with RAC1 (By similarity). Forms a complex composed of at least WDR26, a G-beta:gamma unit, and PLCB2 (By similarity).
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. This protein may be involved in the transduction of bitter taste stimuli.
The receptor-mediated activation of PLC-beta-2 is most effectively mediated by one G-protein alpha subunit, alpha-16.
Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes (By similarity). 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. Also has monoacylglycerol (MAG) lipase activity: hydrolyzes 2-arachidonoylglycerol (2-AG), thereby acting as a regulator of endocannabinoid signaling pathways. Has a strong preference for very-long-chain lipid substrates; substrate specificity is likely due to improved catalysis and not improved substrate binding (By similarity).
Heterodimer of SAE1 and UBA2/SAE2. The heterodimer corresponds to the two domains that are encoded on a single polypeptide chain in ubiquitin-activating enzyme E1. Interacts with UBE2I (By similarity).
The heterodimer acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2 (By similarity).
Proton-sensing G-protein coupled receptor couples to multiple intracellular signaling pathways, including GNAS/cAMP, GNAQ/phospholipase C (PLC), and GNA13/Rho pathways. Acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the GNA12/GNA13/Rho GTPase signaling pathway. In the brain may mediate central respiratory sensitivity to CO(2)/H(+).
Belongs to the eukaryotic ribosomal protein eL33 family.
Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Required for the proliferation and viability of hematopoietic cells.
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. Also a component of a CK2-SPT16-SSRP1 complex which forms following UV irradiation, composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B. 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. Interacts with isoform gamma of TP63. Interacts with FYTTD1/UIF (By similarity). Interacts with SRF (PubMed:10336466). Interacts with NEK9 (By similarity).
Phosphorylated by CK2 following UV but not gamma irradiation. Phosphorylation inhibits its DNA-binding activity (By similarity).
Ubiquitinated. Polyubiquitinated following caspase cleavage resulting in degradation of the N-terminal ubiquitinated part of the cleaved protein (By similarity).
Does not have 2'-5'-OAS activity, but can bind double-stranded RNA. Displays antiviral activity via an alternative antiviral pathway independent of RNase L (By similarity).
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 (By similarity).
As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway.
Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
Preferentially expressed by lymphocytes in lymph node and spleen.
Tyrosine-phosphorylated upon T-cell activation. The tyrosine phosphorylation site is multifunctional and may associate with the SH2 domains of phospholipase C-gamma-1, GRB-2, and PI3-K upon T-cell receptor activation.
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.
Expressed in the liver by hepatocytes. Also present in other cells such as monocytes, fibroblasts or keratinocytes.
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. Interacts with C3b. Interacts with complement factor H.
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. Essential cofactors for these reactions include factor H and C4BP in the fluid phase and membrane cofactor protein/CD46 and CR1 on cell surfaces. 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.
Belongs to the non-lysosomal glucosylceramidase family.
Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramide (GlcCer) to free glucose and ceramide.
Binds to actin filaments in muscle and non-muscle cells (PubMed:7568216, PubMed:22812662). Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction (PubMed:22812662). Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.
Homodimer (PubMed:7568216, PubMed:22812662). Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain (PubMed:7568216, PubMed:22812662). 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) (By similarity).
Phosphorylated at Ser-283 by DAPK1 in response to oxidative stress and this phosphorylation enhances stress fiber formation in endothelial cells.
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. 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. Acetylation disrupts interaction with NUDT15 and promotes degradation (By similarity).
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. 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. 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 (By similarity).
Homotrimer. Interacts with p300/EP300; the interaction occurs on chromatin in UV-irradiated damaged cells. Interacts with CREBBP (via transactivation domain and C-terminus); the interaction occurs on chromatin in UV-irradiated damaged cells. 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). Forms a complex with activator 1 heteropentamer in the presence of ATP. Interacts with EXO1, POLH, POLK, DNMT1, ERCC5, FEN1, CDC6 and POLDIP2. Interacts with APEX2; this interaction is triggered by reactive oxygen species and increased by misincorporation of uracil in nuclear DNA. Forms a ternary complex with DNTTIP2 and core histone (By similarity). Interacts with KCTD10 (PubMed:15982757). Interacts with PPP1R15A (By similarity). Interacts with SMARCA5/SNF2H (By similarity). Interacts with BAZ1B/WSTF; the interaction is direct and is required for BAZ1B/WSTF binding to replication foci during S phase (By similarity). Interacts with HLTF and SHPRH. Interacts with NUDT15. Interaction is disrupted in response to UV irradiation and acetylation. 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. Interacts with DDX11. Interacts with EGFR; positively regulates PCNA. Interacts with PARPBP. Interacts (when ubiquitinated) with SPRTN; leading to enhance RAD18-mediated PCNA ubiquitination. Interacts (when polyubiquitinated) with ZRANB3. Interacts with SMARCAD1. Interacts with CDKN1C. Interacts with PCLAF (via PIP-box). Interacts with RTEL1 (via PIP-box); the interaction is direct and essential for the suppression of telomere fragility. Interacts with FAM111A (via PIP-box); the interaction is direct and required for PCNA loading on chromatin binding. Interacts with LIG1. Interacts with SETMAR. Interacts with ANKRD17. Interacts with FBXO18/FBH1 (via PIP-box); the interaction recruits the DCX(DTL) complex and promotes ubiquitination and degradation of FBXO18/FBH1. Interacts with POLN (By similarity). Interacts with SDE2 (via PIP-box); the interaction is direct and prevents ultraviolet light induced monoubiquitination (By similarity). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR; interaction at least with PCNA occurs during DNA replication (By similarity). Interacts with MAPK15; the interaction is chromatin binding dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2. Interacts with PARP10 (via PIP-box) (By similarity). Interacts with DDI2 (By similarity). Interacts with HMCES (via PIP-box) (By similarity). Interacts with TRAIP (via PIP-box) (By similarity). Interacts with UHRF2 (By similarity). 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 (By similarity).
Methylated on glutamate residues by ARMT1.
Phosphorylated. Phosphorylation at Tyr-211 by EGFR stabilizes chromatin-associated PCNA (By similarity).
Ubiquitinated. 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 (By similarity).
Down-regulated in ischemia/reperfusion (I/R) kidneys. Up-regulated by testosterone and moderately down-regulated by estradiol.
Expressed in the kidney; in the proximal tubule of the outer medulla. Expression is greater in the kidney of male than of female.
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 (By similarity). Mediates the influx of agmatine, serotonin, choline, ranitidine, histamine, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP and amiloride (By similarity). Mediates the influx of adrenaline, noradrenaline (norepinephrine), dopamine, cimetidine, famotidine, metformin, N-1-methylnicotinamide (NMN), 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), oxaliplatin and cisplatin. 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.
Detected in brain (at protein level). Highly expressed in kidney and placenta. Detected in skin, breast, heart, lung, liver, prostate, spleen, small intestine, colon and stomach.
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.
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-349 by AURKA might locally participate in the control of the onset of mitosis. Phosphorylation by MELK at Ser-166 promotes localization to the centrosome and the spindle poles during mitosis. Phosphorylation at Ser-319 and Ser-370 by MAPK14 is required for binding to 14-3-3 proteins (By similarity).
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 (By similarity).
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.
Mainly expressed in testis and at lesser levels in brain.
Belongs to the HIBADH-related family. 3-hydroxyisobutyrate dehydrogenase subfamily.
Higher level in kidney, liver, and heart than in muscle.
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. Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA). Interacts with SERTAD3. Interacts with TIPIN. Interacts with TIMELESS. Interacts with PPP4R2; the interaction is direct, DNA damage-dependent and mediates the recruitment of the PP4 catalytic subunit PPP4C. Interacts (hyperphosphorylated) with RAD51. Interacts with SMARCAL1; the interaction is direct and mediates the recruitment to the RPA complex of SMARCAL1. Interacts with RAD52 and XPA; those interactions are direct and associate RAD52 and XPA to the RPA complex. Interacts with FBH1. Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks. Interacts with DDI2 (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. 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.
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.
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 (By similarity).
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. Promotes apoptosis in response to cellular stress mediated by exposure to anisomycin or UV. Stimulates ATP hydrolysis, but not the folding of unfolded proteins mediated by HSPA1A (in vitro) (By similarity). Co-chaperone for HSPA8/Hsc70. Plays a role in protein transport into mitochondria via its role as co-chaperone (PubMed:10816573).
Identified in a complex with HSPA1B and BAX. Interacts with RNF207.
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.
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.
Mitochondrial amino-acid transporter (By similarity). Does not act as a serine transporter: not able to mediate transport of serine into mitochondria (By similarity). Transports citrate (PubMed:12150972).
Component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. Also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair (By similarity).
Expressed in heart, brain, spleen, lung, liver, muscle, kidney, testis, spleen and skeletal muscle.
Monomer. May form homodimer. Interacts with LNX, MAGI1, DLG4, PRKCABP, TJP1 and CTNNB1. Interacts with MPDZ; recruits MPDZ to intercellular contact sites. Interacts with JAML (homodimeric form) (By similarity).
Palmitoylated on Cys-259 and/or Cys-260; required for proper localization to the plasma membrane.
The Ig-like C2-type 1 domain mediates homodimerization and interaction with JAML.
The PDZ-binding motif mediates interaction with MPDZ and MAGI1.
Belongs to the thymidylate kinase family.
Belongs to the PNRC family. PNRC1 subfamily.
Interacts with many nuclear receptors including AR, ESR1, ESRRA, ESRRG, NR3C1/GR, NR5A1, PGR, TR, RAR and RXR. Interacts with GRB2 (By similarity).
Nuclear receptor coactivator. May play a role in signal transduction (By similarity).
The interaction between PNRC1 and nuclear receptors is dependent on the SH3 binding motif.
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. May play a role of negative regulator in cardiomyocyte hypertrophy induced by angiotensin II through an inhibition of p38 mitogen-activated protein kinase pathway. Attenuates type-1 angiotensin II receptor growth promoting effect and angiotensin II-induced phosphorylation of protein kinase AKT and of STAT3.
Interacts with RACK1, and with the carboxy-terminal region of AGTR1.
Detected in testis where it is highly expressed in germ cells, and also expressed at lower levels in Sertoli cells (at protein level).
In testis, first detected in stage VI seminiferous tubules where it is strongly expressed at the apical ectoplasmic speclialization (ES). Initially detected around the entire spermatid head, then during stage VII becomes tightly restricted to the concave side of the spermatid head. From late stage VIII through to stage XII, expressed once again around the entire spermatid head. In stage VIII-IX tubules, detected at lower levels at the basal ES associated with the blood-testis barrier. Detected at the apical spermatid-Sertoli cell junction in stage VIII-XII tubules.
Interacts with PALLD (PubMed:23565266). Associates with actin (PubMed:23565266). However, does not bind F-actin directly (By similarity).
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.
RNAi-mediated knockdown in testis tissue results in misorientation of spermatids, indicating loss of polarity. Transport of germ cells across the seminiferous epithelium is disrupted leading to partial spermatid entrapment in the epithelium. Premature spermatid release is also detected in stage VII tubules. F-actin is mislocalized and found on the convex side of the spermatid head, in contrast to wild type where it is tightly restricted to the concave side. PALLD localization is also abnormal, showing more diffuse expression away from the spermatid head.
Belongs to the band 7/mec-2 family. Flotillin subfamily.
Expressed during embryogenesis, postnatal stages and in adult.
Heterooligomeric complex of flotillin-1 and flotillin-2 and caveolin-1 and caveolin-2. Interacts with ECPAS (By similarity).
Heterooligomeric complex of flotillin-1 and flotillin-2 and caveolin-1 and caveolin-2. Interacts with ECPAS.
May act as a scaffolding protein within caveolar membranes, functionally participating in formation of caveolae or caveolae-like vesicles.
May play a role in axon growth and regeneration. May be involved in epidermal cell adhesion and epidermal structure and function.
ZDHHC5-catalyzed palmitoylation may be required for the formation of higher-order complexes and for neurite outgrowth in cultured neural stem cells.
Acts as transcriptional coactivator of estrogen and progesterone receptors (ESR1 and PGR) upon hormone activation. In presence of estrogen, binds to ESR1-responsive promoters. Required for YAP1 coactivation function on PGR activity. Synergizes with WBP2 in enhancing PGR activity (By similarity). 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 (By similarity).
Phosphorylated in repsonse to EGF as well as estrogen and progesterone hormones. Tyr-192 and Tyr-232 are phosphorylated by YES and SRC inducing nuclear translocation.
The PPxY motif 1 mediates interaction with NEDD4 (By similarity). The PPxY motif 2 is required for the coactivation function (By similarity).
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 (By similarity).
Expressed in all tissues tested, including liver, adrenal decapsular tissue, adrenal capsular tissue, corpus luteum, testis, submandibular gland, thymus, brain, cerebellum and heart. Highest levels in testis.
Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14. Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, PEA15, SGK1 and MKNK2. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation. Interacts with TPR. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock. Interacts with CDKN2AIP (By similarity). Interacts with CAVIN4 (PubMed:24567387). Interacts with GIT1; this interaction is necessary for MAPK3 localization to focal adhesions (PubMed:15923189). Interacts with ZNF263 (By similarity). Interacts with EBF4.
Highest levels within the nervous system, expressed in different tissues, mostly in intestine, placenta and lung.
Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-203 and Tyr-205 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 FLT3 and KIT signaling. Ligand-activated ALK induces tyrosine phosphorylation (By similarity). Dephosphorylated by PTPRJ at Tyr-205 (By similarity). Dually phosphorylated on Thr-203 and Tyr-205, which activates the enzyme.
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.
The publication has been retracted as they falsified western blot data.
Hydrolase that deubiquitinates target proteins such as FOXO4, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:16111684, PubMed:16328052). 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 (By similarity). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (By similarity). 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 (By similarity). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. 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 (By similarity). Deubiquitinates KMT2E preventing KMT2E proteasomal-mediated degradation (By similarity). Involved in cell proliferation during early embryonic development (By similarity). 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 (By similarity). 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 (By similarity). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (By similarity). 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 (By similarity). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (By similarity). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing transcription factor FOXP3 which is crucial for Treg cell function (By similarity). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (By similarity). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (By similarity). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (By similarity). Involved in the regulation of WASH-dependent actin polymerization at the surface of endosomes and the regulation of endosomal protein recycling (By similarity). It maintains optimal WASH complex activity and precise F-actin levels via deubiquitination of TRIM27 and WASHC1 (By similarity).
Monomer. Homodimer (PubMed:16111684). Part of a complex with DAXX, MDM2, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts with MDM2; the interaction is independent of p53/TP53. Interacts with DAXX; the interaction is direct and independent of MDM2 and p53/TP53. Component of a complex composed of KMT2E, OGT and USP7; the complex stabilizes KMT2E, preventing KMT2E ubiquitination and proteosomal-mediated degradation (By similarity). Interacts (via MATH domain) with KMT2E (By similarity). Interacts with OGT (By similarity). Interacts with FOXO4; the interaction is enhanced in presence of hydrogen peroxide and occurs independently of p53/TP53. Interacts with p53/TP53; the interaction is enhanced in response to DNA damage; the interaction is impaired by TSPYL5. Interacts with PTEN; the interaction is direct. Interacts with ATXN1 and the strength of interaction is influenced by the length of the poly-Gln region in ATXN1. A weaker interaction seen with mutants having longer poly-Gln regions. Interacts with KIAA1530/UVSSA. Interacts with MEX3C and antagonizes its ability to degrade mRNA. Interacts with DNMT1 and UHRF1. Interacts with FOXP3. Interacts (via MATH domain) with RNF220 (By similarity). Associated component of the Polycomb group (PcG) multiprotein PRC1-like complex (By similarity). Interacts with EPOP (By similarity). Interacts with OTUD4 and USP9X; the interaction is direct (By similarity). Interacts with CRY2 (By similarity). Interacts with REST (By similarity). Interacts with ERCC6 (By similarity). Part of a complex consisting of USP7, MAGEL2 and TRIM27; directly interacts with MAGEL2; directly interacts with TRIM27 (By similarity).
Strongly expressed in the testis, spleen and brain. Weakly expressed in the stomach, small intestine, skeletal muscle and uterus.
The C-terminus plays a role in its oligomerization.
Ubiquitinated at Lys-870 (By similarity). Polyubiquitinated.
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). Probably play and important roles in the energy metabolism of spermatozoa (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 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 (By similarity).
Interacts with H3K4me3 and to a lesser extent with H3K4me2 (By similarity). 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. HTATTIP/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. Component of a SWR1-like complex (By similarity).
Auto-ubiquitinated. Auto-ubiquitination leads to degradation by the proteasome.
Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31 (By similarity). LUBAC has a MW of approximately 600 kDa suggesting a heteromultimeric assembly of its subunits (By similarity). Interacts with beta-I-type (PRKCB1) and zeta-type protein kinase C (PRKCZ) (PubMed:9514928). Interacts with UBE2L3 (By similarity). Interacts with IREB2 only in iron-rich conditions (By similarity). Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner (By similarity). Interacts with EYA1, TAB2, TAB3, MAP3K7 TRAF6 and RIPK1. Interacts with IRF3 (By similarity).
E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates (By similarity). Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination (By similarity). Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome (PubMed:18303026). 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 (By similarity). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways (By similarity). Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation (By similarity). 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 (By similarity). 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 (By similarity). LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin (By similarity). The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation (By similarity). Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis (By similarity). Binds polyubiquitin of different linkage types (By similarity).
Phosphorylated. In vitro, phosphorylation inhibits auto-ubiquitination activity.
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.
Heterotetramer of two type I and two type II keratins. keratin-4 is generally associated with keratin-13.
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.
Unlike most P2XRs, P2RX6 does not seem to form homotrimers or heterotrimers.
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. The main inhibitory site appears to be Thr-72 (By similarity).
Inhibitor of the PP1 regulatory subunit PPP1CA.
Activated by CLOCK and BMAL1 heterodimers and light; inhibited by period genes (PER1, PER2 and PER3) and cryptochrome genes (CRY1 and CRY2).
Expressed at high levels in testis and at lower levels in brain, lung, ovary, spleen, thymus and uterus.
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 (By similarity).
Brain. Detected in the cerebellum, hippocampus, olfactory system, piriform and entorhinal cortex, supraoptic nucleus of the hypothalamus, substantia nigra, and other mesencephalic areas.
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. 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). Binds to the cytoplasmic domain of amyloid protein (APP) (By similarity). Interacts (via PDZ 1 and 2 domains) with FSPB (By similarity). Isoform 2 interacts (via its truncated PID domain) with active, GTP-bound RAB6A and RAB6B (By similarity).
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.
The PID domain, truncated by 11 amino acids, as observed in isoform 2, but not full-length, mediates the interaction with RAB6A.
The autoinhibitory helix linker occludes the APP binding site.
This isoform interacts with RAB6 GTPases.
Arg-343 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 its phosphorylation.
Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (PubMed:9422795). Interacts with MYO1C (By similarity). Interacts with ERBB2 (By similarity). Interacts with DDX11 (By similarity). Interacts with RECQL5 (By similarity).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Forms the polymerase active center together with the second largest subunit. A single stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol I. A bridging helix emanates from RPA1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol I by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (By similarity).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ12 subfamily.
Forms a water-specific channel that provides the plasma membranes of red cells and kidney proximal tubules with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient.
Homotetramer (By similarity). Interacts with EPHB2; involved in endolymph production in the inner ear. Identified in a complex with STOM (By similarity).
Pharmacologically inhibited by submillimolar concentrations of mercury.
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.
Endoplasmic reticulum transmembrane protein involved in vesicle-mediated transport, which is required for neutrophil function. Required for vesicle-mediated transport; it is however unclear whether it is involved in early secretory pathway or intracellular protein transport. Acts as a regulator of neutrophil function, probably via its role in vesicle-mediated transport: required for defense against fungal pathogens and for granulocyte colony-stimulating factor (GM-CSF) signaling pathway; possibly by regulating glycosylation and/or targeting of proteins contributing to the viability and migration of neutrophils.
Belongs to the complex I NDUFB6 subunit family.
High level in the brain, moderate amounts in the eye and skeletal muscle, and small amounts in tongue and pituitary.
Receptor for melanin-concentrating hormone, coupled to G proteins that inhibit adenylyl cyclase.
Cytosolic 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide (PubMed:1848231, PubMed:10585460, PubMed:7822273, PubMed:17884809, PubMed:17302434). May also have an NADP(+)-dependent aldehyde dehydrogenase activity towards formaldehyde, acetaldehyde, propionaldehyde, and benzaldehyde (PubMed:1848231).
In the C-terminal section; belongs to the aldehyde dehydrogenase family. ALDH1L subfamily.
In the N-terminal section; belongs to the GART family.
Phosphopantetheinylation at Ser-354 by AASDHPPT is required for the formyltetrahydrofolate dehydrogenase activity.
The C-terminal aldehyde dehydrogenase domain has an NADP-dependent dehydrogenase activity (PubMed:10585460, PubMed:7822273, PubMed:17302434). It catalyzes the oxidation of formate, released by the hydrolysis of formyltetrahydrofolate, into CO2 (Probable).
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:17884809). 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 (PubMed:10585460, PubMed:7822273, PubMed:17884809, PubMed:17302434).
Functions as a beta-subunit for CLCNKA and CLCNKB chloride channels. In the kidney CLCNK/BSND heteromers mediate chloride reabsorption by facilitating its basolateral efflux. In the stria, CLCNK/BSND channels drive potassium secretion by recycling chloride for the basolateral SLC12A2 cotransporter.
Interacts with CLCNK channels. Forms probably heteromers with CLCNKA and CLCNKB.
Palmitoylation is necessary for activation of plasma membrane-inserted CLC-K/barttin channels.
Regulated in parallel with CLCNKA under furosemide treatment. A significant decrease occurred after furosemide treatment in inner medulla (0.5 fold), whereas cortical and outer medulla levels remained unaffected. Regulation with CLCNKA in inner medulla is limited to the thin limb; levels in collecting ducts were not affected by furosemide treatment. During furosemide treatment selective down-regulation with CLCNKA in thin limb plays a role in maintaining salt and water homeostasis.
Expressed from day 9 of pregnant uterus. Highest level at day 12, specifically in the decidua and weakly, in the myometrium. Levels decline thereafter.
Expressed in the involuting mammary gland, ovarian corpus luteum and prostate. In ovaries, low levels found in granulosa cells. High levels in corpora lutea of pregnant animals.
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 (By similarity). May also act as a regulator of adult uterine morphology and function (PubMed:12063187). May also increase apoptosis during ovulation possibly through modulation of FZ1/FZ4/WNT4 signaling (PubMed:12960062). Has phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake (By similarity).
Up-regulated 48 hours after estrogen treatment mainly in the uterine endometrial stroma (PubMed:12063187). Induced in ovarian granulosa cells after 12 hours treatment with chorionic gonadotrophin (CG). Further up-regulated in corpora lutea by the luteotrophic hormone PRL (PubMed:12960062).
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 (By similarity).
Expressed in the liver and brain (at protein level) (PubMed:11988075). Highest activity is found in the liver and adrenals followed by the testes and other organs, absent in adipose tissue (PubMed:5094766).
Inhibited by a shortage of insulin and an increase of glucagon.
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:10049752, PubMed:22216341, PubMed:11988075, PubMed:14563830, PubMed:24070791). 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 (PubMed:11988075). It can also desaturate (11E)-octadecenoate (trans-vaccenoate) at carbon 6 generating (6Z,11E)-octadecadienoate (PubMed:24070791). In addition to Delta-6 activity, this enzyme exhibits Delta-8 activity with slight biases toward n-3 fatty acyl-CoA substrates (By similarity).
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.
Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Acetylates only arylamines.
There are two forms of NAT2: a rapid isoform (NAT2*21A) and a slow isoform (NAT2*21B).
Able to form oligomers (By similarity). Interacts with ODAD1 (By similarity).
May play a role in the control of meiotic division and germ cell differentiation through regulation of pairing and recombination during meiosis (By similarity). Required for sperm flagella assembly (By similarity). May play a role in the assembly and function of the outer dynein arm-docking complex (ODA-DC). ODA-DC mediates outer dynein arms (ODA) binding onto the axonemal doublet microtubules (By similarity).
Detected at high levels in spleen, lymph nodes, thymus and liver. Observed also in kidney and testis, but not in brain or heart.
Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends (PubMed:7957253). Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA. Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells. Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity (By similarity). 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.
Seems to be synthesized as an inactive precursor protein and converted into an active mature enzyme by removal of the N-terminal precursor peptide during apoptosis.
Expressed in neuronal cell body and neurites, and prominently enriched in the axonal growth cone.
Homodimer. Part of a complex consisting of ABI1, EPS8 and SOS1. Interacts with BAIAP2. Interacts with SHB and LANCL1. Interacts with EGFR; mediates EPS8 phosphorylation. Interacts with MYO15A and WHRN.
Phosphorylation at Ser-625 and Thr-629 by MAPK following BDNF treatment promotes removal from actin and filopodia formation. Phosphorylated by several receptor tyrosine kinases (By similarity).
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 (By similarity).
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 specifically in late stage spermatocytes. In the cerebellum, emergence of beta-2 isoform coincides with granule cells maturation and exhibits postnatal developmental increases. Expression is specifically reduced in weaver mutant.
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 (By similarity).
Activated by threonine and tyrosine phosphorylation. Inhibited by dual specificity phosphatases, such as DUSP1 (By similarity). Phosphorylation and activation in response to DNA damaging agents, serum stimulation. Constitutively activated when phosphorylated on Tyr-178. Activity depends on the relative rates of MAPK15 autophosphorylation and dephosphorylation by PTPN1 (By similarity).
Atypical MAPK protein that regulates several process such as autophagy, ciliogenesis, protein trafficking/secretion and genome integrity, in a kinase activity-dependent manner. Controls both, basal and starvation-induced autophagy throught its interaction with GABARAP, MAP1LC3B and GABARAPL1 leading to autophagosome formation, SQSTM1 degradation and reduced MAP1LC3B inhibitory phosphorylation. Regulates primary cilium formation and the localization of ciliary proteins involved in cilium structure, transport, and signaling. Prevents the relocation of the sugar-adding enzymes from the Golgi to the endoplasmic reticulum, thereby restricting the production of sugar-coated proteins. Upon amino-acid starvation, mediates transitional endoplasmic reticulum site disassembly and inhibition of secretion. Binds to chromatin leading to MAPK15 activation and interaction with PCNA, that which protects genomic integrity by inhibiting MDM2-mediated degradation of PCNA. Regulates DA transporter (DAT) activity and protein expression via activation of RhoA. In response to H(2)O(2) treatment phosphorylates ELAVL1, thus preventing it from binding to the PDCD4 3'UTR and rendering the PDCD4 mRNA accessible to miR-21 and leading to its degradation and loss of protein expression (By similarity). Also functions in a kinase activity-independent manner as a negative regulator of growth (PubMed:9891064). Phosphorylates in vitro FOS and MBP (PubMed:11875070). During oocyte maturation, plays a key role in the microtubule organization and mei- otic cell cycle progression in oocytes, fertilized eggs, and early embryos (By similarity). Interacts with ESRRA promoting its re-localization from the nucleus to the cytoplasm and then prevents its transcriptional activity (By similarity).
Autophosphorylated on Thr-176 and Tyr-178; activates the enzyme.
C-terminal domain, rather than the kinase activity, is required for the full function of the enzyme. This region may be a protein interaction domain that regulates kinase localization, activation and transcriptional activity. When C-terminally truncated, the enzyme shows a reduction in the Thr-Glu-Tyr (TEY) phosphorylation level, in the in vitro kinase activity, in its nuclear localization and in its inhibitory effect on cell growth.
Interacts with CSK/c-Src, ABL1, RET and TGFB1I1. Interacts with GABARAP, MAP1LC3B and GABARAPL1; controls, in a kinase-dependent fashion, both basal and starvation-induced autophagy. Interacts with ESRRA; promotes re-localization of ESRRA to the cytoplasm through a XPO1-dependent mechanism then inhibits ESRRA transcriptional activity. Interacts with PCNA; the interaction is chromatin binding- and kinase activity-dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2 (By similarity). Interacts with DVL2 (By similarity). Interacts with CLIC3; MAPK15 does not phosphorylates CLIC3 (PubMed:9880541).
The N-terminal region (1-20) is the minimal region necessary for ubiquitination and further proteasomal degradation.
Ubiquitinated. Ubiquitination may allow its tight kinase activity regulation and rapid turnover. May be ubiquitinated by a SCF E3 ligase.
Ubiquitously expressed at a weak level. Highest expression is found in testis and to a lower extent in lung.
Involved in both glial cell differentiation and axonal network formation during neurogenesis. Promotes astrocyte differentiation and transforms cerebellar astrocytes into radial glia. Also induces axonal extension in small and intermediate neurons of sensory ganglia by activating nearby satellite glia (By similarity).
Belongs to the universal ribosomal protein uL14 family.
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).
Homotetramer (By similarity). 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 (By similarity).
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.
Inhibited by ruthenium red, a potent blocker of TRPV channels (PubMed:14712238). Selectively inhibited by A-967079 (PubMed:21402443).
Oxidation of Cys-634 and Cys-859 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. Shows 8-fold preference for divalent over monovalent cations. Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of irritants, such as allylthiocyanate (AITC) found in mustard oil or wasabi, cinnamaldehyde, diallyl disulfide (DADS) from garlic, and acrolein, an irritant from tears gas and vehicle exhaust fumes (By similarity). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (By similarity). 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).
Specifically expressed in a subset of nociceptive neurons. Expressed in dorsal root ganglia.
TRPA1 activation by electrophiles occurs though covalent modification of specific cysteine residues in the N-terminal cytoplasmic domain (By similarity).
The ANK repeat domain consists of a convex stem structure followed by a crescent-shaped structure that surrounds the protein core.
Belongs to the vasopressin/oxytocin family.
Interacts with oxytocin receptor (Ki=1.5 nM) (By similarity). Interacts with vasopressin V1aR/AVPR1A (Ki=37 nM), V1bR/AVPR1B (Ki=222 nM), and V2R/AVPR2 receptors (Ki=823 nM) (By similarity).
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) (By similarity).
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 (PubMed:16289032). Represses IFIH1-mediated cellular antiviral response (By similarity).
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 (By similarity).
Manganese or cobalt are requested for FAD-AMP lyase activity.
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.
Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis. Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Appears to modulate glycerol gluconeogenesis in liver. Important regulator of appetite and adiposity; increased expression of the protein in liver after nutrient excess increases circulating satiety hormones and reduces appetite-stimulating neuropeptides and thus seems to provide a feedback mechanism to limit weight gain.
Subject to complex allosteric regulation. The enzyme can assume an active R-state, or an inactive T-state. Intermediate conformations may exist. AMP acts as allosteric inhibitor. AMP binding affects the turnover of bound substrate and not the affinity for substrate. Fructose 2,6-bisphosphate acts as competitive inhibitor. Fructose 2,6-bisphosphate and AMP have synergistic effects.
Homotrimer or homotetramer constituted of isoform 1 and/or isoform 2 and isoform 3 (PubMed:10224102). 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).
Phosphorylation at Ser-308 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 (PubMed:10224102). Maintains epithelial barrier function by recruiting MARVELD2/tricellulin to tricellular tight junctions (By similarity).
Specifically expressed in liver. Also detected in kidney and lung.
Interacts with CEP152; the interaction is mutually exclusive with CEP63.
It is uncertain whether Met-1 or Met-22 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).
Belongs to the GTP-binding elongation factor family. LepA subfamily.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. LepA subfamily.
Promotes mitochondrial protein synthesis. May act as a fidelity factor of the translation reaction, by catalyzing a one-codon backward translocation of tRNAs on improperly translocated ribosomes. Binds to mitochondrial ribosomes in a GTP-dependent manner.
Belongs to the P-Pant transferase superfamily. AcpS family.
Catalyzes the post-translational modification of target proteins by phosphopantetheine. Can transfer the 4'-phosphopantetheine moiety from coenzyme A, regardless of whether the CoA is presented in the free thiol form or as an acetyl thioester, to a serine residue of a broad range of acceptors including the acyl carrier domain of FASN.
Major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. May participate in generating perivascular beta-protein which ultimately aggregates into amyloid-beta deposits.
Citrullination at Arg-56 (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 bind to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. H1 histones 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 (By similarity).
Phosphatidylinositol phosphatase required for auditory function. May act by regulating the level of phosphatidylinositol 4,5-bisphosphate (PIP2) level in the basal region of hair bundles. Can dephosphorylate a broad range of phosphatidylinositol phosphates, including phosphatidylinositol 3,4,5-trisphosphate and most phosphatidylinositol monophosphates and diphosphates. Phosphate can be hydrolyzed from the D3 and D5 positions in the inositol ring. Has low tyrosine-protein phosphatase activity; however, the relevance of such activity in vivo is unclear. Plays an important role in adipogenesis of mesenchymal stem cells (MSCs). Regulates the phosphorylation state of AKT1 by suppressing the phosphatidylinositol 3,4,5-trisphosphate (PIP3) level in MSCs and preadipocyte cells (By similarity).
Up-regulated during the period of mesangial cell migration and proliferation that follows mesangial cell injury.
Homodimer (By similarity). Interacts with AHI1 (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 (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.
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. In vitro also methylates unmodified 'Lys-20' (H4K20me0) of histone H4 and nucleosomes (By similarity). 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. 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 (By similarity). 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). Interacts (via C-terminus) with FRG1 (By similarity).
Inhibited by 6,7-Dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine (A-196). A-196 is competitive with the histone peptide substrate H4K20me1 but non competitive with S-adenosyl-L-methionine.
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 (By similarity).
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.
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).
Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41 and VPS72/YL1. The NuA4 complex interacts with MYC and the adenovirus E1A protein. MORF4L1 may also participate in the formation of NuA4 related complexes which lack the KAT5/TIP60 catalytic subunit, but which include the SWI/SNF related protein SRCAP. Component of the MSIN3A histone deacetylase complex, which includes SIN3A, HDAC2, ARID4B, MORF4L1, RBBP4/RbAp48, and RBBP7/RbAp46. Interacts with MRFAP1 and RB1. May also interact with one or more as yet undefined members of the TLE (transducin-like enhancer of split) family of transcriptional repressors (By similarity).
Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histone H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. NuA4 may also play a direct role in DNA repair when directly recruited to sites of DNA damage. Also a component of the MSIN3A complex which acts to repress transcription by deacetylation of nucleosomal histones (By similarity).
During G0 and early G1 phase of the cell cycle, phosphorylated on Ser-636 and on 5 sites within the domain B. Phosphorylation on Ser-669 in G1 leads to its ubiquitin-dependent proteolysis (By similarity).
Interacts with AATF, KMT5B and KMT5C. 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 USP4 (By similarity). Part of the peroxisome proliferator activated receptor alpha (PPAR-alpha) interacting complex (PRIC). Interacts with RINT1 (By similarity). Interacts with PML (By similarity). Interacts with RBBP9 (PubMed:9697699).
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 (By similarity).
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.
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 (By similarity).
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.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A2 subfamily.
Homotrimer (By similarity). Interacts with AJUBA (PubMed:11860269).
Localized in brain and is highly enriched in the Purkinje cell layer in cerebellum.
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:1448170, PubMed:7913472). 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:1448170). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (By similarity). Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate (By similarity).
Interacts with MYC (By similarity). Interacts (via IBM motifs) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (By similarity).
Phosphorylation increases its interaction with PSIP1.
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 (By similarity).
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 (PubMed:22314358). 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. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1 and AMBRA1. PI3KC3-C1 probably associates with PIK3CB. Interacts with AMBRA1, GOPC, GRID2. Forms a complex with PPP2CA and AMBRA1; AMBRA1 and BECN1 components of the complex regulate MYC stability via different pathways (By similarity). 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. Interacts with cytosolic HMGB1; inhibits the interaction of BECN1 and BCL2 leading to promotion of autophagy. Interacts with USP10, USP13, DAPK1, RAB39A. Interacts with SLAMF1 (By similarity). Interacts with the poly-Gln domain of ATXN3; the interaction causes deubiquitination at Lys-400 and stabilizes BECN1. Interacts with VMP1 (PubMed:17724469). Interacts with TRIM5; the interaction causes activation of BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2 (By similarity). Interacts with active ULK1 (phosphorylated on 'Ser-317') and MEFV simultaneously (By similarity). Interacts with WDR81 and WDR91; negatively regulates the PI3 kinase/PI3K activity associated with endosomal membranes (By similarity). Interacts with LAPTM4B; competes with EGFR for LAPTM4B binding; regulates EGFR activity (By similarity). Interacts with TRIM50 (By similarity). Interacts with TRIM16 (By similarity). Interacts with ATG14; this interaction is increased in the absence of TMEM39A (By similarity). Interacts with WASHC1; preventing interaction with AMBRA1 and the DCX(AMBRA1) complex and subsequent ubiquitination (By similarity). Interacts with TRIM17 (By similarity). Interacts with BCL2L10/BCL-B (via BH1 domain) (By similarity). Interacts with SH3BGRL (By similarity).
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 (By similarity).
Phosphorylation at Thr-117 by DAPK1 reduces its interaction with BCL2 and BCL2L1 and promotes induction of autophagy. 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.
Plays a central role in autophagy. 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. Essential for the formation of PI3KC3-C2 but not PI3KC3-C1 PI3K complex forms. Involved in endocytosis. May play a role in antiviral host defense (By similarity).
Polyubiquitinated by NEDD4, both with 'Lys-11'- and 'Lys-63'-linkages (By similarity). 'Lys-11'-linked polyubiquitination leads to degradation and is enhanced when the stabilizing interaction partner VPS34 is depleted (By similarity). Deubiquitinated by USP10 and USP13, leading to stabilize the PIK3C3/VPS34-containing complexes (By similarity). Polyubiquitinated at Lys-400 with 'Lys-48'-linkages (By similarity). 'Lys-48'-linked polyubiquitination of Lys-400 leads to degradation (By similarity). Deubiquitinated by ATXN3, leading to stabilization (By similarity). Ubiquitinated at Lys-435 via 'Lys-63'-linkage by the DCX(AMBRA1) complex, thereby increasing the association between BECN1 and PIK3C3 to promote PIK3C3 activity (By similarity).
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 (By similarity). As some binding is observed with BECN1 lacking the ECD, other domains of BECN1 may also interact with ATXN3 (By similarity).
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.
Interacts with DNMT3A and DNMT3B. 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 methylated CpG containing oligonucleotides (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 (By similarity). Interacts with UHRF2 (By similarity). Interacts with FANCD2 (By similarity).
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 crosslinks (ICLs) leading to FANCD2 activation (By similarity).
Phosphorylation at Ser-295 of the linker region decreases the binding to H3K9me3. Phosphorylation at Ser-631 by CDK1 during M phase impairs interaction with USP7, preventing deubiquitination and leading to degradation by the proteasome (By similarity).
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). 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. The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC) (By similarity).
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. 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 (By similarity).
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-631 prevents interaction with USP7 and subsequent deubiquitination. Polyubiquitination may be stimulated by DNA damage (By similarity).
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).
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.
Expressed in the brain, adrenal medulla and anterior pituitary. In the brain, localized to the hippocampal formation, the endocrine hypothalamus, the olfactory system, and in anatomically distinct structures in the pons-medulla.
Extensively processed in glucagonoma tissue by limited proteolysis at conserved basic residues. Alternative processing are seen in different tissues. The proglucagon-converting enzymes present in transformed alpha-cells are likely candidates to be involved in tissue-specific processing.
First expressed in the brain around embryonic days 13-14, and peaks by postnatal day 20.
Secretogranin-1 is a neuroendocrine secretory granule protein, which may be the precursor for other biologically active peptides.
Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide (By similarity). Does not exhibit calcium-activated chloride channel (CaCC) activity (By similarity). May play a role in cell-cell interactions (By similarity).
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.
Homodimer. Only one subunit is competent to transfer the CoA moiety to the acceptor carboxylate (3-oxo acid).
Key enzyme for ketone body catabolism. Catalyzes the first, rate-limiting step of ketone body utilization in extrahepatic tissues, by transferring coenzyme A (CoA) from a donor thiolester species (succinyl-CoA) to an acceptor carboxylate (acetoacetate), and produces acetoacetyl-CoA. Acetoacetyl-CoA is further metabolized by acetoacetyl-CoA thiolase into two acetyl-CoA molecules which enter the citric acid cycle for energy production (By similarity). Forms a dimeric enzyme where both of the subunits are able to form enzyme-CoA thiolester intermediates, but only one subunit is competent to transfer the CoA moiety to the acceptor carboxylate (3-oxo acid) and produce a new acyl-CoA. Formation of the enzyme-CoA intermediate proceeds via an unstable anhydride species formed between the carboxylate groups of the enzyme and substrate (By similarity).
Belongs to the complex I subunit 3 family.
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Interacts with TMEM186. Interacts with TMEM242 (By similarity).
Core subunit of respiratory chain NADH dehydrogenase (Complex I) which is composed of 45 different subunits. Interacts with TMEM186. Interacts with TMEM242.
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.
Necessary for protein translocation in the endoplasmic reticulum.
Transaminase with broad substrate specificity. Has transaminase activity towards aminoadipate, kynurenine, methionine and glutamate. Shows activity also towards tryptophan, aspartate and hydroxykynurenine. Accepts a variety of oxo-acids as amino-group acceptors, with a preference for 2-oxoglutarate, 2-oxocaproic acid, phenylpyruvate and alpha-oxo-gamma-methiol butyric acid. Can also use glyoxylate as amino-group acceptor (in vitro).
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs.
Phosphorylated by MAPK1/ERK2 and MAPK3/ERK1.
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).
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.
Defects in Unc5c are the cause of cerebellar vermis defect (cvd) and hobble (hob) phenotypes. Cvd and hob rats exhibit cerebellar and midbrain defects, possibly as a result of abnormal neuronal migration, and exhibit laminar structure abnormalities in the fused cerebellar hemispheres and ectopic cerebellar tissues in the cerebello-pontine junction.
Detected in brain (at protein level) (PubMed:22405201). Mainly expressed in brain. Also expressed in kidney. Not expressed in developing or adult lung.
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) (By similarity). Interacts (via death domain) with DAPK1 (By similarity). Interacts (via cytoplasmic domain) with TUBB3; this interaction is decreased by NTN1/Netrin-1 (By similarity).
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 (By similarity). 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 (By similarity). It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (PubMed:11387206).
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. Shows a preference for AGC or AGA.
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.
Expressed in the jejunum (at protein level) (PubMed:12620923). Expressed in lung, skeletal muscle, heart, brain, kidney, intestine, liver, and placenta (PubMed:9516450, PubMed:12620923).
Expressed in the jejunum in 13-14 days old animals (at protein level) (PubMed:12620923). Expressed in the kidney in 13-14 days old animals (PubMed:12620923).
Sodium-dependent multivitamin transporter that transports pantothenate, biotin and lipoate (By similarity). Required for biotin and pantothenate uptake in the instestine (By similarity). Plays a role in the maintenance of intestinal mucosa integrity, by providing the gut mucosa with biotin (By similarity). May play a role in the transport of biotin and pantothenate into the brain across the blood-brain barrier (By similarity). May also be involved in the sodium-dependent transport of iodide ions (By similarity).
Belongs to the glycosyl hydrolase 39 family.
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 (By similarity). 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. Plays a role in the immune response of alternatively activated or M2 macrophages in processes such as wound healing and tissue regeneration, immune defense against multicellular pathogens and parasites, and immune suppression and allergic inflammation; the regulatory outcome seems to be organ specific. In tumor-infiltrating dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) plays a role in suppression of T cell-mediated antitumor immunity.
Homotrimer (PubMed:15315440, PubMed:16266687). Interacts with CMTM6 (By similarity).
Inactivated by diethyl pyrocarbonate (DEPC).
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.
Thought to encode a transcription factor. It may have a role in kidney cell differentiation. May play a regulatory role in mammalian development (By similarity).
Expressed in testis, spleen and brain (at protein level).
Receptor for endocannabinoid N-arachidonyl glycine (NAGly) (PubMed:24431468). However, conflicting results about the role of NAGly as an agonist are reported (By similarity). Can also be activated by plant-derived and synthetic cannabinoid agonists (PubMed:24431468). The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase (By similarity). May contribute to regulation of the immune system (By similarity). 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 (PubMed:24431468). Mediates NAGly-induced process of reorganization of actin filaments and induction of acrosomal exocytosis (By similarity).
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 (By similarity). 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 (PubMed:19319189). 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 (By similarity). Interacts with ARBB2, LAMTOR3, MAPK1/ERK2 and RAF1 (PubMed:7565670, PubMed:9733512, PubMed:11226259, PubMed:14993270). Interacts with MAPK1/ERK2 (By similarity). Interacts with MORG1 (By similarity). Interacts with PPARG (By similarity). Interacts with VRK2 (By similarity). Interacts with SGK1 (By similarity). Interacts with BIRC6/bruce (By similarity). 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 (By similarity). Interacts with TRAF3IP3 (By similarity).
Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase kinases (BRAF or MEKK1) positively regulates kinase activity (PubMed:10769026). Also phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK (PubMed:12876277, PubMed:14993270). MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to cellular adhesion and leads to inhibition of Ser-298 phosphorylation by PAK (PubMed:14993270). Autophosphorylated at Ser-218 and Ser-222, autophosphosphorylation is promoted by NEK10 following UV irradiation (By similarity).
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. Activation occurs through phosphorylation of Ser-218 and Ser-222. MAP2K1/MEK1 binds KSR1 or KSR2 releasing the inhibitory intramolecular interaction between KSR1 or KSR2 protein kinase and N-terminal domains (By similarity). This allows KSR1 or KSR2 dimerization with BRAF leading to BRAF activation and phosphorylation of MAP2K1 (By similarity). 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.
The proline-rich region localized between residues 270 and 307 is important for binding to RAF1 and activation of MAP2K1/MEK1.
Highly expressed in the duodenum and jejunum.
Potent stimulator of insulin secretion and relatively poor inhibitor of gastric acid secretion.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ15 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 (By similarity).
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.
Homohexamer. Organized in a ring with a central cavity. The ATP-binding and proteolytic domains (AP-domain) form a hexameric chamber, while the N-terminal domain is arranged as a trimer of dimers. DNA and RNA binding is stimulated by substrate and inhibited by ATP binding. Interacts with TWNK and mitochondrial DNA polymerase subunit POLG.
Acetylation of Lys-380 by CREBBP enhances transcriptional activity. Acetylation of Lys-380 by EP300. Deacetylation of Lys-380 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner. Acetylation at Lys-379 increases stability. Deacetylation at Lys-379 by SIRT6 decreases its stability, thereby regulating cell senescence.
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. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (By similarity). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (By similarity). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2.
Forms homodimers and homotetramers (By similarity). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. Interacts with USP7 and SYVN1. Interacts with HSP90AB1 (PubMed:8663025). Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-380) with L3MBTL1. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3. Interacts (via C-terminus) with POU4F2 (via C-terminus). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53. Interacts with AFG1L; mediates mitochondrial translocation of TP53. Interacts with UBD (By similarity). Interacts with TAF6 (By similarity). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1. Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity. Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-18 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-379) with L3MBTL1. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest (By similarity). Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3. Interacts (via C-terminus) with POU4F2 (via C-terminus). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53. Interacts with AFG1L; mediates mitochondrial translocation of TP53. Interacts with UBD (By similarity). Interacts with TAF6 (By similarity). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent. Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (By similarity). Interacts with PRMT5 in response to DNA damage; the interaction is TTC5/STRAP dependent (By similarity). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (By similarity). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (By similarity). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (By similarity). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (By similarity). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (By similarity). Interacts with S100A4; this interaction promotes TP53 degradation (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (By similarity). Interacts with NQO1; this interaction is NADH-dependent, stabilizes TP53 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome (By similarity). Interacts with DAZAP2 at TP53 target gene promoters; the interaction is triggered by DNA damage and leads to modulation of the expression of a subset of TP53 target genes, reducing DNA damage-induced cell death by limiting the expression of cell death-mediating TP53 target genes (By similarity). Interacts (via N-terminus) with ZNF768 (via zinc-finger domains); interaction might be facilitated by TP53 oligomerization state (By similarity).
Monomethylated at Lys-370 by SETD7, leading to stabilization and increased transcriptional activation. Monomethylated at Lys-368 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity. Lys-370 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-368. Dimethylated at Lys-371 by EHMT1 and EHMT2. Monomethylated at Lys-380 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity. Demethylation of dimethylated Lys-368 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (By similarity). Monomethylated at Arg-331 and dimethylated at Arg-333 and Arg-335 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (By similarity).
Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter (By similarity). Phosphorylated on Thr-18 by VRK1, which may prevent the interaction with MDM2. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Probably phosphorylated on by CDK7 in a CAK complex in response to DNA damage. Phosphorylated by HIPK1. Phosphorylated on Ser-390 following UV but not gamma irradiation. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated at Ser-313 and Ser-390 by CDK2 in response to DNA-damage (By similarity). Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (By similarity).
Sumoylated with SUMO1. Sumoylated at Lys-384 by UBC9 (By similarity).
The [KR]-[STA]-K motif is specifically recognized by the SETD7 methyltransferase.
Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation. Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome. Ubiquitinated by MKRN1, which leads to proteasomal degradation. Deubiquitinated by USP10, leading to stabilize it. Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation. Ubiquitination by TOPORS induces degradation. Deubiquitination by USP7, leading to stabilize it. Ubiquitinated by COP1, which leads to proteasomal degradation (By similarity). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (By similarity). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (By similarity).
p53 is found in increased amounts in a wide variety of transformed cells. p53 is frequently mutated or inactivated in many types of cancer.
Depletion by RNAi alters oligodendrocyte differentiation and enhances opioid analgesia.
Expressed in ependymocytes and neurons throughout the CNS from the olfactory bulb to the spinal cord. Expressed by progenitor, mature and satellite oligodendrocytes and by Schwann cells (at protein level). Expressed in liver, intestine, kidney, brain, lung and heart. Expressed by retinal cells.
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. 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).
Homotrimer (By similarity). Interacts with KCNA2; cocaine consumption leads to increased interaction (By similarity). Forms a ternary complex with ANK2 and ITPR3. The complex is disrupted by agonists (PubMed:11149946). Interacts with KCNA4 (PubMed:11988171). 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.
Belongs to the LanC-like protein family.
Interacts with SLC35A2; the interaction is reduced in the presence of SLC35A4 (By similarity). Found in a complex with SLC35A2 and SLC35A4 (By similarity).
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 (By similarity).
Expressed at moderate levels in nearly all tissues and cells including brain, spleen, and testes with the higher expression in the heart and lung and lower expression in skeletal muscle and kidney. Undetectable in liver. Expressed in many areas of the brain with very strong expression in the hippocampus, piriform cortex, and the suprachiasmatic nucleus.
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.
Belongs to the flagellar radial spoke RSP3 family.
Interacts with the D-type cyclins CCND1, CCND2 and CCND3. Interaction with D-type cyclins may modulate transcriptional activation by this protein.
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. Binds to the consensus sequence 5'-CCCG[GT]ATGT-3'.
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).
Interacts with SH3 domain-containing proteins LCK, CRK and SORBS1. Interacts with LCP2 and ZAP70. Interacts with CBL. 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.
Lack of Cblb expression is the cause of the Komeda diabetes-prone (KDP) phenotype, characterized by autoimmune destruction of pancreatic beta cells and rapid onset of overt diabetes with no sex difference and no significant T-cell lymphopenia. The KPD rat is a spontaneous animal model for human type 1 diabetes mellitus.
Phosphorylated on tyrosine and serine residues upon TCR or BCR activation, and upon various types of cell stimulation.
The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.
The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme.
The UBA domain interacts with poly-ubiquitinated proteins.
This protein has one functional calcium-binding site.
A conserved histidine residue in the third TMD (His-107) may play an essential role in the pH sensitivity of SLCO1A4/OATP1A4-mediated substrate transport.
Highly expressed in brain, liver, and kidney but not expressed in heart, spleen, lung, skeletal muscle, and testis.
Mediates the Na(+)-independent transport of organic anions such as taurocholate, cholate, 17-beta-glucuronosyl estradiol, prostaglandin E2, estrone 3-sulfate, L-thyroxine (T4), the cardiac glycosides ouabain and digoxin and thyroid hormones (PubMed:19129463). May play an especially important role in the brain accumulation and toxicity of digoxin and in the hepatobiliary and renal excretion of cardiac glycosides. Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).
Membrane topology is controversial (PubMed:11601977). Membrane topology structure with endoplasmic reticulum lumen orientation of the catalytic domains while the C-terminus is in the cytosol have been suggested by one study (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:11601977). These contracductoty 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:7499345). Has higher activity towards CRBP-bound retinol than with free retinol (By similarity). Oxidizes 3-alpha-hydroxysteroids. Oxidizes androstanediol and androsterone to dihydrotestosterone and androstanedione. Can also catalyze the reverse reaction (By similarity).
The C-terminal region plays a crucial role in controlling the activity of RDH16 and its required for endoplasmic reticulum (ER) retention.
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.
Highest levels in spinal cord, heart, kidney and lung.
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 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 (By similarity). Interacts (GTP-bound form) with EHBP1 (By similarity). Interacts with EHD1 (By similarity). 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 (By similarity). Interacts with RAB3IP (By similarity). Interacts with MYO5B (By similarity). Interacts with PIFO (By similarity). Interacts with BIRC6/bruce (By similarity). Interacts with OCRL (By similarity). Interacts with AHI1 (By similarity). Interacts with DCDC1 (By similarity). Interacts with LRRK2; interaction facilitates phosphorylation of Thr-72 (By similarity). Interacts with RAB31P, GDI1, GDI2, CHM, RABGGTA, RABGGTB, TBC1D15 and INPP5B; these interactions are dependent on Thr-72 not being phosphorylated (By similarity). Interacts with RILPL1 and RILPL2; these interactions are dependent on the phosphorylation of Thr-72 by LRRK2 (By similarity). Interacts with DZIP1; prevents inhibition by the GDP-dissociation inhibitor GDI2 (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 (Probable). 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 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 (By similarity). Regulates the compacted morphology of the Golgi (By similarity). Together with MYO5B and RAB11A participates in epithelial cell polarization (By similarity). Also involved in membrane trafficking to the cilium and ciliogenesis (By similarity). 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 (PubMed:21041651). Involved in autophagy (By similarity).
Homohexamer (By similarity). Interacts with BCS1L (By similarity).
Inhibited by ruthenium red or its derivative Ru360.
Mitochondrial proton/calcium antiporter that mediates proton-dependent calcium efflux from mitochondrion (By similarity). Crucial for the maintenance of mitochondrial tubular networks and for the assembly of the supercomplexes of the respiratory chain (By similarity). Required for the maintenance of the tubular shape and cristae organization (By similarity). In contrast to SLC8B1/NCLX, does not constitute the major factor for mitochondrial calcium extrusion (By similarity). Essential for early embryonic development (By similarity).
E3 ubiquitin-protein ligase that regulates selective mitochondrial autophagy by mediating 'Lys-63'-linked polyubiquitination of BNIP1. Acts in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, which targets misfolded proteins that accumulate in the endoplasmic reticulum (ER) for ubiquitination and subsequent proteasome-mediated degradation. Protects cells from ER stress-induced apoptosis. Responsible for the cotranslational ubiquitination and degradation of CFTR in the ERAD pathway. Also acts as a regulator of the innate antiviral response by catalyzing 'Lys-27'-linked polyubiquitination of CGAS, thereby promoting CGAS cyclic GMP-AMP synthase activity. Preferentially associates with the E2 enzymes UBE2J1 and UBE2J2.
The RING-type zinc finger domain is responsible for E3 ubiquitin ligase activity.
Acts as a transcriptional repressor. Binds to E-box sequences in the immunoglobulin heavy chain enhancer as well as in the regulatory regions of many other tissue-specific genes. 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 (By similarity).
Belongs to the delta-EF1/ZFH-1 C2H2-type zinc-finger family.
Interacts (via N-terminus) with SMARCA4/BRG1.
May play a role in an as yet undefined retina-specific signal transduction. Could bind to photoactivated-phosphorylated red/green opsins.
Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor. 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.
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. 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. Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) via ERN1/IRE1-alpha. Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (By similarity). 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 (By similarity). 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. Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4. Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (By similarity). Required for hematopoietic stem cell function and hematopoiesis. Required for cardiac homeostasis (By similarity).
Interacts with DDRGK1 (via PCI domain) (By similarity). Interacts with UFC1 (By similarity). Interacts with RELA (By similarity). Interacts with TRIP4 (By similarity). Interacts with CDK5RAP3; the interaction is direct (PubMed:20531390). Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage (By similarity).
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. Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome.
Ubiquitously expressed with expression detected in brain, skeletal muscle, lung, heart, gall bladder, liver, small intestine, pancreas, spleen and kidney (at protein level) (PubMed:20228063). At 8 weeks after birth, high expression in the Purkinje cell layer of the cerebellum (PubMed:20531390).
Somewhat implicated in the biogenesis of peroxisomes.
Initially, this protein was identified as a carnitine/acylcarnitine transporter (By similarity). Later, a study conducted by Palmieri and coworkers demonstrated that SLC25A29 is mainly involved in the translocation of basic amino acids (By similarity).
Mitochondrial transporter of arginine, lysine, homoarginine, methylarginine and, to a much lesser extent, ornithine and histidine. Does not transport carnitine nor acylcarnitines. Functions by both counter-exchange and uniport mechanisms. Plays a physiolocical role in the import of basic amino acids into mitochondria for mitochondrial protein synthesis and amino acid degradation.
Belongs to the WD repeat PRL1/PRL2 family.
Identified in the spliceosome C complex. 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 (via its WD40 repeat domain) directly with CDC5L (via its C-terminal); the interaction is required for mRNA splicing but not for spliceosome assembly. Also interacts directly in the complex with BCAS2 and PRPF19. Interacts with USB1 (By similarity).
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.
Interacts with ZNF224 via the zinc-finger region. Interacts with WTAP, AMER1 and SRY. Homodimer. Interacts with WTIP. Interacts with actively translating polysomes. Detected in nuclear ribonucleoprotein (mRNP) particles. Interacts with U2AF2. Interacts with HNRNPU via the zinc-finger region. Interacts with CITED2 (By similarity).
Presence of the KTS motif hinders interactions between DNA and zinc-finger 4.
Transcription factor that plays an important role in cellular development and cell survival. Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3'. 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. Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing. Isoform 1 has lower affinity for DNA, and can bind RNA.
Catalyzes the transfer of phosphatidylinositol between membranes (PubMed:18636990). Also catalyzes the transfer of phosphatidylcholine and sphingomyelin between membranes (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 (By similarity).
Constitutive phosphorylation of Ser-262 has no effect on phospholipid transfer activity but is required for Golgi targeting.
Expressed abundantly in brain, kidney, liver, and lung, but in a lesser amount in testis.
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 (By similarity).
Component of a complex composed of RGS9, 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). Interacts with RGS6 and RGS7 (By similarity).
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 (By similarity). May play an important role in neuronal signaling, including in the parasympathetic, but not sympathetic, control of heart rate (By similarity).
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).
Allosterically activated by S-adenosyl-methionine/AdoMet. Activated by S-adenosylhomocysteine/AdoHcy. Binds non-covalently to a heme group that may control the redox sensitivity of the enzyme.
Belongs to the cysteine synthase/cystathionine beta-synthase family.
Expressed in liver, kidney and brain. Highly expressed in the hippocamus and cerebellum.
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 (By similarity). Also involved in the production of hydrogen sulfide, a gasotransmitter with signaling and cytoprotective effects on neurons (PubMed:20149843, PubMed:8558235).
Autocatalytic cleavage of USP1 following UV irradiation inactivates it, leading to an increase in ubiquitinated PCNA, recruitment of POLH and translesion synthesis.
Interacts with FANCD2 and PCNA. Interacts with WDR48. Interacts with ATAD5; the interaction regulates USP1-mediated PCNA deubiquitination.
Negative regulator of DNA damage repair which specifically deubiquitinates monoubiquitinated FANCD2. Also involved in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA. Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity.
Ubiquitinated by the CRL2(KLHDC2) complex following autocatalytic cleavage, leading to its degradation: the CRL2(KLHDC2) complex recognizes the diglycine (Gly-Gly) at the C-terminus.
Interacts with the GATOR1 complex; interaction is disrupted when BMT2/SAMTOR binds S-adenosyl-L-methionine. Interacts with the KICSTOR complex; interaction is disrupted when BMT2/SAMTOR binds S-adenosyl-L-methionine.
S-adenosyl-L-methionine-binding protein that acts as an inhibitor of mTORC1 signaling via interaction with the GATOR1 and KICSTOR complexes. 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. Upon methionine starvation, S-adenosyl-L-methionine levels are reduced, thereby promoting the association with GATOR1 and KICSTOR, leading to inhibit mTORC1 signaling. Probably also acts as a S-adenosyl-L-methionine-dependent methyltransferase.
Receptor for cysteinyl leukotrienes. The response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (By similarity).
Belongs to the paired homeobox family. Unc-4 subfamily.
Expressed in a narrow layer adjacent to the ventricular zone of the dorsal spinal cord, preceding overt neuronal differentiation.
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).
Acetylated by EP300, leading to impair phosphoenolpyruvate substrate-binding and promote its homodimerization and subsequent translocation to the nucleus. Deacetylation by SIRT6 promotes its nuclear export into the cytoplasm, leading to suppress its nuclear localization and oncogenic function.
Acetylation at Lys-305 is stimulated by high glucose concentration, it decreases enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy.
Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. The ratio between the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival.
FGFR1-dependent tyrosine phosphorylation is reduced by interaction with TRIM35.
Has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity.
Isoform M2 is allosterically activated by D-fructose 1,6-bisphosphate (FBP). Inhibited by oxalate and 3,3',5-triiodo-L-thyronine (T3). The activity of the tetrameric form is inhibited by PML. Selective binding to tyrosine-phosphorylated peptides releases the allosteric activator FBP, leading to inhibition of PKM enzymatic activity, this diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Glycolytic flux are highly dependent on de novo biosynthesis of serine and glycine, and serine is a natural ligand and allosteric activator of isoform M2.
Isoform specifically expressed during embryogenesis that has low pyruvate kinase activity by itself and requires allosteric activation by D-fructose 1,6-bisphosphate (FBP) for pyruvate kinase activity. In addition to its pyruvate kinase activity in the cytoplasm, also acts as a regulator of transcription in the nucleus by acting as a protein kinase. Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase. Catalyzes phosphorylation of STAT3 at 'Tyr-705' and histone H3 at 'Thr-11' (H3T11ph), leading to activate transcription. Its ability to activate transcription plays a role in cancer cells by promoting cell proliferation and promote tumorigenesis (By similarity). Promotes the expression of the immune checkpoint protein CD274 in BMAL1-deficient macrophages. May also act as a translation regulator for a subset of mRNAs, independently of its pyruvate kinase activity: associates with subpools of endoplasmic reticulum-associated ribosomes, binds directly to the mRNAs translated at the endoplasmic reticulum and promotes translation of these endoplasmic reticulum-destined mRNAs (By similarity). Plays a role in caspase independent cell death of tumor cells (By similarity).
Monomer and homotetramer; exists as a monomer in the absence of D-fructose 1,6-bisphosphate (FBP), and reversibly associates to form a homotetramer in the presence of FBP. The monomeric form binds 3,3',5-triiodo-L-thyronine (T3). Tetramer formation induces pyruvate kinase activity. The tetrameric form has high affinity for the substrate and is associated within the glycolytic enzyme complex. FBP stimulates the formation of tetramers from dimers. Homodimer; exists in a dimeric form in tumor cells and the dimeric form has less affinity for the phosphoenolpyruvate substrate. The homodimer converts into a protein kinase. Interacts with HERC1, POU5F1 and PML. Interacts with EGLN3; the interaction hydroxylates PKM under hypoxia and enhances binding to HIF1A. Interacts with HIF1A; the interaction is enhanced by binding of EGLN3, promoting enhanced transcription activity under hypoxia. Interacts with TRIM35; this interaction prevents FGFR1-dependent tyrosine phosphorylation. Interacts with JMJD8. Interacts with TRAF4. Interacts with (phosphorylated) CTNNB1; leading to activate transcription.
Pyruvate kinase isoform expressed in adult tissues, which replaces isoform M2 after birth. In contrast to isoform M2, has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity.
There are 4 isozymes of pyruvate kinase in mammals (L, R, M1, M2) encoded by 2 different genes: PKLR and PKM. The L and R isozymes are generated from the PKLR by differential splicing of RNA; the M1 and M2 forms are produced from the PKM gene by differential splicing. 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 as well as in most cancer cells.
Belongs to the major facilitator superfamily. Spinster (TC 2.A.1.49) family.
Sphingolipid transporter. May be involved in necrotic or autophagic cell death (By similarity).
Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1B. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with MYC and RRN3. Interacts with p53/TP53; the interaction prevents the association of SL1/TIF-IB with UBTF and represses RNA polymerase I transcription (By similarity).
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 (By similarity).
Belongs to the universal ribosomal protein uS12 family.
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, vitamin D3, and retinoic acid.
May be involved in cell proliferation and survival of hormone-dependent tumor cells. Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) (By similarity).
Phosphorylated on serine. Prolactin stimulate serine phosphorylation.
Constitutively phosphorylated at Ser-412 in the cytoplasm. At the plasma membrane, is rapidly dephosphorylated, a process that is required for clathrin binding and beta-2 adrenergic receptor/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 (By similarity). 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 (By similarity).
Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. 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). Interacts with GPR143 (By similarity). Interacts with MAP2K4/MKK4 (By similarity). Interacts with HCK and CXCR1 (phosphorylated). Interacts with ACKR3 and ACKR4 (By similarity). Interacts with ARRDC1; the interaction is direct (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (By similarity).
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. Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface (By similarity).
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 (By similarity).
Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.
May be involved in protection from oxidative damage.
Acts as a guanine-nucleotide exchange factor (GEF). Promotes guanine-nucleotide exchange on ARF1, ARF3 and ARF6. Promotes the activation of ARF factors through replacement of GDP with GTP. The cell membrane form, in association with ARL4 proteins, recruits ARF6 to the plasma membrane (By similarity). Involved in neurite growth (By similarity).
Binds via its PH domain to the inositol head group of phosphatidylinositol 3,4,5-trisphosphate. The PH domain is necessary and sufficient for plasma membrane relocalization (By similarity).
Heteromer. Composed of TAMALIN, CYTH2 and at least one GRM1. Interacts with ARRB1. Interacts with ARL4D; the interaction is direct (By similarity). Directly interacts with CCDC120 through the coiled coil domain; this interaction stabilizes CCDC120, possibly by preventing its ubiquitination, and is required for neurite growth in a neuroblastoma cell line. Interacts with FRMD4A (By similarity). Interacts (via N-terminal domain) with INAVA (via N-terminal domain) (By similarity).
On embryonic days 15 (15 dpc) and 18 dpc, a weak expression is seen in the mantle and ventricular germinal zones throughout the neuraxis. On postnatal days 0 (P0) and P7, weakly expressed in the gray matter, but not in the white matter, throughout the brain. In the cerebellum, the expression is seen in the external granule cell layer.
The coiled coil domain is involved in interaction with CCDC120.
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.
Defects in Myo5a are a cause of Dilute-opisthotonus (dop). Dop rats have diluted coat color and are occasionally associated with severe neurological disorders.
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 (PubMed:19812310). Interacts with MLPH. 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 (By similarity). 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.
Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+) (PubMed:1322410, PubMed:24018048). 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+) (PubMed:1322410, PubMed:24018048). 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 (PubMed:1322410, PubMed:24018048). 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 (PubMed:1322410, PubMed:24018048). Inhibited by immunosuppressant drug FK506 (tacrolimus) in complex with FKBP12 and also by immunosuppressant drug cyclosporin A (CsA) in complex with PPIA/cyclophilin A; the inhibition is Ca(2+)-dependent (By similarity).
Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:1322410, PubMed:24018048). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (By similarity). In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (By similarity). In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (By similarity). Positively regulates the CACNA1B/CAV2.2-mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (PubMed:23699505). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (By similarity). Dephosphorylates and inactivates transcription factor ELK1 (By similarity). Dephosphorylates DARPP32 (By similarity). May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins (By similarity). Required for postnatal development of the nephrogenic zone and superficial glomeruli in the kidneys, cell cycle homeostasis in the nephrogenic zone, and ultimately normal kidney function (By similarity). Plays a role in intracellular AQP2 processing and localization to the apical membrane in the kidney, may thereby be required for efficient kidney filtration (By similarity). Required for secretion of salivary enzymes amylase, peroxidase, lysozyme and sialic acid via formation of secretory vesicles in the submandibular glands (By similarity). Required for calcineurin activity and homosynaptic depotentiation in the hippocampus (By similarity). Required for normal differentiation and survival of keratinocytes and therefore required for epidermis superstructure formation (By similarity). Positively regulates osteoblastic bone formation, via promotion of osteoblast differentiation (By similarity). Positively regulates osteoclast differentiation, potentially via NFATC1 signaling (By similarity). May play a role in skeletal muscle fiber type specification, potentially via NFATC1 signaling (By similarity). Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB (By similarity). Required for antigen-specific T-cell proliferation response (By similarity).
Expressed in neonatal cardiomyocytes (at protein level) (PubMed:11114196). Expressed in hippocampal presynaptic termini (at protein level) (PubMed:23699505).
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) (By similarity). 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 PPP3CA/calcineurin A, calcineurin B and calmodulin (By similarity). Interacts (via calcineurin B binding domain) with regulatory subunit PPP3R1/calcineurin B (By similarity). Interacts (via calmodulin-binding domain) with calmodulin; the interaction depends on calmodulin binding to Ca(2+) (By similarity). Forms a complex composed of MYOZ2 and ACTN1 (By similarity). Within the complex interacts with MYOZ2 (By similarity). Interacts with MYOZ1 (By similarity). Interacts with MYOZ3 (By similarity). Interacts with CIB1; the interaction increases upon cardiomyocyte hypertrophy (By similarity). Interacts with CHP1 and CHP2 (PubMed:10593895, PubMed:18815128). Interacts with CRTC1. Interacts with CRTC2 (By similarity). Interacts with DNM1L; the interaction dephosphorylates DNM1L and promotes its translocation to mitochondria (By similarity). Interacts with CMYA5; this interaction represses calcineurin activity in muscle (By similarity). Interacts (constitutively active form) with SYNPO2 (By similarity). Interacts with scaffold protein AKAP5 (via IAIIIT motif); the interaction recruits PPP3CA to the plasma membrane following L-type Ca(2+)-channel activation (By similarity). Interacts with NFATC2 (By similarity). Interacts with RCAN3 (By similarity). Interacts with PPIA. Interacts with RCAN1 (By similarity). Interacts with UNC119 (By similarity). Interacts with C16orf74 (via PxIxIT motif, when phosphorylated on 'Thr-76') (By similarity). Interacts (via N-terminus) with MAP3K14/NIK (via C-terminus and kinase domain) (By similarity). Interacts with TRAF3 (By similarity). Interacts with SPATA33 (via PQIIIT motif) (By similarity).
Possible isomerization of Pro-309 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.
Filament-forming cytoskeletal GTPase. 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).
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 (By similarity). 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 (By similarity). Interacts with SEPTIN14 (via C-terminus) (By similarity). Interacts with DYRK1A (PubMed:18938227). Interacts with SLC6A3/DAT and SNCA/alpha-synuclein. Interacts with STX1A; in the striatum. Interacts with XIAP (via BIR3 domain) following the induction of apoptosis. Interacts with AREL1 (via HECT domain); in the cytoplasm following induction of apoptosis (By similarity).
Septins polymerize into heterooligomeric protein complexes that form filaments.
Belongs to the TFIIF beta subunit family.
TFIIF is a general transcription initiation factor that binds to RNA polymerase II and helps to recruit it to the initiation complex in collaboration with TFIIB.
May activate the lysosomal degradation of sphingolipids.
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family. PYROXD1 subfamily.
Probable FAD-dependent oxidoreductase; involved in the cellular oxidative stress response (By similarity). Required for normal sarcomere structure and muscle fiber integrity (By similarity).
Forms homooligomers. Interacts with MFN2; may form heterooligomers. Interacts with PHB1 and PHB2; recruits them to cardiolipin-enriched mitochondrial membranes and stabilizes them. Interacts with CACNA2D2 (By similarity).
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 (By similarity).
Could play a role in taste reception. Could be necessary for the concentration and delivery of sapid molecules in the gustatory system.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv10.2/KCNH5 sub-subfamily.
Detected in adult testis and in embryonic and adult brain, but not in other tissues. Highly expressed in specific brain areas, such as neocortex, olfactory bulb, primary olfactory cortex and brain stem. In cortex, expression is concentrated in a narrow band toward the middle lamella (layer IV). Moderately expressed in spinal cord, dorsal thalamic nuclei, medial hypothalamus, colliculus, lateral lemniscus, pontine nuclei and Islands of Calleja.
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 channel is down-regulated to 10% residual activity by 400 nano molar cytosolic calcium ions.
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 (By similarity).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1I subfamily.
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.
Expressed predominantly in brain (at protein level).
Interacts with AP1G1 and AP2A1 components of the adapter protein complexes AP-1 and AP-2. Interacts with the GAE domain proteins GGA1, GGA2 and GGA3 (By similarity). Interacts with AP2A2.
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.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1B subfamily.
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.
Interneurons in the cerebral cortex and hippocampus.
Neuropeptide with neuronal depressant and sleep-modulating properties.
There is a transient increase in cortistatin-expressing cells in the second postnatal week in all cortical areas and in the dentate gyrus. A transient expression is observed in the hilar region at P16.
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 (By similarity).
Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5. LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer. Interacts with LAMTOR1 and LAMTOR2; the interaction is direct. 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. The Ragulator complex interacts with SLC38A9; the probable amino acid sensor. 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 MAP2K1/MEK1 and MAPK2 (By similarity). Interacts with MORG1 (By similarity).
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. 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. Required for mono- and trimethylation on histone H3 'Lys-4' (H3K4me3), dimethylation on histone H3 'Lys-79' (H3K4me3). Required for Hox gene transcription. 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 PAF1C (By similarity).
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (By similarity). The PAF1 complex interacts with PHF5A. Within the PAF1 complex interacts directly with PHF5A (By similarity). Component of the SKI complex which consists of SKIC8, SKIV2L and TTC37 (By similarity).
Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM1 sub-subfamily.
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 (By similarity). Impermeable to zinc ions (By similarity). In addition, forms heteromultimeric ion channels with TRPM3 which are permeable for calcium and zinc ions (By similarity). Essential for the depolarizing photoresponse of retinal ON bipolar cells. It is part of the GRM6 signaling cascade. Calcium channel which may play a role in metastasis suppression. May act as a spontaneously active, calcium-permeable plasma membrane channel (By similarity).
Interacts with TRPM3; the interaction results in the formation of a heteromultimeric cation channel complex.
Expressed in subsets of taste receptor cells of the tongue and palate epithelium and exclusively in gustducin-positive cells. Expressed in 15% taste bud cells in circumvallate and foliate papillae but only in 2% in fungiform papillae. Expressed in the duodenum, antrum and fundus (part of the stomach) and in gastric endocrine cells.
Highest levels occur in the ileum followed by spleen, brain, thyroid, ovary and uterus. Low levels are found in the liver, kidney, jejunum and lung with lowest levels in the heart.
Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules and MHC class II antigen presentation. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L.
Dual specificity phosphatase; can dephosphorylate both phosphotyrosine and phosphoserine or phosphothreonine residues. Can dephosphorylate glucokinase (in vitro). Has phosphatase activity with the synthetic substrate 6,8-difluoro-4-methylumbelliferyl phosphate and other in vitro substrates.
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. May play a role in the metabolism of endogenous lipids such as epoxide-containing fatty acids. Metabolizes the abundant endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid (AA) and glycerol (By similarity).
Inhibited by 10-hydroxystearamide and methoxy-arachidonyl fluorophosphate.
Interacts with RHOA, GNA13 and SLC1A6. Interacts with GNA12, PLXNB1 and PLXNB2 (By similarity). Interacts (via DH domain) with GCSAM (via C-terminus) (By similarity).
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 (By similarity).
Phosphorylated by MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14).
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.
Belongs to the methylmalonyl-CoA epimerase family.
This promotes the activity of RNA polymerase II.
Phosphorylation on Thr-318 and Thr-319 may be crucial for rapid desensitization. Phosphorylation on Thr-318 may be necessary for phosphorylation on Thr-319 to occur.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase (PubMed:1323836). May play a role during reproduction (PubMed:1647979).
Testis, particularly in spermatocytes and spermatids but not in spermatogonia. Low levels in the brain.
May play a role in vesicle-mediated protein trafficking from the Golgi stack through the trans-Golgi network.
Ubiquitous; expression was highest in testis and in brain. Detected in every part of the brain.
Homotetramer. Component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3. Interacts with TRMT10C/MRPP1; forming the MRPP1-MRPP2 subcomplex of the mitochondrial ribonuclease P complex.
In addition to mitochondrial dehydrogenase activity, moonlights as a component of mitochondrial ribonuclease P, a complex that cleaves tRNA molecules in their 5'-ends. Together with TRMT10C/MRPP1, forms a subcomplex of the mitochondrial ribonuclease P, named MRPP1-MRPP2 subcomplex, which displays functions that are independent of the ribonuclease P activity. The MRPP1-MRPP2 subcomplex catalyzes the formation of N(1)-methylguanine and N(1)-methyladenine at position 9 (m1G9 and m1A9, respectively) in tRNAs; HSD17B10/MRPP2 acting as a non-catalytic subunit. 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. Associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly.
Mitochondrial dehydrogenase involved in pathways of fatty acid, branched-chain amino acid and steroid metabolism. Acts as (S)-3-hydroxyacyl-CoA dehydrogenase in mitochondrial fatty acid beta-oxidation, a major degradation pathway of fatty acids. Catalyzes the third step in the beta-oxidation cycle, namely the reversible conversion of (S)-3-hydroxyacyl-CoA to 3-ketoacyl-CoA. Preferentially accepts straight medium- and short-chain acyl-CoA substrates with highest efficiency for (3S)-hydroxybutanoyl-CoA. Acts as 3-hydroxy-2-methylbutyryl-CoA dehydrogenase in branched-chain amino acid catabolic pathway. Catalyzes the oxidation of 3-hydroxy-2-methylbutanoyl-CoA into 2-methyl-3-oxobutanoyl-CoA, a step in isoleucine degradation pathway. Has hydroxysteroid dehydrogenase activity toward steroid hormones and bile acids. Catalyzes the oxidation of 3alpha-, 17beta-, 20beta- and 21-hydroxysteroids and 7alpha- and 7beta-hydroxy bile acids. Oxidizes allopregnanolone/brexanolone at the 3alpha-hydroxyl group, which is known to be critical for the activation of gamma-aminobutyric acid receptors (GABAARs) chloride channel. Has phospholipase C-like activity toward cardiolipin and its oxidized species. Likely oxidizes the 2'-hydroxyl in the head group of cardiolipin to form a ketone intermediate that undergoes nucleophilic attack by water and fragments into diacylglycerol, dihydroxyacetone and orthophosphate. Has higher affinity for cardiolipin with oxidized fatty acids and may degrade these species during the oxidative stress response to protect cells from apoptosis. By interacting with intracellular amyloid-beta, it may contribute to the neuronal dysfunction associated with Alzheimer disease (AD). Essential for structural and functional integrity of mitochondria.
Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif that mediates interaction with nuclear receptors.
Expressed in the foot process layer of podocytes in the kidney glomerulus but not in tubules (at protein level).
F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. 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. 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. May also function as a transcriptional coactivator, stimulating transcription mediated by the nuclear hormone receptors PPARG and RARA.
Homodimer; antiparallel. Interacts with MAGI1 (By similarity). Interacts with MICALL2 (preferentially in opened conformation); stimulated by RAB13 activation (By similarity). Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs (By similarity). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (By similarity). Binds TRIM3 at the N-terminus (By similarity). Interacts with PDLIM2 (PubMed:15505042). Identified in a complex with CASK, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (PubMed:15994232). Interacts with PPARG and RARA (By similarity). Binds to VCL; this interaction triggers VCL conformational changes (By similarity). Interacts with SEPTIN14 (By similarity).
May be part of an oligomeric complex which is likely to have a transport or channel function in the erythrocyte membrane.
Homodimer, and heterodimer of GMEB1 and GMEB2. Interacts with the glucocorticoid receptor (NR3C1). May interact with CREB-binding protein (CBP) (By similarity).
Binds STRN, STRN3 and STRN4. Part of a ternary complex containing MOB4/PHOCN, STRN and/or STRN3 and PPA2. Interacts with DNM1 and EPS15. Interacts with nucleoside diphosphate kinase. Interacts with CTTNBP2. Interacts with CTTNBP2NL (By similarity).
Highly expressed in adrenal gland, spinal cord, brain and cerebellum. Detected at lower levels in heart and skeletal muscle, and at very low levels in spleen, liver and intestine.
May play a role in membrane trafficking, specifically in membrane budding reactions.
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 (By similarity). Interacts with CALU.
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.
Activity stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2).
Homodimer. Interacts with SRC and CRK. Interacts with RAB11FIP3. Interacts with PTK2B/PYK2. Interacts with CTTN. Interacts (via SH3 domain) with APC (By similarity). Interacts with REPS2; the interaction is direct (By similarity).
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. Plays a role in ciliogenesis (By similarity).
The PH domain most probably contributes to the phosphoinositide-dependent regulation of ADP ribosylation factors.
Homodimer. Heterodimer with ARL6IP1 (By similarity). Forms multimers (PubMed:11242046). Interacts with ARL6 (By similarity). Interacts with prenylated RAB1A and RAB3A (PubMed:11096102). Interacts with SLC1A1/EAAC1 (PubMed:11242046). Interacts with RTN2 (via first transmembrane domain) (PubMed:19720795). Does not interact with VAMP1, VAMP2 or VAMP3 (PubMed:11096102).
Regulates intracellular concentrations of taurine and glutamate (Ref.5). Negatively modulates SLC1A1/EAAC1 glutamate transport activity by decreasing its affinity for glutamate in a PKC activity-dependent manner (PubMed:11242046). Plays a role in the retention of SLC1A1/EAAC1 in the endoplasmic reticulum (PubMed:19720795).
Ubiquitous (PubMed:11096102). Most abundant in heart and brain (PubMed:11096102). In the embryonic brain cortex, expressed in neurons and astrocytes (PubMed:19720795).
Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-196 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-196 results in a 10-20-fold increase in total activity to generate Ca(2+)/calmodulin-independent activity. Autophosphorylation of the N-terminus Ser-11 and Ser-12 is required for full activation. Inactivated by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-196, thereby terminating autonomous activity and helping to maintain the enzyme in its autoinhibited state (By similarity).
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 (By similarity).
Glycosylation at Ser-185 modulates the phosphorylation of CaMK4 at Thr-196 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.
Heat-stable, acidic, calmodulin-binding protein.
Isoform 1 is expressed in brain and isoform 2 is testis specific.
Monomer. 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-196. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-11 and Ser-12 (By similarity).
The N-terminus of calspermin is blocked.
Belongs to the complex I subunit 4L 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.
Interacts with PSEN1 and PSEN2. Binds OPA1 (By similarity).
P-beta is proteolytically processed (beta-cleavage) in a PARL-dependent manner.
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). Promotes changes in mitochondria morphology regulated by phosphorylation of P-beta domain (By similarity). Required for processing of CLPB into a form with higher protein disaggregase activity by removing an autoinhibitory N-terminal peptide.
Tetrahedron-shaped homododecamer built from six homodimers.
Expressed in forebrain, hippocampus, midbrain, cerebellum, and testis. Expressed in forebrain, hippocampus, midbrain, and cerebellum (at protein level). In the cortex expressed more in laminae II and III than in laminae IV-VI. Expressed within the pyramidal layer of the hippocampus and granular layer of the dentate gyrus as well as in the olfactory bulb. Diffusely expressed within the caudate-putamen and globus pallidus. Diffusely expressed throughout regions of the midbrain. In cerebellum, expressed within the Purkinje and granular layer. Stronger expressed in the cerebellum. Highly expressed in frontal cortex, hippocampus, olfactory bulb, caudate-putamen and cerebellum exhibit (at protein level).
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:9724800, PubMed:17942605). Traps Ca(2+)/calmodulin on CAMK2 (PubMed:17942605).
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 (By similarity).
Leucettine L41 inhibits its kinase activity and affects the regulation of alternative splicing mediated by phosphorylation of SR proteins.
Palmitoylated; which is required for presynaptic clustering.
Phosphorylated; which does not affect kinetic parameters or subcellular location.
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).
Heterotetramer of two type I and two type II keratins (By similarity). Forms a heterodimer with KRT14 (By similarity). Interacts with NOD2 (By similarity).
Interacts through its C-terminal region with the PDZ domain-containing proteins GRIP1, GRIP2 and PICK1. Interacts with PDZ domains 4 and 5 of GRIP1 and with the PDZ domain of PICK1 (By similarity).
Receptor for prolactin-releasing peptide (PrRP). Implicated in lactation, regulation of food intake and pain-signal processing.
Widely expressed, with highest levels in pituitary, cerebellum, and hypothalamus.
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.
Forms a signaling complex with RASGRP1 and DGKZ (By similarity). In its GTP-bound form interacts with PLCE1 (PubMed:11179219). Interacts with TBC1D10C (By similarity). Interacts with RGL3 and RASSF5 (By similarity). Interacts with HSPD1 (By similarity). Interacts with PDE6D (By similarity). Interacts with IKZF3 (By similarity). Interacts with RACK1 (By similarity). Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14 (PubMed:19319189). Interacts (active GTP-bound form) with RGS14 (via RBD 1 domain) (PubMed:19319189, PubMed:19878719). 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 (By similarity). Interacts (in GTP-bound form) with Oog1 (By similarity).
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.
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).
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).
In contrast to human counterpart, it lacks a signal sequence.
Acts as an adapter protein downstream of several growth factor receptors to promote cell proliferation, migration, and redistribution of actin fibers (By similarity). Specifically involved in INS/insulin signaling pathway by mediating MAPK1/ERK2-MAPK3/ERK1 activation and DNA synthesis (PubMed:24216110). Promotes insulin-mediated membrane ruffling (PubMed:24216110). In response to vasoconstrictor peptide EDN1, involved in the activation of RAP1 downstream of PTK2B via interaction with phosphorylated BCAR1 (By similarity). Inhibits cell migration and invasion via regulation of TGFB-mediated matrix digestion, actin filament rearrangement, and inhibition of invadopodia activity (By similarity). May inhibit TGFB/SMAD signaling, via facilitating BCAR1 and SMAD2 and/or SMAD3 interaction (By similarity). Regulates EGF-induced DNA synthesis (By similarity). Required for the maintenance of ocular lens morphology and structural integrity, potentially via regulation of focal adhesion complex signaling (By similarity). Acts upstream of PTPRA to regulate the localization of BCAR1 and PTPRA to focal adhesions, via regulation of SRC-mediated phosphorylation of PTPRA (By similarity). Positively regulates integrin-induced tyrosine phosphorylation of BCAR1 (By similarity). Acts as a guanine nucleotide exchange factor (GEF) for small GTPases RALA, RAP1A and RRAS (By similarity). However, in a contrasting study, lacks GEF activity towards RAP1 (By similarity).
Part of a complex comprised of PTPRA, BCAR1, BCAR3 and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (By similarity). Within the complex, interacts (via SH2 domain) with PTPRA (when phosphorylated on 'Tyr-792') (By similarity). Interacts (via Ras-GEF domain) with BCAR1 (PubMed:24216110). Interacts (via Ras-GEF domain) with NEDD9 (By similarity). Interacts with PTK2/FAK1 (By similarity). Interacts with PTPN1. Interacts (via SH2 domain) with EGFR (when tyrosine-phosphorylated) (By similarity).
The Ras-GEF domain appears to adopt a closed conformation rendering it incapable of carrying out canonical exchange factor function, this closed conformation is probably required for interaction with BCAR1.
The SH2 domain mediates interaction with tyrosine-phosphorylated proteins (By similarity). However, not involved in the binding to phosphorylated BCAR1 (By similarity). Required for cell cycle progression in response to INS/insulin (By similarity). Required for regulation of EGF-induced DNA synthesis (By similarity).
The guanine nucleotide exchange factor (GEF) activity is controversial. One study showed GEF activity towards RALA, RAP1A and RRAS (By similarity). However, in another study, a construct containing only the Ras-GEF domain lacks GEF activity towards RAP1 (By similarity).
Inhibits the transcriptional repressor activity of REST by inhibiting its binding to DNA, thereby derepressing transcription of REST target genes.
Interacts (via N- and C-termini) with REST (via zinc-finger DNA-binding domain); the interaction inhibits REST repressor activity.
Expression was highest in embryos and neonates, peaking at 4 days of age in both calvaria and long bones and decreasing steadily with age to very low levels in 8-month-old long bones. The age-related decrease was less marked in calvaria by 8 months.
Highly expressed in skeletal muscle (PubMed:15044443). Also expressed in leg tendons/ligaments and osteoblasts (PubMed:17951249). In long bones and teeth, present in knee joint and periodontal ligaments (at protein level) (PubMed:17951249).
Hormone that acts as a ligand for natriuretic peptide receptor NPR3/NPR-C and promotes bone growth and physical endurance in muscle. Acts as a regulator of osteoblast differentiation and bone growth by binding to natriuretic peptide receptor NPR3/NPR-C, thereby preventing binding between NPR3/NPR-C and natriuretic peptides, leading to increase cGMP production. Required to enhance physical endurance: induced following physical exercise in muscle and promotes cGMP production, probably by interacting with NPR3/NPR-C. May act as an autocrine and paracrine factor linked to glucose metabolism in skeletal muscle.
Is down-regulated by 1,25-dihydroxy vitamin D3.
Binds and promotes bundling of vimentin filaments originating from the Golgi.
Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool.
Homooctamer, including four polyglutamate binding sites. The subunits are arranged as a tetramer of dimers, and form a planar ring-shaped structure.
In the C-terminal section; belongs to the cyclodeaminase/cyclohydrolase family.
In the N-terminal section; belongs to the formiminotransferase family.
Specifically expressed in liver (at protein level).
Acetylation at Lys-374 dramatically reduces catalytic activity.
Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase (PubMed:10521434). Plays a critical role in the generation of NADPH, an important cofactor in many biosynthesis pathways (By similarity). May act as a corneal epithelial crystallin and may be involved in maintaining corneal epithelial transparency (By similarity).
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) (By similarity). Transports also an anionic cyclopentapeptide endothelin antagonist, BQ-123 (PubMed:10692506).
Deficient rats develop ectopic mineralization in the skin, eyes, and the arterial blood vessels. Plasma inorganic pyrophosphate (PPi) level is reduced by 70 % in deficient rats leading to a lowered PPi/Pi ratio.
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.
Predominantly expressed in the liver and to a lesser extent in kidney, small intestine, and colon.
Belongs to the peptidase M67A family. CSN5 subfamily.
Binds DNA as a homodimer or as a heterodimer with JUN or ATF2/CREBP1.
Binds to the cAMP response element and activates transcription.
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Tribbles subfamily.
Detected only in the lung. Not detected in the heart, brain, spleen, liver, skeletal muscle, kidney and testis.
Expression induced during programmed cell death evoked in neuronal cells by NGF-depletion.
Inactive protein kinase which acts as a regulator of the integrated stress response (ISR), a process for adaptation to various stress (By similarity). Inhibits the transcriptional activity of DDIT3/CHOP and is involved in DDIT3/CHOP-dependent cell death during ER stress. May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells (By similarity). 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 (PubMed:15469416). 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. Interacts with MAPK kinases and regulates activation of MAP kinases (By similarity). Can inhibit APOBEC3A editing of nuclear DNA (By similarity).
Interacts with AKT1, AKT2, MAP2K1 and MAP2K7. Interacts with ATF4 (By similarity). Interacts with DDIT3/CHOP and inhibits its interaction with EP300/P300. Interacts with APOBEC3C (By similarity). Interacts (via N-terminus) with APOBEC3A (By similarity). Interacts with RELA (By similarity).
The role of this protein in Akt activation has been demonstrated by Du et al for the mouse ortholog but PubMed:15469416 has not been able to reproduce the result in rat hepatocytes.
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).
Component of the large ribosomal subunit. Plays a role in the formation of actively translating ribosomes. May play a role in the embryonic brain development.
Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate. Also able to mediate the exchange of citrate for isocitrate, phosphoenolpyruvate, cis-aconitate and to a lesser extend cis-aconitate, maleate and succinate (PubMed:2804096). 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 (By similarity).
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.
Interacts with either CDK4 or CDK6 protein kinase to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex.
Phosphorylation at Thr-279 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. 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. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals.
Ubiquitinated by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-279 phosphorylation. The DCX(AMBRA1) complex represents the major regulator of CCND2 stability during the G1/S transition (By similarity). Polyubiquitinated by the SCF(FBXL2) complex, leading to proteasomal degradation (By similarity).
Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN. As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites. Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN. Found in a complex with TERF2. Interacts with DCLRE1C/Artemis and DCLRE1B/Apollo. Interacts with ATF2. Interacts with EXD2. Interacts with MRNIP. Interacts with SAMHD1; leading to stimulate 3'-5' exonuclease activity. Interacts (when ubiquitinated) with UBQLN4 (via its UBA domain) (By similarity). 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. The complex may also be required for DNA damage signaling via activation of the ATM kinase. In telomeres the MRN complex may modulate t-loop formation.
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.
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.
Belongs to the universal ribosomal protein uL5 family.
Component of the large ribosomal subunit (LSU). Part of a LSU subcomplex, the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11. Interacts with PML. Interacts with MDM2; negatively regulates MDM2-mediated TP53 ubiquitination and degradation. Interacts with NOP53; retains RPL11 into the nucleolus.
Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs. It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53. Promotes nucleolar location of PML.
Arg-131 was found to be 44% monomethylated and 11% symmetrically dimethylated.
As in other animals, several charge isomers may be produced as a result of optional post-translational modifications, such as phosphorylation of serine or threonine residues, deamidation of glutamine or asparagine residues, citrullination and methylation of arginine residues.
Belongs to the myelin basic protein family.
Found in both the central and the peripheral nervous system.
Is, with PLP, the most abundant protein component of the myelin membrane in the CNS. Has a role in both the formation and stabilization of this compact multilayer arrangement of bilayers. Each splice variant and charge isomer may have a specialized function in the assembly of an optimized, biochemically functional myelin membrane (By similarity).
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.
Binds KMT2A/MLL1. Component of the MLL1/MLL complex, at least composed of KMT2A/MLL1, ASH2L, RBBP5, DPY30, WDR5, MEN1, HCFC1 and HCFC2 (By similarity). Interacts with TASOR (By similarity).
Can degrade fibrillar type I, II, and III collagens.
Cannot be activated without removal of the activation peptide.
Interacts with CD4. Interacts with ALDH16A1.
May play a role as a negative regulatory factor in CD4-dependent T-cell activation.
Endoribonuclease that cleaves tRNAs and rRNAs (PubMed:29563550). Cleaves tRNAs 11 nucleotides from the 3'-terminus at the acceptor stem (PubMed:29563550). Does not act on tRNA(Sec) (PubMed:29563550).
Shows a pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N'-domain that may clamp base-paired RNAs.
Expressed in oligodendrocytes and at lower levels in astrocytes.
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). Acts together with ZNF445. 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.
Zinc fingers 2 and 3 mediate recognition of the target element, ZF2 interacting with the 5' half (TGC) and ZF3 interacting with the 3' half (CGC).
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. 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. Participates as well in T-cell receptor-mediated NF-kappa-B activation. In the presence of TNF, modulates the IKK complex by regulating IKBKG/NEMO ubiquitination leading to the repression of NF-kappa-B.
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. Interacts with IKBKG/NEMO.
The C-terminal 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.
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. Decrotonylated by HDAC3.
Homodimer. Heterodimer with MAPRE3. Interacts with DCTN1, DCTN2, TERF1 and dynein intermediate chain (By similarity). 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. Interacts with MTUS2; interaction is direct and probably targets MTUS2 to microtubules. Interacts with APC2. Interacts with CLASP1. Interacts with CDK5RAP2 (By similarity). According to another report, MAPRE1 does not interact with CDK5RAP2 (PubMed:19553473). Interacts with MACF1 (By similarity). Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity). Interacts with KCNAB2 (PubMed:21357749). Interacts (via C-terminus) with CLIP1. Interacts with SLAIN2 and SLAIN1. Interacts with KIF18B; this interaction is required for efficient accumulation of KIF18B at microtubule plus ends. Interacts with MISP. Interacts with KNSTRN. Interacts with NCKAP5L. Interacts with AKAP9. Interacts with PDE4DIP; this interaction, which is PDE4DIP isoform-specific, is required for its recruitment to the Golgi apparatus. Interacts with CAMSAP2 (By similarity). May form a pericentrosomal complex with AKAP9, CDK5RAP2 and PDE4DIP isoform 2/MMG8/SMYLE; within this complex, MAPRE1 binding to CDK5RAP2 may be mediated by PDE4DIP (By similarity). Contrary to other mammalian species, does not interact with CDK5RAP2, possibly due to the lack of conservation of the MAPRE1-binding motif in rat CDK5RAP2 (Probable). Interacts with AKNA (By similarity). Interacts with GAS2L1, GAS2L2, and GAS2L3 (By similarity). Interacts with RARRES1 and AGBL2 (By similarity).
Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes cytoplasmic microtubule nucleation and elongation. Involved in mitotic spindle positioning by stabilizing microtubules and promoting dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation. 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. Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules. Acts as a regulator of autophagosome transport via interaction with CAMSAP2 (By similarity). May play a role in cell migration (By similarity).
Activates Rho-GTPases by promoting the exchange of GDP for GTP. May be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. Binds Rac-GTPases, but does not seem to promote nucleotide exchange activity toward Rac-GTPases. May stimulate instead the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-GTPases. Forms an intracellular sensing system along with NOD1 for the detection of microbial effectors during cell invasion by pathogens. Involved in innate immune signaling transduction pathway promoting cytokine IL6/interleukin-6 and TNF-alpha secretion in macrophage upon stimulation by bacterial peptidoglycans; acts as a signaling intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Overexpression activates Rho-, but not Rac-GTPases, and increases paracellular permeability. Involved in neuronal progenitor cell division and differentiation. Involved in the migration of precerebellar neurons.
Found in a complex composed at least of ARHGEF2, NOD2 and RIPK2. Interacts with RIPK2; the interaction mediates tyrosine phosphorylation of RIPK2 by Src kinase CSK. Interacts with RIPK1 and RIPK3. Interacts with YWHAZ/14-3-3 zeta; when phosphorylated at Ser-885. Interacts with the kinases PAK4, AURKA and MAPK1. Interacts with RHOA and RAC1. Interacts with NOD1 (By similarity). Interacts (via the N- terminal zinc finger) with CAPN6 (via domain II). Interacts with DYNLT1 (By similarity).
Phosphorylation of Ser-885 by PAK1 induces binding to protein YWHAZ, promoting its relocation to microtubules and the inhibition of its activity. Phosphorylated by AURKA and CDK1 during mitosis, which negatively regulates its activity. Phosphorylation by MAPK1 or MAPK3 increases nucleotide exchange activity. Phosphorylation by PAK4 releases GEF-H1 from the microtubules. Phosphorylated on serine, threonine and tyrosine residues in a RIPK2-dependent manner (By similarity).
The DH (DBL-homology) domain promotes tyrosine phosphorylation of RIPK2 (By similarity). The DH (DBL-homology) domain interacts with and promotes loading of GTP on RhoA.
The PH domain has no affinity for phosphoinositides suggesting that it does not interact directly with membranes.
The phorbol-ester/DAG-type zinc-finger and the C-terminal coiled-coil domains (606-986) are both important for association with microtubules.
NADP-dependent 17-alpha-hydroxysteroid dehydrogenase that converts 5-alpha-androstane-3,17-dione into androsterone. Has lower 3-alpha-hydroxysteroid dehydrogenase activity. Has broad substrate specificity and acts on various 17-alpha-hydroxysteroids, 17-ketosteroids, 3-alpha hydroxysteroids and 3-ketosteroids. Reduction of keto groups is strictly stereoselective. Reduction of 17-ketosteroids yields only 17-alpha-hydroxysteroids. Likewise, reduction of 3-ketosteroids yields only 3-alpha-hydroxysteroids (By similarity).
Rat 3-beta-HSD type II may possess only one transmembrane domain.
Activity is stimulated by Mg(2+) or Mn(2+).
Enriched in alveolar type II cells of lung. Also highly expressed in stomach.
Exhibits acyltransferase activity (PubMed:16864775). 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:16864775). 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:16864775). 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 (PubMed:16864775). Involved in the regulation of lipid droplet number and size (By similarity).
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.
May play a role in anteroposterior axis elongation.
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. Is involved in intracellular targeting of D-type retrovirus gag polyproteins to the cytoplasmic assembly site. May also be a accessory component of axonemal dynein (By similarity).
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 dynein LCs assemble on the IC dimer. DYNLT1 and DYNLT3 compete for association with dynein IC (DYNC1I1 or DYNC1I2). Self-associates. Interacts with RHO. Interacts with DYNC1I1 and DYNC1I2 (By similarity). Interacts with DOC2A, DOC2B and SCN10A. Interacts with PVR. Interacts with SVIL isoform 2 (By similarity). 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. Interacts with ACVR2B and ARHGEF2 (By similarity). Interacts with DNAI4 (By similarity).
Phosphorylated by BMPR2. The phosphorylation status is proposed to regulate the association with the cytoplasmic dynein complex and may have role in cytoplasmic dynein cargo release.
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. Required for neurite outgrowth. 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. 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 (By similarity). Involved in the regulation of mitotic spindle orientation.
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 (By similarity).
Interacts with VRK2 (By similarity). Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1 and MAP3K1/MEKK1. 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.
Belongs to the constitutive coactivator of PPAR-gamma family.
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 (By similarity). 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.
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 (PubMed:18854160). Interacts with CDC42BPA and CDC42BPB (PubMed:25107909).
C1 is a calcium-dependent trimolecular complex of C1q, C1r and C1s in the molar ration of 1:2:2. C1r is a dimer of identical chains, each of which is activated by cleavage into two chains, A and B, connected by disulfide bonds.
C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
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. 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. 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.
Phosphorylated on Tyr residues after T-cell receptor triggering by LCK in association with CD4/CD8. Phosphorylated also by PKC; leading to the TCR complex down-regulation.
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.
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).
Has E3 ubiquitin-protein ligase activity. 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. Inhibits PPP1CA phosphatase activity (By similarity).
Interacts with FASLG and PPP1CA. Interacts with PAK4 and TNFRSF1A (By similarity). Interacts with DLK1, MAP3K10, MAPK8IP1/JIP1, MAPK8IP2/JIP2 and MAPK8IP3/JIP3. Interacts with RAC1 (both active GTP- or inactive GDP-bound forms) (PubMed:22128169).
G-protein coupled receptor for glucagon-like peptide 1 (GLP-1) (PubMed:1326760, PubMed:7813606). Ligand binding triggers activation of a signaling cascade that leads to the activation of adenylyl cyclase and increased intracellular cAMP levels (PubMed:1326760, PubMed:7813606). 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.
Pancreatic islets, stomach, lung, rat insulinoma cell line.
Belongs to the ribulose-phosphate 3-epimerase family.
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 (By similarity).
Interacts (via N-terminus) with UNC13A. Interacts with cytoplasmic dynein light chain DYNLT1. Interacts with UNC13D (By similarity).
Predominantly expressed in brain. Also found in non-neural tissues. Expressed in RBL-2H3 mast cell line.
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 (By similarity).
Activated by phosphorylation at Ser-56. Mutagenesis of Ser-56 abolishes activation.
Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium and/or manganese ions.
Expressed in brain, heart, lung and liver.
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
In Sertoli cells, induced by FSH. In the pineal gland, exhibits night/day variations with a 7-fold increased expression at night. Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway.
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. 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. In turn, promotes LCK phosphorylation and subsequent activation. 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.
Interacts with CD2 (PubMed:16803907). Interacts with CD244 (PubMed:16803907). Interacts with LCK (By similarity).
Belongs to the glycosyltransferase 3 family.
Transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.
Disulfide bond formation is redox-sensitive. The cysteine residues are readily oxidized by several nitric acid (NO) donors and other oxidants to form intramolecular disulfide. Cys-51 can form a disulfide with any other of the cysteine residues with an order of reactivity Cys-9 > Cys-4 > Cys-3.
Highly enriched in brain with restricted expression in neuronal subsets primarily in the cortex, striatum, and hippocampus as well as certain nuclei within the thalamus, hypothalamus and olfactory bulb. Accumulates postsynaptically in dendritic spines of neostriatal neurons.
Interacts with apo-calmodulin; this interaction decreases the affinity of calmodulin for calcium ions.
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 (By similarity).
Phosphorylation is activated by calcium, phospholipids, and diacylglycerol. Phosphorylation inhibits binding to calmodulin both in the presence and absence of calcium.
Regulates the affinity of calmodulin for calcium. Involved in synaptic plasticity and spatial learning (By similarity).
In contrast to the human ortholog, does not seem to interact with FYN.
Interacts with SLC9A3R1/EBP50. In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which is disrupted upon TCR activation (By similarity). When phosphorylated, interacts with CSK. Identified in a complex with LYN and STAT3 (By similarity). Interacts with LYN.
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-314 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 in response to EPO.
Ubiquitously expressed, with highest levels in developing brain, lung, thymus, spleen and testis. Present in mast cells.
Cerebellum, hippocampus and cerebral cortex.
Homooligomer or heterooligomer (probably pentamer) with neuronal pentraxin receptor (NPTXR).
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.
Isoform 2 is expressed only in testis, in the late spermatocytes and early spematids (at protein level).
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 sliver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with PPP1R3B, PPP1R7 and CDCA2. Isoform 2 interacts with SPZ1. Interacts with IKFZ1; the interaction targets PPP1CC to pericentromeric heterochromatin, dephosphorylates IKAROS, stabilizes it and prevents it from degradation. 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 (By similarity). Interacts with NEK2. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth factor-dependent manner (By similarity). Interacts with FOXP3 (By similarity). Interacts with TMEM225 (via RVxF motif) (By similarity). Interacts with MKI67 (By similarity). Interacts with RRP1B; this targets PPP1CC to the nucleolus (By similarity). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (By similarity) (PubMed:10504266, PubMed:10585469, PubMed:7720853, PubMed:9841883). Interacts with DYNLT4 (By similarity).
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.
Activated by potassium ions, but not sodium ions.
Succinylation at Lys-265, 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. 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. The activity of the enzyme is reversible and it can also catalyze the condensation of two acetyl-CoA molecules into acetoacetyl-CoA. Thereby, it plays a major role in ketone body metabolism.
Interacts with mitochondrial RNA polymerase POLRMT. Interacts with TFAM (By similarity).
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 (By similarity).
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.
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.
Interacts with MFAP4. 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.
Proteolytically cleaved by BMP1 which removes the propeptide (By similarity). Also proteolytically cleaved by ADAMTS2 and ADAMTS14, but not by ADAMTS3, at an additional cleavage site downstream of the BMP1 cleavage site (By similarity). 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 (By similarity). Cleavage by ADAMTS2 produces a form with reduced collagen-binding activity (By similarity).
Responsible for the post-translational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin (PubMed:16432278). Regulator of Ras expression. May play a role in tumor suppression. Plays a role in the aortic wall architecture (By similarity).
Sulfated at Tyr-181 and also at either Tyr-177 or Tyr-178 which enhances binding to collagen.
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.
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:10875938). 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 (By similarity). 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).
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 (By similarity).
Acetylation at Lys-458 lowers transcriptional activation by about two-fold.
DNA-binding activity of phosphorylated protein is reduced by fasting and by inducers of intracellular cyclic AMP.
Homodimerization is required for HNF4-alpha to bind to its recognition site (PubMed:12193589). Interacts with CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2 (By similarity). Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionnally inactive (By similarity). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (By similarity).
Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA (By similarity). Phosphorylated in the recognition sequence R-R-S-S near the DNA-binding domain; phosphorylation results in decrease in DNA-binding activity. Phosphorylation of HNF4 depends on the diet and is decreased by a carbohydrate-rich diet and is increased by fasting.
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 (By similarity). 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 (By similarity).
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. Interacts (via N-terminus) with KARS1. Interacts with EPRS1. Forms a linear complex that contains MARS1, EEF1E1, EPRS1 and AIMP2 that is at the core of the multisubunit complex. Binds FUBP1 (via C-terminus). Interacts in both its unphosphorylated and phosphorylated forms with p53/TP53 (via N-terminus) in the nucleus following UV irradiation. Interacts (via N-terminus) with PRKN/parkin (via first RING-type domain). Interacts with TARS3.
Phosphorylated on serine residues in response to UV irradiation.
Required for assembly and stability of the aminoacyl-tRNA synthase complex. Mediates ubiquitination and degradation of FUBP1, a transcriptional activator of MYC, leading to MYC down-regulation which is required for aveolar type II cell differentiation. Blocks MDM2-mediated ubiquitination and degradation of p53/TP53. Functions as a proapoptotic factor.
Ubiquitinated by PRKN, leading to its degradation by the proteasome.
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. 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 (By similarity).
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.
Belongs to the concentrative nucleoside transporter (CNT) (TC 2.A.41) family.
Expressed predominantly in the brush-border membranes of the polarized epithelial cells of jejunum and renal cortical tubules and in the bile canalicular membranes of liver parenchymal cells.
Sodium-dependent and pyrimidine-selective transporter (PubMed:8027026). Exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit) (selective for pyrimidine nucleosides and adenosine) (PubMed:8027026). Transports uridine, cytidine, thymidine, and nucleoside-derived drugs (By similarity).
Component of the mitochondrial ribosome large subunit (39S) which comprises a 16S rRNA and about 50 distinct proteins. Interacts with MALSU1.
May form part of 2 intersubunit bridges in the assembled ribosome. Upon binding to MALSU1, intersubunit bridge formation is blocked, preventing ribosome formation and repressing translation.
It is unlikely that this protein binds calcium as none of the 2 EF-hand domains seem to contain a canonical calcium-binding site.
Although it belongs to the glycosyl hydrolase 22 family, Gly-72 is present instead of the conserved Asp which is an active site residue. It is therefore expected that this protein lacks hydrolase activity.
Expressed in the brain, lung, ovary, uterus and testis (PubMed:22110709). In testis expressed in the germinal epithelium and on the maturing spermatozoa (at protein level) (PubMed:22110709).
May be involved in fertilization (By similarity). Has no detectable bacteriolytic and lysozyme activities in vitro (PubMed:22110709).
Present during stages of postnatal development from 10 to 60 days old (PubMed:22110709).
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.
Appears just before birth, reaches maximum levels after birth, then declines slightly until adulthood.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC2 subfamily.
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(+). Activation by an extracellular pH drop is followed by a rapid pH-independent inactivation. Heteromeric channel assembly seems to modulate channel properties.
Expressed in sciatic nerve and dorsal root ganglion (DRG) (at protein level). Both isoforms display the same expression pattern except in DRG where isoform 2 is more abundantly expressed. Widely distributed throughout the brain. Highly expressed in the main olfactory bulb, neo- and allo-cortical regions, hippocampal formation, habenula, basolateral amygdaloid nuclei, and cerebellum. In the olfactory system, expressed in the glomerular cell layer, the internal granular layer, and the mitral and internal plexiform cell layers. Within the glomerular layer, restricted to the periglomerular cells. In the neocortex, strongly expressed in the large pyramidal neurons in all cortical layers as well as in the oligo-, astro-, or micro-glia cells. In the hippocampal formation, expressed in dentate granule cells and hilar neurons, as well as in pyramidal cells of CA1-CA3 subfields. Expressed in stratum oriens and radiatum of all subfields. Within the thalamus, expressed moderately in the medial and lateral habenula. In the cerebellar cortex expressed in Purkinje cells and granule cells. Expressed at low levels in choroid plexus.
Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with PRKCABP (By similarity). Interacts with STOM; this regulates channel activity. Interacts with ASIC1. Isoform 2 interacts with ASIC3. Heterotrimer of Asic1a-Asic2a interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383). Heterotrimer of Asic1a-Asic2b interacts with the snake venom mambalgin-1 and mambalgin-2 (PubMed:23034652).
Regulated by Zn(2+). Inhibited by anti-inflammatory drugs like salicylic acid.
Seems to be inactive as monomer or in a monomeric assembly and is not activated by mutagenesis of Gly-430. Mutagenesis of Ser-60 into Gly reduces activation by PKC through PRKCABP/PICK-1 of a ASIC3/ACCN3-ASIC2/ASIC2b channel.
Up-regulation upon tissues inflammation is abolished by anti-inflammatory drugs.
Belongs to the bombesin/neuromedin-B/ranatensin family.
Belongs to the phosphatidylserine decarboxylase family. PSD-B subfamily. Eukaryotic type I sub-subfamily.
Catalyzes the formation of phosphatidylethanolamine (PtdEtn) from phosphatidylserine (PtdSer). Plays a central role in phospholipid metabolism and in the interorganelle trafficking of phosphatidylserine.
Heterodimer of a large membrane-associated beta subunit and a small pyruvoyl-containing alpha subunit.
Is synthesized initially as an inactive proenzyme. Formation of the active enzyme involves a self-maturation process in which the active site pyruvoyl group is generated from an internal serine residue via an autocatalytic post-translational modification. Two non-identical subunits are generated from the proenzyme in this reaction, and the pyruvate is formed at the N-terminus of the alpha chain, which is derived from the carboxyl end of the proenzyme. The autoendoproteolytic cleavage occurs by a canonical serine protease mechanism, in which the side chain hydroxyl group of the serine supplies its oxygen atom to form the C-terminus of the beta chain, while the remainder of the serine residue undergoes an oxidative deamination to produce ammonia and the pyruvoyl prosthetic group on the alpha chain. During this reaction, the Ser that is part of the protease active site of the proenzyme becomes the pyruvoyl prosthetic group, which constitutes an essential element of the active site of the mature decarboxylase.
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).
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 (By similarity).
Abundantly expressed in various tissues including lung, stomach, intestine, spleen, mesentery, heart, and, most prominently, aorta.
Receptor for extracellular UTP > ADP = 2-methylthio-ATP > ADP-beta-S > ATP = ATP-gamma-S. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Functionally coupled to phospholipase C.
The H2 subclass of histamine receptors mediates gastric acid secretion. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
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. Interacts with CUL3; indicative for the participation in an E3 ubiquitin ligase complex (By similarity).
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. 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. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth-dependent manner.
Belongs to the complex I LYR family. SDHAF1 subfamily.
Interacts with SDHB within an SDHA-SDHB subcomplex. Also interacts with the iron-sulfur transfer complex formed by HSC20, HSPA9 and ISCU through direct binding to HSC20. Binding of SDHAF1 to SDHB precedes and is necessary for recruitment of the iron-sulfur transfer complex by SDHAF1.
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 SDHAF3. 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.
Adapter protein required for Golgi and endoplasmic reticulum biogenesis. Involved in Golgi and endoplasmic reticulum maintenance during interphase and in their reassembly at the end of mitosis. The complex formed with VCP has membrane fusion activity; membrane fusion activity requires USO1-GOLGA2 tethering and BET1L. VCPIP1 is also required, but not its deubiquitinating activity. Together with NSFL1C/p47, regulates the centrosomal levels of kinase AURKA/Aurora A during mitotic progression by promoting AURKA removal from centrosomes in prophase. Also, regulates spindle orientation during mitosis.
Interacts with VCP. Does not bind ubiquitin.
Present at high level in brain. Also present in liver, kidney, spleen, testis, lung and heart (at protein level).
Expressed in testis and more specifically in ODF, the sperm tail specific cytoskeletal structure. Also expressed in epididymides and brain.
Required for normal spermatogenesis. 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. May also be involved in the general organization of cellular cytoskeleton.
Belongs to the SLAIN motif-containing family.
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 (By similarity).
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. Also acts as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in SCO1 during maturation of MT-CO2/COX2.
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).
Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Forms heterodimers with POT1. Identified in a complex with POT1 and single-stranded telomeric DNA. Interacts with STN1 and TINF2.
Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends. Without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Promotes binding of POT1 to single-stranded telomeric DNA. Modulates the inhibitory effects of POT1 on telomere elongation. The ACD-POT1 heterodimer enhances telomere elongation by recruiting telomerase to telomeres and increasing its processivity. May play a role in organogenesis.
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.
Interacts with EIF4E; this interaction prevents EIF4E from binding to p53/TP53 mRNA and inhibits the assembly of translation initiation complex.
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:27289039). Plays a major role in pre-mRNA alternative splicing regulation (By similarity). Mediates preferentially muscle-specific exon inclusion in numerous mRNAs important for striated cardiac and skeletal muscle cell differentiation (By similarity). 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 (By similarity). Plays a role in the regulation of mRNA stability (By similarity). Binds to 3'-untranslated region (UTR) AU-rich elements in target transcripts, such as CDKN1A and MYOG, leading to maintain their stabilities (By similarity). Involved in myogenic differentiation by regulating MYOG levels (By similarity). Binds to multiple regions in the mRNA 3'-UTR of TP63 isoform 2, hence inducing its destabilization (By similarity). Promotes also the destabilization of the CHRM2 mRNA via its binding to a region in the coding sequence (By similarity). Plays a role in the regulation of mRNA translation (By similarity). 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 (By similarity). Binds to a huge amount of mRNAs (By similarity). 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 (PubMed:27289039).
The RRM domain is necessary for mRNA stability and mRNA translation regulation.
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 (By similarity).
Found in a complex with XPO6, Ran, ACTB and PFN1 (By similarity). Interacts with VASP (By similarity). Interacts with HTT (By similarity). Interacts with SH3BGRL (By similarity). Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio (By similarity).
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.
Belongs to the galactose-1-phosphate uridylyltransferase type 1 family.
Plays an important role in galactose metabolism.
Binds DNA as a dimer (PubMed:8491173). Heterotetramer with PCBD1; formed by a dimer of dimers (By similarity). Interacts with PCBD1 (By similarity). Interacts with BHLHE41 (By similarity).
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' (By similarity). Activates the transcription of CYP1A2, CYP2E1 and CYP3A11 (By similarity).
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.
Interacts with SYNM (By similarity). Interacts with the syntrophins SNTG1 and SNTG2. Interacts with KRT19. 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 (By similarity). Interacts with SYNM; SNTA1 and SNTB1. Interacts with CMYA5. Directly interacts with ANK2 and ANK3; these interactions do not interfere with betaDAG1-binding and are necessary for proper localization in muscle cells. Identified in a dystroglycan complex that contains at least PRX, DRP2, UTRN, DMD and DAG1 (By similarity). Interacts with DTNB (PubMed:10545507). Interacts with PGM5; the interaction is direct (By similarity).
Strongly expressed in skeletal muscle and weak expression observed in newborn brain which increases in adult brain.
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. Interacts with CEBPA (when phosphorylated). Interacts with FNIP1 and FNIP2.
Expressed in fetal and adult lung. Also expressed in brain, heart, liver, skeletal muscle and testes.
In developing lung, high expression at day 17 after which levels decline to barely detectable levels at birth. Levels then increase postnatally until postnatal day 6 and decline in adulthood. Preferentially expressed in proliferating cells.
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 (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 (By similarity).
Interacts with clathrin adapter AP1 complex. This interaction takes place at Golgi membranes and not AP1-positive endosomal membranes. Interacts (when ubiquitinated at Lys-469) with EPS15 (By similarity).
The membrane-associated form is phosphorylated on tyrosine residues.
Ubiquitinated via 'Lys-33'-linked ubiquitin chains by the BCR(KLHL20) E3 ubiquitin ligase complex: 'Lys-33'-linked ubiquitination promotes interaction with EPS15 and facilitates actin polymerization at the trans-Golgi network, thereby facilitating post-Golgi trafficking. Deubiquitinated by ZRANB1/TRABID (By similarity).
G proteins are composed of 3 units, alpha, beta and gamma. In this context, interacts with GNAI2 and GNG2 (By similarity). Interacts with ARHGEF18 and RASD2. Interacts with ATXN10. Interacts with SCN8A.
Binds mitochondrial DNA and plays a role in the regulation of transcription of mitochondrial mRNA and rRNA species.
Interacts with GDI1; this promotes dissociation from membranes; phosphorylation at Ser-84 disrupts this interaction (By similarity). Interacts with GDI2; phosphorylation at Ser-84 disrupts the interaction (By similarity). Interacts with EEA1. Interacts with RIN1 and GAPVD1, which regulate its pathway, probably by acting as a GEF. Interacts with ALS2CL, SUN2, ZFYVE20 and RUFY1. Interacts with RABEP1; one RABEP1 homodimer binds two RAB5A chains, but at opposite sides of the dimer. Interacts with SGSM1, SGSM3 and PIK3CB. Interacts with RINL. May be a component of a complex composed of RAB5A, DYN2 and PIK3C3. Does not interact with the BLOC-3 complex (heterodimer of HPS1 and HPS4). Interacts with CLN5. 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. Contributes to the regulation of filopodia extension. Required for the exosomal release of SDCBP, CD63, PDCD6IP and syndecan. Regulates maturation of apoptotic cell-containing phagosomes, probably downstream of DYN2 and PIK3C3.
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 (By similarity).
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.
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.
Methylation at Arg-192 by PRMT5 impedes Ser-187 phosphorylation and increases interaction with PCNA.
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. 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 PCNA; can bind simultaneously to both PCNA and EP300. Interacts with DDX11; this interaction is direct and increases flap endonuclease activity of FEN1. Interacts with WDR4; regulating its endonuclease activity.
Binds to DNA at the acute-phase response element of the angiotensinogen gene and related nuclear factor kappa-B binding sites through a zinc-finger motif.
Expressed in brain, spleen, kidney, muscle and to a lower extent in liver.
Belongs to the eukaryotic ribosomal protein eL27 family.
Component of the large ribosomal subunit (By similarity). Interacts with RRP1B (By similarity). Component of the large ribosomal subunit. Interacts with RRP1B. Interacts with DHX33 (By similarity).
Component of the large ribosomal subunit (By similarity). Required for proper rRNA processing and maturation of 28S and 5.8S rRNAs (By similarity).
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 (By similarity).
May act as co-chaperone for HSP90 (Potential). Prevents the stimulation of HSP90AB1 ATPase activity by AHSA1. Positive factor in promoting PGR function in the cell (By similarity). 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).
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:28833202). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:28833202). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (By similarity). 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 (By similarity). In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP (By similarity). 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:28833202). Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (By similarity). 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 (By similarity). 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 (By similarity).
Hexamer; forms a trimer of dimers (By similarity). Heterohexamer; oligomerizes with other LRRC8 proteins (LRRC8B, LRRC8C, LRRC8D and/or LRRC8E) to form a heterohexamer (By similarity). Can form homohexamers in vitro, but these have lower conductance than heterohexamers (By similarity). Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E (By similarity). In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist (PubMed:28833202). 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 di-leucine motif is required for lysosomal localization.
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.
Heterodimer of 2 subunits, IMMPL1 and IMMPL2.
Phosphorylated. Phosphorylation by G-protein coupled receptor kinases (GRK) is more efficient than phosphorylation by CK1, CK2 and CaM-kinase II.
Inhibited by 1,2,3-triazole urea covalent inhibitors KT172, DH376 and DO34 (By similarity). Inhibited by p-hydroxy-mercuri-benzoate and HgCl(2), but not to PMSF. Also inhibited by RHC80267. Diacylglycerol lipase activity is inhibited by the phosphorylation of Ser-784 and Ser-810 by CAMK2A (By similarity).
Interacts (via C-terminal) with CAMK2A; leading to the phosphorylation and inhibition of DAGLA enzymatic activity. Interacts (via PPXXF motif) with HOMER1 and HOMER2; this interaction is required for DAGLA membrane localization.
Phosphorylated at Ser-784 and Ser-810 by CAMK2A; phosphorylation by CAMK2A inhibits diacylglycerol lipase activity.
Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG). Preferentially hydrolyzes sn-1 fatty acids from diacylglycerols (DAG) that contain arachidonic acid (AA) esterified at the sn-2 position to biosynthesize 2-AG. Has negligible activity against other lipids including monoacylglycerols and phospholipids. Plays a key role in regulating 2-AG signaling in the CNS. Controls the activity of 2-AG as a retrograde messenger at neuronal synapses. Supports axonal growth during development and adult neurogenesis. Plays a role for eCB signaling in the physiological regulation of anxiety and depressive behaviors. Regulates also neuroinflammatory responses in the brain, in particular, LPS-induced microglial activation.
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 (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.
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.
Probable component of the PAM complex at least composed of a mitochondrial HSP70 protein, GRPEL1 or GRPEL2, TIMM44, TIMM16/PAM16 and TIMM14/DNAJC19. Binds to HSP70, HSC70 and HSJ1B (By similarity).
Ubiquitous. Particularly abundant in heart, kidney and liver.
Expressed in spleen by a variety of myeloid cells including macrophages and dendritic cells (at protein level). Ubiquitously expressed with higher expression in lymphoid tissues.
Overexpression of Tmem176b alters maturation of bone marrow-derived dendritic cells.
Required for the development of cerebellar granule cells (By similarity). May play a role in the process of maturation of dendritic cells.
Up-regulated in tolerated allografts. Down-regulated in activated macrophages.
Expressed at high concentration in the microvillar parallel actin bundle (PAB) of hair cells stereocilia in the cochlea and vestibular system. Detected also at high levels of a number of other sensory cell types, including taste receptor cells, solitary chemoreceptor cells, vomeronasal sensory neurons and Merkel cells. Isoform 1 is detected in testis. Isoforms 2 is detected in small intestine and kidney (at protein level). Isoforms 3, 4, 6 and 8 are expressed in Purkinje cells dendritic spines.
Isoform 2 accumulates in the brush border during enterocyte differentiation and migration along the crypt-villus axis in adults.
Monomer (By similarity). Interacts with PFN2 (By similarity). Binds F-actin in a Ca(2+)-resistant fashion (PubMed:8799813, PubMed:9763424). Interacts (via N-terminal) with BAIAP2 (via SH3-domain) (PubMed:12598619). Interacts with MYO3A (via C-terminus). Interacts with MYO3B (via C-terminus) (By similarity).
Multifunctional actin-bundling protein. Plays a major role in regulating the organization, dimension, dynamics and signaling capacities of the actin filament-rich microvilli in the mechanosensory and chemosensory cells (PubMed:9763424). Required for the assembly and stabilization of the stereociliary parallel actin bundles. Plays a crucial role in the formation and maintenance of inner ear hair cell stereocilia. Involved in the elongation of actin in stereocilia. In extrastriolar hair cells, required for targeting MYO3B to stereocilia tips, and for regulation of stereocilia diameter and staircase formation (By similarity).
The WH2-domain binds actin monomer and mediated actin bundle assembly.
Competitively inhibited by 9-cis-retinoic acid and 13-cis-retinoic acid.
NAD-dependent oxidoreductase with broad substrate specificity that shows both oxidative and reductive activity (in vitro). Has retinol dehydrogenase activity towards all-trans-retinol (in vitro) (By similarity). 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).
Up-regulated by testosterone. Levels are very low in castrated male rats.
Expression in increased by palmitate at protein level but not mRNA level (PubMed:21994399). Expression is down-regulated by microRNA miR-9, miR29a and miR-29b-1 (at protein level) (PubMed:21994399).
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 (By similarity). Plays an important role in de novo sphyngolipid biosynthesis which is crucial for adipogenesis (By similarity).
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. 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.
Interacts with COMMD1, COMMD2 COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8, COMMD9, COMMD10, WASHC1. Interacts directly with WASHC2C. 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. Interacts with VPS35L; associates with the retriever complex. Interacts with SNX17 and SNX31.
This P450 is active in 15-beta-hydroxylation of steroid sulfates.
Abundantly expressed in granule neurons at all developmental stages.
Expressed in the brain, with a prominent distribution in striatum.
Orphan receptor with constitutive G(s) signaling activity that activate cyclic AMP. Promotes neurite outgrowth and blocks myelin inhibition in neurons.
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.
Sodium-phosphate symporter which seems to play a fundamental housekeeping role in phosphate transport by absorbing phosphate from interstitial fluid for normal cellular functions such as cellular metabolism, signal transduction, and nucleic acid and lipid synthesis. In vitro, sodium-dependent phosphate uptake is not significantly affected by acidic and alkaline conditions, however sodium-independent phosphate uptake occurs at acidic conditions. May play a role in extracellular matrix and cartilage calcification as well as in vascular calcification. Functions as a retroviral receptor (By similarity).
Widely expressed with highest levels in liver, heart and brain.
Brain (at protein level). Also found in the heart, liver, kidney and testis.
Detected as early as 18 dpc in the developing cerebral cortex, and expression reaches its peak at P1, declines after P10, and remains at a relatively low level throughout adulthood. At 18 dpc, expressed in the forebrain, midbrain, and hindbrain. Within the forebrain, it is expressed in postmitotic cells of the cortical plate. At this stage, it can also be detected in other structures of central and peripheral nervous systems, including the trigeminal ganglion, superior cervical ganglion, retina and olfactory epithelium. Expression in the cortex is high at birth and declines substantially by P20. At P7, expressed in all cortical layers, and in the hippocampus, expression is high in the cell body layers of all subdivisions. Within the brain, expression decreases through development but continues to be expressed at high levels in the olfactory bulb, hippocampus, and cerebellum into adulthood.
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 (By similarity). Association with CREBBP facilitates transcription while the association with SMARCA4/BRG1 suppresses CREST-mediated transcription in resting neurons.
The MFD (multi-functional domain) domain is involved in transcription transactivation, nuclear body targeting and dimerization. Inhibits dendritic growth in cultured neurons.
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.
ABC transporter associated with antigen processing (PubMed:17018292). In complex with TAP1 mediates unidirectional translocation of peptide antigens from cytosol to endoplasmic reticulum (ER) for loading onto MHC class I (MHCI) molecules (By similarity). Uses the chemical energy of ATP to export peptides against the concentration gradient (By similarity). 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 (By similarity). As a component of the peptide loading complex (PLC), acts as a molecular scaffold essential for peptide-MHCI assembly and antigen presentation (By similarity).
Heterodimer of TAP1 and TAP2 (TAP1-TAP2). A component of the peptide loading complex (PLC), interacts via TAPBP with MHCI heterodimer; this interaction mediates peptide-MHCI assembly.
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.
E3 ubiquitin-protein ligase that plays a role in the limitation of the innate immune response. Mediates inhibition of the RLR signaling pathway by ubiquitinating RIGI and IFIH1 receptors, leading to their proteasomal degradation. Promotes also the neddylation of IKBKG/NEMO, stabilizing NFKBIA, and thereby inhibiting of NF-kappa-B nuclear translocation and activation.
Belongs to the proteasome subunit S10 family.
Heterodimer of CALCRL and RAMP1, RAMP2 or RAMP3.
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.
Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Acetylates both arylamines and arylalkylamines.
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:13211595, PubMed:5871820, PubMed:3579310). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:13211595, PubMed:5871820). Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan (By similarity). 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 (By similarity).
Hexokinase is an allosteric enzyme inhibited by its product D-glucose 6-phosphate. Hexokinase activity is inhibited by N-acetyl-D-glucosamine.
Monomer (By similarity). Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity). Interacts with VDAC1. The HK1-VDAC1 complex interacts with ATF2 (By similarity). 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. The catalytic activity is associated with the C-terminus while regulatory function is associated with the N-terminus. Each domain can bind a single D-glucose and D-glucose 6-phosphate molecule.
Homodimerization via the leucine zipper domains is required for autophosphorylation.
Binds NEDD4. Interacts with 14-3-3 proteins. Interacts with MAVS.
Plays a positive role in the antiviral innate immune signaling pathway. Mechanistically, interacts with MAVS and functions as a positive regulator to promote 'Lys-63'-linked polyubiquitination of MAVS and thus strengthens the interaction between MAVS and TRAF2 (By similarity). Also plays a role in axon and dendrite arborization during cranial nerve development (PubMed:24044555). May also be important for neural crest migration and early development of other anterior structures including eye, brain and cranial cartilage (PubMed:24044555).
Expressed in the embryo and in early postnatal weeks. On and before P14, distributes in a homogeneous way, throughout the brain. By P21, high expression observed in the molecular layer of the cerebellum and in the olfactory bulb. The maximum expression and the adult pattern of distribution in the brain occurs by P30. By P30, P45 and P90, highest expression occurs in the molecular layer of the cerebellum and in the olfactory bulb, and relatively high expression in the hippocampus, cerebral cortex, thalamus and corpus striatum.
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.
Highly expressed in cerebellum, olfactory bulb, hippocampus, cerebral cortex, thalamus, and corpus striatum. In the hippocampus, strong expression around the pyramidal cells of the stratum pyramidale and in the stratum lucidum of the CA2-CA3 regions. In the olfactory bulb, particularly strong expression in the external plexiform layer. In the cerebellum, concentrates in the molecular layer, particularly in Purkinje cells, where it is found at the base of dendritic spines/protrusions, at the dendritic branching points and in some GABAergic synapses.
Septins polymerize into heterooligomeric protein complexes that form filaments, and can associate with cellular membranes, actin filaments and microtubules (By similarity). Forms homooligomers (By similarity). GTPase activity is required for filament formation (By similarity). Interacts with SEPTIN7 (PubMed:15485874). Interacts with SEPTIN9 and SEPTIN12 (By similarity).
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:3355813, PubMed:9733776, 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 (PubMed:9733776). Regulates fatty acid release from adipocytes, and contributes to systemic insulin sensitivity (By similarity).
Expressed most strongly in liver, then kidney, and at lower levels in heart and brain.
Eye; expressed in a photosensitive subset of retinal ganglion cells (at protein level).
Photoreceptor that binds cis-retinaldehydes (By similarity). Contributes to pupillar reflex, photoentrainment and other non-image forming responses to light (By similarity). May be involved in the optokinetic visual tracking response (By similarity). May be involved in the regulation of retinal hyaloid vessel growth and regression (By similarity).
Although PubMed:18321853 show that TESC-binding results in the maturation and accumulation of SLC9A1 at the cell surface, previous studies with human SLC9A1 report that TESC-binding results in a decrease in activity.
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.
N-glycosylated and O-glycosylated in the N-terminal region.
Oligomer (PubMed:21543739). Interacts with CALM1 in a calcium-dependent manner (By similarity). Interacts with TESC (PubMed:18321853). Interacts (via residues 504-563; the juxtamembrane region of the cytoplasmic C-terminal domain) with CHP1 (PubMed:12576672). The interaction with CHP1 occurs at the plasma membrane in a calcium-dependent manner (By similarity). Interacts with CHP2 (PubMed:12576672). The interaction with CHP2 occurs in a calcium-dependent manner (By similarity).
The interacting region with TESC is conflicting: It has been reported that SLC9A1 interacts with TESC via the juxtamembrane region of the cytoplasmic C-terminal domain, including residues 505-571 (PubMed:18321853). However, studies with human SLC9A1 report the interaction with TESC via residues 503-545 or via residues 633-815.
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.
Interacts with CPNE1 and CPNE4 (By similarity). Interacts with COMMD1, COMMD2 COMMD3, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8, COMMD9, COMMD10. Interacts with CUL1, CUL2, CUL3, SKP1, BTRC. 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. Interacts with VPS35L; associates with the retriever complex. Interacts with SNX17 and SNX31 (By similarity).
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. 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. 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.
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 (By similarity). Enhances histone H4 gene transcription but does not seem to bind DNA directly (By similarity).
Phosphorylation of Thr-321 by PKA 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 (PubMed:27756895). 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. Interacts with GRIA1 and GRIA2 (PubMed:27756895). Interacts with MPP2 (PubMed:27756895).
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 (By similarity). Promotes synapse formation.
Expressed at higher levels in the cerebral cortex of juveniles than adults (at protein level).
Forms homooligomers. Interacts with PLAUR (via the UPAR/Ly6 domains), ADAMTS4 and CTSB. Interacts with HGF; the interaction increases the mitogenic activity of HGF.
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 (By similarity).
FABPs are thought to play a role in the intracellular transport of long-chain fatty acids and their acyl-CoA esters.
Heart, but also skeletal muscle, kidney, brain and mammary gland.
Actin binding affinity is primarily determined by CH domain 1.
Homodimer. Interacts with the syntrophins SNTA1; SNTB1 and SNTB2. Interacts with SYNM. Interacts (via its WWW and ZZ domains) with DAG1 (via the PPXY motif of betaDAG1); the interaction is inhibited by the tyrosine phosphorylation of the PPXY motif of DAG1 (By similarity). Interacts with DTNB (PubMed:10545507). Interacts with PGM5 (PubMed:7890770).
May play a role in anchoring the cytoskeleton to the plasma membrane.
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.
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. Also ubiquitinates the caspases CASP8 and CASP10, promoting their proteasomal degradation, to negatively regulate apoptosis downstream of death domain receptors. Also 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.
The RING-type zinc finger is required for the ubiquitination of target proteins.
Ubiquitous. Detected in cerebrum, cerebellum, midbrain, brain stem, hippocampus, striatum, liver, heart, lung, kidney, muscle, spleen and testis.
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 (By similarity).
This is one of two isocytochromes C found in the testis. The other is identical with the form found in other rat tissues. These cytochromes are assumed to be located in the sperm.
Facilitates DNA repair, cell cycle progression, and cell proliferation through its interaction with CIAO2B.
Interacts with CIAO2B; the interaction is direct. Interacts with MMS19; the interaction is indirect.
Belongs to the zinc-containing alcohol dehydrogenase family. Class-II subfamily.
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. Stimulates also mature basophils, eosinophils, and monocytes to become functionally activated. In addition, plays an important role in neural cell proliferation and survival. Participates as well in bone homeostasis and inhibits osteoclast differentiation by preventing NF-kappa-B nuclear translocation and activation. Mechanistically, exerts its biological effects through a receptor composed of IL3RA subunit and a signal transducing subunit IL3RB. Receptor stimulation results in the rapid activation of JAK2 kinase activity leading to STAT5-mediated transcriptional program. Alternatively, contributes to cell survival under oxidative stress in non-hematopoietic systems by activating pathways mediated by PI3K/AKT and ERK.
Calcium appears to inhibit ligand binding to the receptor, most probably by interacting with a distinct calcium-binding protein which then inhibits the receptor.
Expressed in the fetal brain and peripheral tissues.
Homotetramer. Interacts with TRPC4 (PubMed:11163362). 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 (By similarity). Interacts with CABP1 (via N-terminus) (PubMed:12032348). 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. Interacts with AHCYL2 (with lower affinity than with AHCYL1) (By similarity). Interacts with BCL2L10; the interaction is increased in the presence of AHCLY1 (By similarity). Interacts with BOK (via BH4. domain); protects ITPR1 from proteolysis by CASP3 during apoptosis (By similarity).
Intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5-trisphosphate. Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1 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.
Palmitoylated by ZDHHC6 in immune cells, leading to regulation of ITPR1 stability and function.
Phosphorylated by cAMP kinase (PKA). Phosphorylation prevents the ligand-induced opening of the calcium channels. Phosphorylation by PKA increases the interaction with inositol 1,4,5-trisphosphate and decreases the interaction with AHCYL1.
Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium.
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.
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.
Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake. Acts together with LRP2 to mediate endocytosis of high-density lipoproteins, GC, hemoglobin, ALB, TF and SCGB1A1. Acts together with AMN to mediate endocytosis of the CBLIF-cobalamin complex. Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the CBLIF-cobalamin complex. Ligand binding requires calcium. Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface.
Expressed at 6 dpc in primitive endoderm cells, in apical membrane invaginations, in endocytic vesicles, endoplasmic reticulum and Golgi apparatus. At the egg cylinder stage (7-8 dpc), expressed in visceral and parietal endoderm. From the early headfold stage (8.9 dpc), expressed in ectodermal cells lining the proamniotic cavity. At 10 dpc, detected in the newly forming neuroepithelium.
Expressed to intestinal, renal and yalk sac apical membranes. In kidney, expressed in the proximal tubule.
Interacts with AMN (PubMed:14576052, PubMed:29402915). Component of the cubam complex composed of one CUBN trimer and one AMN chain (By similarity). The cubam complex can dimerize (By similarity). Interacts with LRP2 in a dual-receptor complex in a calcium-dependent manner (PubMed:9478979). Found in a complex with PID1/PCLI1, LRP1 and CUBNI. Interacts with LRP1 and PID1/PCLI1 (PubMed:20237569) (By similarity).
The CUB domains 5 to 8 mediate binding to CBLIF and ALB. CUB domains 1 and 2 mediate interaction with LRP2.
The cubam complex is composed of a 400 Angstrom long stem and a globular crown region. The stem region is probably formed by AMN and the CUBN N-terminal region, including the EGF-like domains. The crown is probably formed by the CUBN CUB domains.
The precursor is cleaved by a trans-Golgi proteinase furin, removing a propeptide.
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.
Interacts with CDK5R1 (p35 form) (PubMed:10721722). CDK5RAP1, CDK5RAP2 and CDK5RAP3 show competitive binding to CDK5R1 (By similarity). Forms a complex with CDK5R1 and CDK5 (By similarity).
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) (By similarity). Essential for efficient and highly accurate protein translation by the ribosome (By similarity). Specifically inhibits CDK5 activation by CDK5R1 (By similarity). Essential for efficient mitochondrial protein synthesis and respiratory chain (By similarity).
Belongs to the TRAPP small subunits family. Sedlin subfamily.
Part of the multisubunit TRAPP (transport protein particle) complex. Interacts with ENO1, PITX1, SF1, TRAPPC2L and TRAPPC3.
Prevents ENO1-mediated transcriptional repression and antagonizes ENO1-mediated cell death. May play a role in vesicular transport from endoplasmic reticulum to Golgi (By similarity).
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. Interacts with MBL2 through its carbohydrate moiety. This interaction may inhibit its catalytic activity (By similarity).
Kidney, intestinal brush borders and salivary ducts.
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.
Proteolytically activated by trypsin in the intestinal lumen and kallikrein-related peptidases in other tissues.
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 (By similarity). However other experiments later demonstrated that SLC25A19 is a thiamine diphosphate transporter and not a mitochondrial deoxyribonucleotide carrier (By similarity).
Previously identified as the mitochondrial deoxyribonucleotide carrier. However other experiments later demonstrated that SLC25A19 is a thiamine diphosphate transporter and not a mitochondrial deoxyribonucleotide carrier.
Belongs to the PX domain-containing GAP family.
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.
May play a role in the development and maintenance of the nervous system (By similarity). Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation.
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.
Autoacetylation at Lys-433 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. 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. 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. H3K14ac promotes transcriptional elongation by facilitating the processivity of RNA polymerase II. Acts as a key regulator of hematopoiesis by forming a complex with BRD1/BRPF2, directing KAT7/HBO1 specificity towards H3K14ac and promoting erythroid differentiation (By similarity). 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. 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. 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. Acts as an inhibitor of NF-kappa-B independently of its histone acetyltransferase activity (By similarity).
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. Interacts with MCM2 and ORC1. Interacts with the androgen receptor (AR); in the presence of dihydrotestosterone. Interacts with CDT1 (By similarity). Interacts with MAP2K1 and CUL1 (By similarity). Interacts with p53/TP53; leading to inhibit histone acetyltransferase activity. Interacts with MIS18BP1 (By similarity).
Histone acetyltransferase activity is inhibited by GMNN in the context of a complex with CDT1, inhibiting histone H4 acetylation and DNA replication licensing.
Phosphorylated at Ser-51 and Ser-54 by ATR in response to DNA damage, promoting its ubiquitination by the CRL4(DDB2) complex and subsequent degradation. Phosphorylation at Ser-51 and Ser-54 by ATR in response to ultraviolet-induced DNA, promotes localization to DNA damage sites. Phosphorylation at Ser-58 by PLK1 during mitosis seems important for prereplicative complex formation and DNA replication licensing, and requires prior phosphorylation at Thr-86 and Thr-89 by CDK1 (By similarity). Phosphorylated by MAP2K1, which accelerates its degradation (By similarity).
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-339, leading to proteasomal degradation. Ubiquitinated by the CRL4(DDB2) complex following phosphorylation by ATR, leading to its subsequent degradation.
Heterotetramer of two PDHA2 and two PDHB subunits. The heterotetramer interacts with DLAT, and is part of the multimeric pyruvate dehydrogenase complex that contains multiple copies of pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (DLAT, E2) and lipoamide dehydrogenase (DLD, E3). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (By similarity).
Pyruvate dehydrogenase activity is inhibited by phosphorylation of PDHA2; it is reactivated by dephosphorylation.
Inhibitory receptor on lymphocytes that negatively regulates antigen receptor signaling via PTPN6/SHP-1 and PTPN11/SHP-2. May interact in cis (on the same cell) or in trans (on other cells) with TNFRSF14. 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.
Interacts with tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2. Interacts with TNFRSF14/HVEM (via cysteine-rich domain 1).
Phosphorylated on Tyr residues by TNFRSF14 and by antigen receptors cross-linking, both inducing association with PTPN6 and PTPN11.
Acts as a synapse-to-nucleus messenger to promote NMDA receptor-mediated excitotoxicity in neurons in a JUN-dependent manner (PubMed:27458189). 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 (By similarity). Might promote apoptosis in T cells (By similarity).
Expressed in brain (PubMed:15629447, PubMed:27458189). Expressed in the cerebral cortex and especially in hippocampal neural cells (at protein level) (PubMed:15629447, PubMed:27458189).
Expression detected at postnatal day 7 and expression increases until 4 weeks after birth.
Forms a complex with NMDA receptor zeta subunit GRIN1 and epsilon subunit GRIN2B (PubMed:27458189). Interacts with GRIN2B (PubMed:27458189). Interacts with GRIN1; the interaction is reduced upon NMDA receptor activity (PubMed:27458189). Found in a postsynaptic membrane complex with DLG4 and GRIN1 (PubMed:15629447, PubMed:27458189). Interacts with DLG4 (via PDZ3 domain and to lesser degree via PDZ2 domain) (PubMed:15629447, PubMed:27458189). Interacts with FBXW7 (PubMed:27458189). Found in a complex with JUN and FBXW7 (By similarity). Interacts with JUN and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (By similarity). Interacts with SRC (By similarity).
Tyrosine phosphorylated, possibly by SRC.
Up-regulated in hepatocytes after treatment with the procarcinogen N-nitrosodiethylamine (NDEA).
Although related to peptidase M14 family, lacks the active site residues and zinc-binding sites, suggesting that it has no carboxypeptidase activity.
As a positive regulator of collagen fibrillogenesis, it is probably involved in the organization and remodeling of the extracellular matrix (By similarity). May positively regulate MAP-kinase activity in adipocytes, leading to enhanced adipocyte proliferation and reduced adipocyte differentiation. May also positively regulate NF-kappa-B activity in macrophages by promoting the phosphorylation and subsequent degradation of I-kappa-B-alpha (NFKBIA), leading to enhanced macrophage inflammatory responsiveness. Can act as a transcriptional repressor.
Interacts with different types of collagen, including collagens I, III, and V (By similarity). Interacts with GNG5, NFKBIA, MAPK1, MAPK3 and PTEN. May interact with calmodulin. Interaction with MAPK1 may stimulate DNA-binding. Binds to DNA in vitro.
The F5/8 type C domain binds to different types of collagen, including collagens I, III, and V.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA M5U methyltransferase family.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A8 subfamily.
Creatine:sodium symporter which mediates the uptake of creatine (PubMed:12433955, PubMed:8297374, PubMed:15702372, PubMed:32115505). Plays an important role in supplying creatine to the brain via the blood-brain barrier (By similarity).
Expressed in the small intestine (at protein level) (PubMed:12433955, PubMed:15702372). Expressed in the brain, heart, skeletal muscle and kidney (PubMed:8297374). Expressed in the leukocytes (PubMed:32115505).
Was originally thought to be a choline transporter.
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 (By similarity).
Brain-specific. Highly concentrated at synapses.
Expression of isoform 2 is predominant at 18 dpc, but decreased during postnatal development paralleling increased expression of isoform 4 and isoform 5.
Interacts with CNKSR2 and DLG4 (PubMed:12390249). Interacts with CTNND2/Catenin delta-2. Forms a complex with N-cadherin through CTNND2 (By similarity). Interacts with CAMK2A (PubMed:10827168).
Required for normal synaptic spine architecture and function. Necessary for DISC1 and GRM5 localization to postsynaptic density complexes and for both N-methyl D-aspartate receptor-dependent and metabotropic glutamate receptor-dependent long term depression (By similarity).
This is the only isoform to have a potential transmembrane domain.
Activated by 200-1000 micromolar concentrations of calcium and inhibited by calpastatin.
Calcium-regulated non-lysosomal thiol-protease which catalyze limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. Proteolytically cleaves MYOC at 'Arg-226'. Proteolytically cleaves CPEB3 following neuronal stimulation which abolishes CPEB3 translational repressor activity, leading to translation of CPEB3 target mRNAs.
Forms a heterodimer with a small (regulatory) subunit (CAPNS1) (PubMed:19020622, PubMed:19020623). Interacts with CPEB3; this leads to cleavage of CPEB3 (By similarity).
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).
Proteolytically cleaved from a C-terminal extension in the course of the conversion of the proteasome from its latent form into its active form.
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. Interacts with NOTCH3. Interacts with ZFAND1 (By similarity).
Interacts with TUBGCP2, TUBGCP3 and B9D2. Interacts with CDK5RAP2; the interaction is leading to centrosomal localization of TUBG1 and CDK5RAP2. Interacts with PIFO. Interacts with SAS6 and NUP62 at the centrosome (By similarity). Interacts with EML3 (phosphorylated form) and HAUS8 (By similarity).
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 (By similarity).
'Asrij' stands for 'blood' in Sanskrit as this protein is strongly expressed in blood vessels.
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).
The OCIA domain is necessary and sufficient for endosomal localization.
Belongs to the eukaryotic ribosomal protein eS10 family.
Component of the small ribosomal subunit. Interacts with PRMT5. The methylated form interacts with NPM1 (By similarity).
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 (By similarity).
Dual specificity phosphatase able to dephosphorylate phosphotyrosine, phosphoserine and phosphothreonine residues, with a preference for phosphotyrosine as a substrate.
Interacts with PPP1CA, PPP1CB and PPP1CC/PPP1G.
Regulatory subunit of protein phosphatase 1.
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 in several dozen cells in the dorsal retrotrapezoid nucleus/parafacial respiratory group (at protein level).
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 (PubMed:17208656). Inhibits voltage-gated sodium channels but enhances voltage-gated potassium channels in hippocampal neurons (PubMed:33059246). 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).
Binds DNA. Can associate with the proximal promoter regions of PAX6 and SP4, and their known targets including ARR3, RHO, OPN1MW2 and OPN1SW.
Transcriptional regulator that plays a role in retinal development and maintenance.
Highly expressed in brain, spleen and kidney, followed by liver and heart.
In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (By similarity). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (PubMed:16707451). Acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (By similarity). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (By similarity). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (By similarity). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (By similarity).
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 (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 (By similarity). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (By similarity). Interacts (via C-terminus) with the closed form of HSP90AA1 (via the middle domain and TPR repeat-binding motif) (By similarity). Interacts with TSC2; the interaction stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:16707451). Interacts with DOCK7 (By similarity). Interacts with FBXW5 (By similarity). Interacts with TBC1D7 (By similarity). Interacts with WDR45B (By similarity). Interacts with RPAP3 and URI1 (By similarity).
The putative coiled-coil domain is necessary for interaction with TSC2.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with RGS22. Interacts with NTSR1.
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Acts as an activator of phospholipase C (By similarity). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs) (By similarity). Together with GNAQ, required for heart development (By similarity).
Cell surface receptor that plays a functionally redundant role in the inhibition of neurite outgrowth mediated by MAG (PubMed:15673660). 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 (By similarity). Protects motoneurons against apoptosis; protection against apoptosis is probably mediated by MAG (PubMed:26335717). 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).
Detected in adult brain, in neocortex, hippocampus, striatum and dorsal root ganglion neurons, and in retina (at protein level) (PubMed:15673660). In brain, detected in cerebral cortex and hippocampus. Weak or no expression detected in the cerebellum, thalamus or striatum (PubMed:12694398).
Expression is high in adult, but very low in neonate dorsal root ganglion neurons (at protein level).
Interaction with MAG is controversial, and may be indirect (Probable). Interacts with MAG (PubMed:15673660, PubMed:19420245, PubMed:21308849). Does not interact with OMG and RTN4 (PubMed:15673660).
N-glycosylated (PubMed:19420245, PubMed:21308849). O-glycosylated (PubMed:19420245). Contains terminal sialic acid groups on its glycan chains (PubMed:19420245).
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.
May play a role in late hair differentiation.
Interacts in its sumoylated form with PIAS2/PIASX which enhances its transcriptional activator activity. Interacts with MAD2L2; the interaction is direct and promotes phosphorylation by the kinases MAPK8 and/or MAPK9. Interacts with POU1F1.
On mitogenic stimulation, phosphorylated on C-terminal serine and threonine residues by MAPK1. Ser-382 and Ser-388 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-382 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 (By similarity). Upon bFGF stimulus, phosphorylated by PAK1 (PubMed:17156131).
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 (By similarity) (PubMed:17156131). Induces target gene transcription upon JNK-signaling pathway stimulation (PubMed:17156131).
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:28209804). Plays an important role in fatty acid metabolism in brain and the acyl-CoAs produced may be utilized exclusively for the synthesis of the brain lipid.
Contains exon 13. No differences in the affinity for fatty acids and CoA. Decreased affinity for ATP. Could play an important role at lower ATP levels. Expressed at lower level in the brain compared to isoform 1.
Expressed predominantly in brain and, to a much lesser extent, in heart and adrenal.
Isoform 1 is detected 10 days after birth, and increased in a coordinate fashion during the development of brain, and the amount did not decrease when myelination was completed.
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.
Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8.
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.
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. However, by simultaneous interactions, recruits FYN which subsequently phosphorylates and activates SLAMF1. 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 (PubMed:16223723).
Interacts with CD84, CD244, LY9, SLAMF1 and FYN (By similarity). Interacts with NTRK1, NTRK2 and NTRK3.
Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with SELPLG/PSGL1. May have a role in capillary morphogenesis.
Interacts with SELPLG/PSGL1 and PODXL2 through the sialyl Lewis X epitope. SELPLG sulfation appears not to be required for this interaction.
Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class I subfamily.
Binds to type I and type II collagen, fibronectin and TGF-beta. Forms a ternary complex with MFAP2 and ELN. Interacts with DPT (By similarity).
May affect the rate of fibrils formation (By similarity). May be implicated in the dilatation of the rat cervix.
The amount of DSPG per cervix increases 4-fold during pregnancy, then falls precipitously within 1 day post partum.
The attached glycosaminoglycan chain can be either chondroitin sulfate or dermatan sulfate depending upon the tissue of origin.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:15337525). 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:15337525). Within the adrenocorticotropic hormone signaling pathway, produces phosphatidic acid which in turn activates NR5A1 and subsequent steroidogenic gene transcription (By similarity). Also functions downstream of the nerve growth factor signaling pathway being specifically activated in the nucleus by the growth factor (PubMed:15337525). Through its diacylglycerol activity also regulates synaptic vesicle endocytosis (By similarity).
Interacts with RHOA (constitutively activated, GTP-bound); the interaction inhibits DGKQ. Interacts with PRKCE. Interacts with PRKCH. Interacts with PLCB1. Interacts with NR5A1; the interaction requires both LXXLL motifs in DGKQ and is required for full phosphatidic acid-mediated activation of NR5A1.
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.
Widely expressed with higher expression in the brain and, to a lesser extent, in the small intestine, duodenum, and liver (PubMed:9099683). In brain, expressed in gray matter (PubMed:9099683). Expression is most intense in the cerebellar cortex and hippocampus, while moderate expression is seen in the olfactory bulb neuronal layers and brain stem nuclei (PubMed:9099683). In the cerebellar cortex, equally expressed in both the Purkinje cell somata and the granule cells (PubMed:9099683).
The protein contains a transactivation domain (TAD) which may be required for transcriptional activation of a subset of target genes.
Transcription regulator that may syncronize transcriptional and translational programs.
Expressed in the eye, with higher expression in lens epithelium than in lens fiber cells at postnatal day 15.
Homodimer and heterodimer (By similarity). Able to interact with SPRED1 to form heterodimers (By similarity). Interacts with RAS (By similarity). May interact with ZDHHC13 (via ANK repeats) and ZDHHC17 (via ANK repeats) (By similarity). Interacts with TESK1 (PubMed:17974561). Interacts with NF1 (By similarity).
Negatively regulates Ras signaling pathways and downstream activation of MAP kinases. Recruits and translocates NF1 to the cell membrane, thereby enabling NF1-dependent hydrolysis of active GTP-bound Ras to inactive GDP-bound Ras (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).
Phosphorylated on serine and threonine residues. Phosphorylated on tyrosine. Phosphorylation of Tyr-224 and Tyr-227 are required for ubiquitination.
Ubiquitinated; leading to degradation by the proteasome.
Part of the tectonic-like complex which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition.
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 (By similarity). Interacts with ARRB2 (PubMed:12850288). Interacts with APPL2; interaction is independent of follicle stimulating hormone stimulation (By similarity).
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.
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.
Inhibited in cells after FCER1A triggering.
May play a role in the regulation of T and B-lymphocyte development and signal transduction.
Oxidized at active site cysteine. Treatment with pervanadate (vanadate and H(2)O(2)) or with antigen enhanced oxidation of active site cysteine.
Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium (By similarity).
Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (By similarity). Regulates glycogen metabolism in liver, but not in muscle (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (By similarity). May be involved in the regulation of replication in pancreatic beta-cells (PubMed:17242403). Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (By similarity). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity).
Monomer. Interacts with ARRB2, AXIN1 and CTNNB1/beta-catenin (By similarity). Interacts with CTNND2 (By similarity). Interacts with LMBR1L (By similarity). Interacts with DDX3X (By similarity). Interacts with TNFRSF10B (By similarity).
Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279 (By similarity).
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 following LPS stimulation (By similarity). Interacts with LPS (By similarity).
Component of the TLR4 signaling complex. Mediates the innate immune response to bacterial lipopolysaccharide (LPS) leading to cytokine secretion and the inflammatory response (By similarity).
Highly expressed in cortical astrocytes and in cerebellar granule neurons.
Catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD) coenzyme.
In the C-terminal section; belongs to the PAPS reductase family. FAD1 subfamily.
Homodimer (via SH3-domain). Interacts with PTPN22. 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. Interacts with SRCIN1. Interacts with RHOH. Interacts (via SH2 domain) with SCIMP; this interaction is dependent on phosphorylation of SCIMP 'Tyr-96' (By similarity). 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 (PubMed:21873224). Interacts with LRRK1 (By similarity).
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 (By similarity).
Phosphorylated at Ser-364 by PKA, leading to increased activity. Autophosphorylated (By similarity).
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.
Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation.
Expressed in the heart (PubMed:15862299). Expressed in cardiac myocytes (at protein level) (PubMed:15862299).
Forms a complex with class II HDACs in undifferentiating cells. On myogenic differentiation, HDACs are released into the cytoplasm allowing MEF2s to interact with other proteins for activation. Interacts with EP300 in differentiating cells; the interaction acetylates MEF2C leading to increased DNA binding and activation. Interacts with HDAC7 and CARM1. Interacts with HDAC4 and HDAC9; the interaction with HDACs represses transcriptional activity. Interacts with LPIN1. Interacts with MYOCD. Interacts with AKAP13. Interacts with FOXK1; the interaction inhibits MEF2C transactivation activity (By similarity). Interacts (via N-terminus) with HABP4; this interaction decreases DNA-binding activity of MEF2C in myocardial cells in response to mechanical stress (PubMed:15862299). Interacts with JPH2; interaction specifically takes place with the Junctophilin-2 N-terminal fragment cleavage product of JPH2 (By similarity). Interacts (via MADS box) with SOX18 (By similarity).
Phosphorylated on Ser-59; which enhances DNA binding activity. Phosphorylated on Ser-396; which is required for Lys-391 sumoylation and inhibits transcriptional activity.
Proteolytically cleaved in cerebellar granule neurons on several sites by caspase 3 and caspase 7 following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.
Sumoylated on Lys-391 with SUMO2 but not SUMO1; which represses transcriptional activity.
The beta domain is required for enhancement of transcriptional activity.
Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes (PubMed:15862299). Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. Enhances transcriptional activation mediated by SOX18. Plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex. Necessary for proper development of megakaryocytes and platelets and for bone marrow B-lymphopoiesis. Required for B-cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T-cell-dependent antigens and for normal induction of germinal center B-cells. May also be involved in neurogenesis and in the development of cortical architecture (By similarity).
May play a role in the interactions between neurites derived from specific subsets of neurons during development.
Present in brain and peaks at 15 dpc during embryonic development. Also present in the spinal cord (at protein level).
Restricted to the nervous system. Abundantly expressed in the fetal brain.
Could be involved in the unfolded protein response (UPR) pathway.
May be involved in tissue-specific alternative RNA processing events.
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 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.
Glycosylation at Asn-628 is necessary both for surface expression and neutral endopeptidase activity.
Inhibited in a dose dependent manner by sialorphin.
Myristoylation is a determinant of membrane targeting.
Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:2966343). Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond (PubMed:2966343). Catalyzes cleavage of bradykinin, substance P and neurotensin peptides (By similarity). Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9 (PubMed:2966343). Involved in the degradation of the atrial natriuretic factor (ANF) (PubMed:2966343). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers (By similarity).
Belongs to the Clp1 family. Clp1 subfamily.
Component of the tRNA splicing endonuclease complex, composed of CLP1, TSEN2, TSEN15, TSEN34 and TSEN54. 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. Its role in tRNA splicing and maturation is required for cerebellar development. 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 (By similarity).
Muscle myosin is a hexameric protein that consists of 2 heavy chain subunits (MHC), 2 alkali light chain subunits (MLC) and 2 regulatory light chain subunits (MLC-2). Interacts with ECPAS. Interacts (via C-terminus) with LRRC39.
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.
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.
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. 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 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.
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 (By similarity).
Monoubiquitinated. Ubiquitination activates deubiquitination activity in vitro.
May function in the transport of nucleosides and/or nucleoside derivatives between the cytosol and the lumen of an intracellular membrane-bound compartment.
The C-terminal domain is necessary for retention within intracellular membranes.
Interacts with DDRGK1. Interacts with TRIP4; deufmylates TRIP4.
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. Does not hydrolyze SUMO1 or ISG15 ubiquitin-like proteins. Through TRIP4 deufmylation may regulate intracellular nuclear receptors transactivation and thereby regulate cell proliferation and differentiation.
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.
Detected in juxtaparanodal zones in the central nervous system and at nerve terminal plexuses of basket cells in the cerebellum (at protein level) (PubMed:20089912). Brain. High levels in cerebellar Purkinje cells. Expressed in pyramidal cells of the Ammons's horn and granular cells of the dentate gyrus in the hippocampus as well as cerebral cortex and striatum. High levels in dorsal horn of spinal cord.
High levels in developing brain and spinal chord, sensory neurons of dorsal root and trigeminal ganglia, myenteric neurons of the intestine as well as in non-neuronal cells of adrenal, thymus and submandibular glands of 15 dpc embryos.
Interacts through its PDZ domains with NETO1. Interacts with NOS1/nNOS through second PDZ domain (PubMed:8922396). Interacts with KCNJ2/Kir2.1 (via C-terminus) through one of its PDZ domains (By similarity). Interacts with KCNJ4 (By similarity). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1 (PubMed:16630835). Interacts with LRFN2 and LRFN4. Interacts with FASLG (By similarity). Interacts with ADAM22 (PubMed:20089912). Interacts with DGKI (via PDZ-binding motif) (PubMed:21119615).
Palmitoylation of isoform 1 and isoform 2 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).
Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity of bile salts. Plays a role in the recruitment of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin (SM) molecules to nonraft membranes and to further enrichment of SM and cholesterol in raft membranes in hepatocytes. Required for proper phospholipid bile formation. Indirectly involved in cholesterol efflux activity from hepatocytes into the canalicular lumen in the presence of bile salts in an ATP-dependent manner. May promote biliary phospholipid secretion as canaliculi-containing vesicles from the canalicular plasma membrane. In cooperation with ATP8B1, functions to protect hepatocytes from the deleterious detergent activity of bile salts. Does not confer multidrug resistance.
Expressed in the liver (PubMed:15159385). Expressed in hepatocytes (PubMed:7948020, PubMed:10067174).
Interacts with HAX1 (PubMed:15159385). May interact with RACK1 (By similarity).
Phosphorylated. Phosphorylation is required for PC efflux activity. Phosphorylation occurs on serine and threonine residues in a protein kinase A- or C-dependent manner. May be phosphorylated on Thr-41 and Ser-46.
Translocation activity is inhibited by the ATPase inhibitor vanadate and the calcium channel blocker verapamil. Translocation activity is enhanced by the addition of the bile salt taurocholate.
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:19140243). Interacts with ATP6V1H and MEGF10 (By similarity). Interacts with EGFR and TTGN1 (PubMed:10228163, PubMed:9812899, PubMed:12121421). Interacts with F2R (By similarity). Interacts with PIP5K1C; tyrosine phosphorylation of PIP5K1C weakens the interaction (By similarity). Interacts with KIAA0319; required for clathrin-mediated endocytosis of KIAA0319 (By similarity). Interacts with DVL2 (via DEP domain) (PubMed:20947020). Interacts with KCNQ1; mediates estrogen-induced internalization via clathrin-coated vesicles (By similarity). Interacts with P2RX4 (via internalization motif) (PubMed:15985462). Together with AP2A1 or AP2A2 and AP2B1, it interacts with ADAM10; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (By similarity). Probably interacts with ACE2 (via endocytic sorting signal motif); the interaction is inhibited by ACE2 phosphorylation (By similarity). Interacts with RALBP1; the interaction is direct (By similarity). Interacts with TMEM106B (via N-terminus) (By similarity).
Component of the adaptor protein complex 2 (AP-2) (PubMed:14745134, PubMed:15473838). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways (PubMed:14745134, PubMed:15473838). Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation (PubMed:14745134, PubMed:15473838). AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome (PubMed:14745134, PubMed:15473838). The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components (PubMed:14745134, PubMed:15473838). Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation (PubMed:14745134, PubMed:15473838). AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis (PubMed:14745134, PubMed:15473838). AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface (By similarity). 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 (PubMed:15985462). AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway (By similarity). During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10 (By similarity). The AP-2 mu (AP2M1) subunit binds to transmembrane cargo proteins; it recognizes the Y-X-X-Phi motifs (PubMed:15985462). The surface region interacting with to the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at Thr-156 in membrane-associated AP-2 (PubMed:15985462, PubMed:11516654). The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1 (By similarity). Plays a role in endocytosis of frizzled family members upon Wnt signaling (PubMed:20947020).
Phosphorylation at Thr-156 increases the affinity of the AP-2 complex for cargo membrane proteins during the initial stages of endocytosis.
Required for the assembly of dynein arms.
Component of the Golgi to ER traffic (GET) complex, which is composed of GET1, CAMLG/GET2 and GET3 (PubMed:23041287). Within the complex, GET1 and CAMLG form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer (By similarity). Interacts with CAMLG/GET2 (via C-terminus) (PubMed:23041287). GET3 shows a higher affinity for CAMLG than for GET1 (By similarity).
Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (PubMed:23041287). 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:23041287). Required to ensure correct topology and ER insertion of CAMLG (By similarity).
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 (By similarity).
Component of complexes involved in DNA repair and protein ubiquitination. May play a role in the regulation of the circadian clock.
The core of the protein consists of three WD40 beta-propeller domains.
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 (By similarity).
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 (By similarity).
Heterodimer with MPP1 (By similarity). 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 (By similarity). Component of a complex composed of PALS1, CRB1 and MPP4 (By similarity). Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3 (By similarity). Component of a complex composed of PALS1, CRB1 and EPB41L5. Within the complex, interacts (via HOOK domain) with EPB41L5 (via FERM domain), and interacts with CRB1 (via intracellular domain) (By similarity). 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 (By similarity). Component of a complex composed of CRB3, PALS1 and PATJ (By similarity). Interacts (via PDZ domain) with PATJ (via N-terminus). Interacts with EZR (By similarity). Interacts (via PDZ domain) with CRB1 (via C-terminal ERLI motif) (By similarity). 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 (By similarity). Interacts with WWTR1/TAZ (via WW domain) (By similarity). Interacts with MPP7 (By similarity). Interacts (via PDZ domain) with CRB3 (via C-terminus) (By similarity). Interacts with LIN7C. Interacts with MPDZ. Interacts with PARD6B. Interacts with SC6A1. Interacts with CDH5; the interaction promotes PALS1 localization to cell junctions and is required for CDH5-mediated vascular lumen formation and endothelial cell (By similarity). Interacts with NPHP1 (via coiled coil and SH3 domains) (By similarity). Interacts with NPHP4 (By similarity). Interacts with CRB2 (By similarity).
Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells (By similarity). 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 (By similarity). 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). May play a role in the T-cell receptor-mediated activation of NF-kappa-B (By similarity). 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 (PubMed:20237282). 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.
Antiparallel homodimer; disulfide-linked. Antiparallel heterodimer with PDGFA; disulfide-linked. The PDGFB homodimer interacts with PDGFRA and PDGFRB homodimers, and with heterodimers formed by PDGFRA and PDGFRB. The heterodimer composed of PDGFA and PDGFB interacts with PDGFRB homodimers, and with heterodimers formed by PDGFRA and PDGFRB. Interacts with XLKD1 (By similarity). Interacts with LRP1 (By similarity). Interacts with SORL1 (via the N-terminal ectodomain) (By similarity).
Expressed in a distinct subpopulation of smooth muscle cells in injured arteries.
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 proliferation and recruitment of pericytes and vascular smooth muscle cells in the central nervous system, skin, lung, heart and placenta. Required for normal blood vessel development, and for normal development of kidney glomeruli. Plays an important role in wound healing. Signaling is modulated by the formation of heterodimers with PDGFA (By similarity).
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. 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. Plays a role in the regulation of cell cycle and cell adhesion. Has an inhibitory role on AR-signaling pathway through the induction of receptor proteosomal degradation.
Expressed in brain (PubMed:9030614). Expressed in neurons (PubMed:9030614). Expressed in mature oligodendrocytes (OLGs) (PubMed:23891804). Expressed in oligodendroglia progenitor cells (OPCs) and immature oligodendrocytes (OLGs) in the neonatal brain (at protein level) (PubMed:14613971).
Homodimer (By similarity). Forms heterodimer with FXR1; heterodimerization occurs in a methylation-dependent manner (By similarity). Forms heterodimer with FXR2 (By similarity). Homooligomer (By similarity). 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 (By similarity). Part of a ribonucleoprotein complex with AGO2/EIF2C2 and miRNAs (By similarity). Interacts with AGO2/EIF2C2 (By similarity). Interacts (via C-terminus) with CACNA1B; this interaction induces a decrease in the number of presynaptic functional CACNA1B channels at the cell surface (PubMed:24709664). Interacts with CYFIP1; this interaction recruits CYFIP1 to capped mRNA. 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 (By similarity). Interacts with methylated histone H3 (By similarity). Interacts with IGF2BP1; this interaction allows to recruit IGF2BP1 to mRNA in a FMR1-dependent manner (By similarity). Interacts (via N-terminus) with KCNMB4 (By similarity). Interacts with KCNT1 (via C-terminus); this interaction alters gating properties of KCNT1 (PubMed:20512134). Interacts (via C-terminus) with KIF5A; this interaction is increased in a mGluR-dependent manner (By similarity). Interacts (via phosphorylated form) with MCRS1 (via N-terminus) (By similarity). Interacts with MOV10; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs (By similarity). Interacts with MYO5A and PURA; these interactions occur in association with polyribosome (By similarity). Interacts with NCL (By similarity). Interacts with NUFIP1 (By similarity). Interacts (via N-terminus) with NUFIP2 (By similarity). Interacts with NXF1; this interaction occurs in a mRNA-dependent and polyribosome-independent manner in the nucleus (By similarity). Interacts with NXF2 (via N-terminus); this interaction is direct and occurs in a NXF1 mRNA-containing mRNP complexes (By similarity). Interacts with RANBP9; this interaction is direct and inhibits binding of FMR1 to RNA homomer (By similarity). Interacts with RPLP0 (By similarity). Interacts (via C-terminus) with SMN (via C-terminus); this interaction is direct and occurs in a RNA-independent manner (By similarity). Interacts with TDRD3 (via C-terminus); this interaction is direct (By similarity). Interacts with YBX1; this interaction occurs in association with polyribosome (By similarity). Interacts with nucleosome (By similarity). Associates with polyribosome; this association occurs in a mRNA-dependent manner (PubMed:9030614, PubMed:9144248, PubMed:14613971, PubMed:16571602). Associates with messenger ribonucleoprotein particles (mRNPs) (PubMed:16571602). Associates with microtubules in a kinesin- and dynein-dependent manner (By similarity). Interacts with HABP4 (By similarity). Interacts with SND1 (By similarity).
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. Methylation is necessary for heterodimerization with FXR1, association with polyribosomes, recruitment into stress granules and translation of FMR1 target mRNAs. Methylated by PRMT1, PRMT3 and PRMT4, in vitro.
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:9144248). Plays a role in the alternative splicing of its own mRNA (By similarity). 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:9144248). 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 (By similarity). 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 (By similarity). Facilitates the assembly of miRNAs on specific target mRNAs (By similarity). Also plays a role as an activator of mRNA translation of a subset of dendritic mRNAs at synapses (By similarity). 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 (By similarity). 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 (By similarity). Binds to intramolecular G-quadruplex structures in the 5'- or 3'-UTRs of mRNA targets (By similarity). Binds to G-quadruplex structures in the 3'-UTR of its own mRNA (By similarity). Binds also to RNA ligands harboring a kissing complex (kc) structure; this binding may mediate the association of FMR1 with polyribosomes (By similarity). Binds mRNAs containing U-rich target sequences (By similarity). 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 (By similarity). 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 (By similarity). May associate with nascent transcripts in a nuclear protein NXF1-dependent manner (By similarity). 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) (By similarity). Moreover, plays a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity (By similarity). 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 (PubMed:24709664). 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 (By similarity). 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 (By similarity).
Phosphorylated on several serine residues. Phosphorylation at Ser-478 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.
The N-terminal 134 amino acids are necessary for homodimerization and RNA-binding. The N-terminal 298 amino acids are sufficient to interact with KCNMB4 and to regulate presynaptic action potential (AP) duration in neurons. The two agenet-like domains are necessary for binding to histone H3 in a methylation-dependent manner. The KH domains are necessary for mediating miRNA annealing to specific RNA targets. The KH 2 domain is necessary for binding to kissing complex (kc) RNA ligands. The RGG box domain is necessary for binding to mRNA targets that contain G-quadruplex structures. 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. The RGG box domain is necessary for binding to its own mRNA. The RGG-box domain is necessary for binding to homomer poly(G).
Up-regulated in response to the activation of group I metabotropic glutamate receptors at synapses (PubMed:9144248). Rapidly and transiently up-regulated in response to light exposure in the cell bodies and dendrites of visual cortical neurons (at protein level) (PubMed:15564573).
Component of the biogenesis of lysosome-related organelles complex-2 (or BLOC2) composed of HPS3, HPS5 and HPS6. Interacts with HPS5 and HPS3. Interacts with biogenesis of lysosome-related organelles complex-1 (BLOC1) (By similarity). Interacts with AP-3 complex (PubMed:19010779). Interacts with DCTN1 and dynein intermediate chain (By similarity).
May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules. Acts as cargo adapter for the dynein-dynactin motor complex to mediate the transport of lysosomes from the cell periphery to the perinuclear region. Facilitates retrograde lysosomal trafficking by linking the motor complex to lysosomes, and perinuclear positioning of lysosomes is crucial for the delivery of endocytic cargos to lysosomes, for lysosome maturation and functioning.
Shares a common promoter with APAF1 from which the 2 genes are transcribed in opposite directions.
Target of p53/TP53 with pro-apoptotic function.
Plays a role in the regulatory network through which muscle cells coordinate their structural and functional states during growth, adaptation, and repair.
Belongs to the helicase family. RecQ subfamily.
Hydrolyzes and transfers gamma-glutamyl moieties from glutathione and other gamma-glutamyl compounds to acceptors.
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).
It is uncertain whether Met-1 or Met-2 is the initiator.
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).
Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.
Expression abundant in lung, less abundant in testis, barely detectable in liver, and not detectable in neonatal kidney, adult kidney, brain, heart, or spleen.
Heterodimer of CDKN2B with CDK4 or CDK6.
Interacts strongly with CDK4 and CDK6. Potent inhibitor. Potential effector of TGF-beta induced cell cycle arrest (By similarity).
Autophosphorylated. Phosphorylated by ATM (By similarity).
Moderately inhibited by staurosporine, a broad-range protein kinase inhibitor.
Phosphorylated on Ser-1038 by MAPK14. This phosphorylation is required PCDH8 for endocytosis.
Self-associates. Interacts with MAP2K3 and MAP2K6. Interacts with tubulins. Interacts with MAP3K7 and interfers with MAP3K7-binding to CHUK and thus prevents NF-kappa-B activation (By similarity). Isoform 2 interacts with PCDH8; this complex may also include CDH2.
Serine/threonine-protein kinase involved in different processes such as membrane blebbing and apoptotic bodies formation DNA damage response and MAPK14/p38 MAPK stress-activated MAPK cascade. Phosphorylates itself, MBP, activated MAPK8, MAP2K3, MAP2K6 and tubulins. Activates the MAPK14/p38 MAPK signaling pathway through the specific activation and phosphorylation of the upstream MAP2K3 and MAP2K6 kinases. 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. May affect microtubule organization and stability. May play a role in the osmotic stress-MAPK8 pathway. Prevents MAP3K7-mediated activation of CHUK, and thus NF-kappa-B activation. Isoform 2, but not isoform 1, is required for PCDH8 endocytosis. Following homophilic interactions between PCDH8 extracellular domains, isoform 2 phosphorylates and activates MAPK14/p38 MAPK which in turn phosphorylates isoform 2. This process leads to PCDH8 endocytosis and CDH2 cointernalization. Both isoforms are involved in MAPK14/p38 MAPK activation.
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. Once phosphorylated on its C-terminal threonine, moesin is activated leading to interaction with F-actin and cytoskeletal rearrangement. These rearrangements regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. 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 (By similarity). Modulates phagolysosomal biogenesis in macrophages (By similarity). Participates also in immunologic synapse formation (By similarity).
In resting T-cells, part of a PAG1-SLC9A3R1-MSN complex which is disrupted upon TCR activation. Interacts with SLC9A3R1. Interacts with PPP1R16B. Interacts with PDZD8. Interacts with SELPLG and SYK; these interactions mediate the activation of SYK by SELPLG. Interacts with PDPN (via cytoplasmic domain); this interaction activates RHOA and promotes epithelial-mesenchymal transition. Interacts with SPN/CD43 cytoplasmic tail (By similarity). Interacts with CD44 (By similarity). Interacts with ICAM2 (By similarity). Interacts with ICAM3 (via C-terminus). Interacts with PDZD8. Interacts with F-actin. Interacts with CD46 (By similarity). 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. Phosphorylation on Thr-558 by STK10 negatively regulates lymphocyte migration and polarization (By similarity).
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.
Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).
Belongs to the eukaryotic RPC3/POLR3C RNA polymerase subunit family.
Component of the RNA polymerase III (Pol III) complex consisting of 17 subunits (By similarity). RPC3/POLR3C, RPC6/POLR3F and RPC7/POLR3G form a Pol III subcomplex (By similarity). Directly interacts with POLR3G and POLR3GL. Directly interacts with POLR3F/RPC39. Interacts with GTF3C4. As part of the RNA polymerase III (Pol III) complex, interacts with PKP2 (By similarity).
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific core component of RNA polymerase III which synthesizes small RNAs, such as 5S rRNA and tRNAs. May direct with other members of the subcomplex RNA Pol III binding to the TFIIIB-DNA complex via the interactions between TFIIIB and POLR3F. May be involved either in the recruitment and stabilization of the subcomplex within RNA polymerase III, or in stimulating catalytic functions of other subunits during initiation. Plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts induce type I interferon and NF-Kappa-B through the RIG-I pathway. Preferentially binds single-stranded DNA (ssDNA) in a sequence-independent manner.
Expressed in brain (at protein level) (PubMed:25172774). Can be found in both somatodendritic and axonal compartment of neurons (PubMed:11461150).
Interacts with GPHN and NSF (PubMed:10900017, PubMed:11461150). Interacts with ATG3, ATG7 and ATG13 (By similarity). Interacts with alpha-tubulin (By similarity). Interacts with beta-tubulin (PubMed:10899939). Interacts with GABRG2 (By similarity). Interacts with RB1CC1 (By similarity). Interacts with ULK1 (By similarity). Interacts with CALR (By similarity). Interacts with DDX47 (By similarity). Interacts with TP53INP1 and TP53INP2 (By similarity). Interacts with TBC1D5 (By similarity). Interacts with TBC1D25 (By similarity). Directly interacts with SQSTM1 (By similarity). Interacts with MAPK15 (By similarity). Interacts with TECPR2 (By similarity). Interacts with PCM1 (By similarity). Interacts with TRIM5 and TRIM21 (By similarity). Interacts with MEFV (By similarity). Interacts with KIF21B (PubMed:25172774). Interacts with WDFY3; this interaction is required for WDFY3 recruitment to MAP1LC3B-positive p62/SQSTM1 bodies (By similarity). Interacts with FLCN; interaction regulates autophagy (By similarity). Interacts with UBA5 (By similarity). Interacts with KBTBD6 and KBTBD7; the interaction is direct and required for the ubiquitination of TIAM1 (By similarity). Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (By similarity).
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. 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. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms. In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy. ATG4B constitutes the major protein for proteolytic activation (By similarity). 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:11461150). 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 (By similarity). 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 (By similarity). Also required for the local activation of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex, regulating ubiquitination a nd degradation of TIAM1, a guanyl-nucleotide exchange factor (GEF) that activates RAC1 and downstream signal transduction. Thereby, regulates different biological processes including the organization of the cytoskeleton, cell migration and proliferation (By similarity). Involved in apoptosis (By similarity).
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 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 (By similarity). Interacts with USP15 and VPS39 (By similarity). Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SDCBP (via C-terminus). Interacts with CAV1 and this interaction is impaired in the presence of SDCBP (By similarity). 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 (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Interacts with NUP214/CAN. Interacts with NUP62 and NUP98 (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 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 (By similarity).
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. Self-associates. Interacts with DYNC1H1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with PCNT.
Phosphorylated during mitosis but not in interphase.
Brain specific. Isoform 1 is expressed in the olfactory bulb, cortex and hippocampus and was also expressed at lower levels in thalamus, cerebellum and spinal cord. Isoform 3 is expressed in pyramidal cells of cortex and hippocampus, striatum, thalamus, hypothalamus, stellate cells of cerebellum, and brainstem. Isoform 2 and isoform 4 are expressed in cortex, hippocampus, thalamus, cerebellum, brainstem and spinal cord. In hippocampal neurons isoform 4 is found abundantly in spine structures. Isoform 2 is abundant in the cell body and also found in dendritic shafts.
Interacts with the C-terminal tail of PRLHR (By similarity). Interacts with EFNB1, EFNB3, GRIA2, GRIA3, CSGP4 and GRIPAP1. Can form homomultimers and heteromultimers with GRIP1.
Isoform 1 expression was relatively low early in development and increased postnatally, reaching a peak at P14. Isoform 3 is detected at low levels prior to P9, whereupon its expression increases, with the highest levels in the adult.
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.
Palmitoylation of isoform 4 mediates membrane location.
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)(+) (By similarity). 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.
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).
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) (By similarity).
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.
Engagement of killer inhibitory receptors (KIR) disrupts the interaction of PLCG1 with LAT and blocks target cell-induced activation of PLC, maybe by inducing the dephosphorylation of LAT.
Expressed in NK cells. Present in lymph node, spleen and thymus (at protein level).
Palmitoylation of Cys-27 and Cys-30 is required for raft targeting and efficient phosphorylation.
Phosphorylated on tyrosines by ZAP70 upon TCR activation, or by SYK upon other immunoreceptor activation; which leads to the recruitment of multiple signaling molecules. Is one of the most prominently tyrosine-phosphorylated proteins detected following TCR engagement. May be dephosphorylated by PTPRJ (By similarity).
Phosphorylated on tyrosines by ZAP70 upon TCR activation, or by SYK upon other immunoreceptor activation; which leads to the recruitment of multiple signaling molecules. Is one of the most prominently tyrosine-phosphorylated proteins detected following TCR engagement. May be dephosphorylated by PTPRJ. Phosphorylated by ITK leading to the recruitment of VAV1 to LAT-containing complexes.
Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development. Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules (By similarity).
When phosphorylated, interacts directly with the PIK3R1 subunit of phosphoinositide 3-kinase and the SH2 domains of GRB2, GRAP, GRAP2, PLCG1 and PLCG2. Interacts indirectly with CBL, SOS, VAV, and LCP2. Interacts with SHB, SKAP2 and CLNK. Interacts with FCGR1A. Interacts with GRB2, PLCG1 and THEMIS upon TCR activation in thymocytes (By similarity). Interacts with THEMIS2 (By similarity).
Associates with components of the U1 and U2 U1 small nuclear ribonucleoprotein complexes.
Heterozygous or homozygous adults display left ventricular dilatation (PubMed:22466703, PubMed:24367651). Left ventricular diastolic diameters are significantly larger, although there is no differences in the systolic ventricular dimensions or contractility indices (PubMed:22466703). Subendocardial fibrosis increases with age and was accompanied by electrical abnormalities, such as widening of the QRS complex, atrioventricular conduction delay and a predisposition to arrhythmia (PubMed:22466703). Rats are at risk of sudden death caused by heart failure (PubMed:22466703, PubMed:24367651).
Phosphorylation regulates the subcellular localization. Phosphorylation of Ser-638 and Ser-640 in the RS (arginine/serine-rich) region promotes nuclear localization of the protein (PubMed:35394688). In contrast, phosphorylation of the C-terminal disordered region promotes localization to cytoplasmic ribonucleoprotein granules (By similarity).
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:23307558, PubMed:24367651, PubMed:24960161, PubMed:25573899, PubMed:27289039, PubMed:33805770, PubMed:35394688). 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:23307558, PubMed:24367651, PubMed:24960161, PubMed:25573899). RBM20-mediated exon skipping is hormone-dependent and is essential for TTN isoform transition in both cardiac and skeletal muscles (PubMed:23307558, PubMed:24367651, PubMed:24960161, PubMed:25573899, PubMed:33805770, PubMed:35394688). RBM20-mediated exon skipping of TTN provides substrates for the formation of circular RNA (circRNAs) from the TTN transcripts (By similarity). Together with RBM24, promotes the expression of short isoforms of PDLIM5/ENH in cardiomyocytes (PubMed:27289039).
Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO3, SKP1, CUL1 and RBX1. Directly interacts with PML, either alone or within the SCF complex (By similarity).
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 (By similarity).
Binds DNA as a homodimer and as a heterodimer. Heterodimer; heterodimerizes with CEBPB. Heterodimer; heterodimerizes with DDIT3/CHOP. Interacts with CEP290 (via an N-terminal region). Interacts with NEK6, DAPK2 (isoform 2) and ZIPK/DAPK3 (By similarity). Interacts (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini) (PubMed:10924501). Forms a heterodimer with TXLNG in osteoblasts (By similarity). 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. Interacts with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors (By similarity). Interacts with ABRAXAS2 (By similarity). Interacts with TRIB3, inhibiting the transactivation activity of ATF4. 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 (By similarity).
Expressed in brain, heart, liver, spleen, lung and muscle, but not testis.
Hydroxylated by PHD3, leading to decreased protein stability.
Phosphorylation at Ser-243 by RPS6KA3/RSK2 in osteoblasts enhances transactivation activity and promotes osteoblast differentiation (By similarity). Phosphorylated on the betaTrCP degron motif at Ser-217, followed by phosphorylation at Thr-211, Ser-222, Ser-229, Ser-233 and Ser-246, promoting interaction with BTRC and ubiquitination. Phosphorylation is promoted by mTORC1 (By similarity). Phosphorylation at Ser-213 by CK2 decreases its stability. Phosphorylated by NEK6 (By similarity).
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) (By similarity). 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. 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 (By similarity). 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. Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress. However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (By similarity). 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. May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (By similarity). 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 (By similarity). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. 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. 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 (By similarity).
Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4. Interaction with EP300/p300 inhibits ubiquitination by SCF(BTRC).
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.
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 (By similarity).
The cofactor is mostly bound to the substrate.
Acetylated. Deacetylation at Lys-48 enhances cytoplasmic localization and kinase activity in vitro.
Activated by forming a complex with STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): STRADA (or STRADB)-binding promotes a conformational change of STK11/LKB1 in an active conformation, which is stabilized by CAB39/MO25alpha (or CAB39L/MO25beta) interacting with the STK11/LKB1 activation loop. Sequestration in the nucleus by NR4A1 prevents it from phosphorylating and activating cytoplasmic AMPK (By similarity).
Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. LKB1 subfamily.
Catalytic component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers STK11/LKB1 in the cytoplasm and stimulates its catalytic activity. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP (By similarity). Interacts with NR4A1, p53/TP53, SMAD4, STK11IP and WDR6 (By similarity). Interacts with NISCH; this interaction may increase STK11 activity (By similarity). Interacts with SIRT1; the interaction deacetylates STK11 (By similarity). Interacts with CDKN1A (By similarity).
Expressed in brain, heart, testis, skeletal muscle and spleen, and weakly in liver and kidney. Isoform 1 is expressed at highest levels in the brain. Isoform 2 is expressed at highest levels in the testis, primarily in postmitotic developing germ cells (at protein level).
Isoform 2 is expressed in testis from 30 days of age, with significantly increased levels by 60 days; this corresponds to the stage when haploid spermatids appear.
Phosphorylated by ATM at Thr-366 following ionizing radiation (IR). Phosphorylation at Ser-431 by RPS6KA1 and/or some PKA is required to inhibit cell growth. Phosphorylation at Ser-431 is also required during neuronal polarization to mediate phosphorylation of BRSK1 and BRSK2. Phosphorylation by PKC/PRKCZ at Ser-397 in isoform 2 promotes metformin (or peroxynitrite)-induced nuclear export of STK11 and activation of AMPK. UV radiation -induced phosphorylation at Thr-366 mediates CDKN1A degradation.
Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, thus promoting their activity: phosphorylates PRKAA1, PRKAA2, BRSK1, BRSK2, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, SIK1, SIK2, SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA, PTEN and possibly p53/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2 and thereby regulates processes including: inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, and B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neuron polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53/TP53 and recruited to the CDKN1A/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11/LKB1 kinase NUAK1. Also acts as a mediator of p53/TP53-dependent apoptosis via interaction with p53/TP53: translocates to the mitochondrion during apoptosis and regulates p53/TP53-dependent apoptosis pathways. Regulates UV radiation-induced DNA damage response mediated by CDKN1A. In association with NUAK1, phosphorylates CDKN1A in response to UV radiation and contributes to its degradation which is necessary for optimal DNA repair (By similarity).
Belongs to the gamma-glutamylcyclotransferase family.
Catalyzes the formation of 5-oxo-L-proline from L-gamma-glutamyl-L-epsilon-lysine.
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. Decreases the binding of JAG1 to NOTCH2 but not that of DLL1. Essential mediator of somite segmentation and patterning.
Facilitates sperm penetration into the layer of cumulus cells surrounding the egg by digesting hyaluronic acid. Involved in induction of the acrosome reaction in the sperm. Involved in follicular atresia, the breakdown of immature ovarian follicles that are not selected to ovulate. Induces ovarian granulosa cell apoptosis, possibly via apoptotic signaling pathway involving CASP8 and CASP3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage. Has no hyaluronidase activity in embryonic fibroblasts in vitro. Has no hyaluronidase activity in granulosa cells in vitro.
Has a role in hair formation. Specific component of keratin intermediate filaments in the inner root sheath (IRS) of the hair follicle (By similarity).
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 (By similarity).
Autophosphorylated on Tyr-744, Tyr-748 and Tyr-749 in the activation loop allowing full activity. Autophosphorylated on Tyr-867 leading to recruitment of downstream partners of the signaling cascade such as PLCG2 (By similarity).
Defects in Mertk are the cause of retinal dystrophy (rdy) in the royal college of surgeons (RCS) rats.
Interacts (upon activation) with TNK2; stimulates TNK2 autophosphorylation. Interacts (via N-terminus) with extracellular ligands LGALS3, TUB, TULP1 and GAS6. Interacts with VAV1 in a phosphotyrosine-independent manner. Interacts with TIMD4; this interaction enhances TIMD4-mediated efferocytosis (By similarity).
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. 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 (By similarity).
Activin receptor type-2 (ACVR2A or ACVR2B) activates the type-1 receptor through phosphorylation of its regulatory GS domain.
Autophosphorylated. Phosphorylated by activin receptor type-2 (ACVR2A or ACVR2B) in response to activin-binding at serine and threonine residues in the GS domain. Phosphorylation of ACVR1B by activin receptor type-2 regulates association with SMAD7 (By similarity).
Forms an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Interacts with TDP2 (By similarity). Interacts with AIP1, FKBP1A, IGSF1, TDGF1, SMAD2, SMAD3 and SMAD7 (By similarity).
The GS domain is a 30-amino-acid sequence adjacent to the N-terminal boundary of the kinase domain and highly conserved in all other known type-1 receptors but not in type-2 receptors. The GS domain is the site of activation through phosphorylation by the II receptors (By similarity).
Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating a many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, type-2 receptors (ACVR2A and/or ACVR2B) act as a primary activin receptors whereas the type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor such as ACVR1B. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor. ACVR1B also phosphorylates TDP2 (By similarity).
Ubiquitinated. Level of ubiquitination is regulated by the SMAD7-SMURF1 complex (By similarity).
Calcium-dependent lectin that mediates cell adhesion by binding to glycoproteins on neighboring cells. Mediates the adherence of lymphocytes to endothelial cells of high endothelial venules in peripheral lymph nodes. Promotes initial tethering and rolling of leukocytes in endothelia.
Interaction with SELPLG/PSGL1 and PODXL2 is required for promoting recruitment and rolling of leukocytes. This interaction is dependent on the sialyl Lewis X glycan modification of SELPLG and PODXL2, and tyrosine sulfation modifications of SELPLG. Sulfation on 'Tyr-51' of SELPLG is important for L-selectin binding.
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).
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.
Chromatin-interacting protein that forms a stable heterodimer with interleukin enhancer-binding factor 3/ILF3 and plays a role in several biological processes including transcription, innate immunity or cell growth. Essential for the efficient reshuttling of ILF3 (isoform 1 and isoform 2) into the nucleus. Together with ILF3, forms an RNA-binding complex that is required for mitotic progression and cytokinesis by regulating the expression of a cluster of mitotic genes. Mechanistically, competes with STAU1/STAU2-mediated mRNA decay. Plays also a role in the inhibition of various viruses including Japanese encephalitis virus or enterovirus 71.
Forms heterodimers with ILF3. ILF2-ILF3 heterodimers may also bind to PRKDC/XRCC7: this may stabilize the interaction of PRKDC/XRCC7 and the heterodimeric complex of G22P1/KU70 and XRCC5/KU80. Forms a complex with ILF3, YLPM1, KHDRBS1, RBMX, NCOA5 and PPP1CA. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with IGF2BP1. Interacts with CRBN; this interaction promotes ubiquitination and subsequent degradation of ILF2.
Ubiquitinated at Lys-166 by CRBN with polyubiquitin chains by the CUL4-RING E3 ligase (CRL4-CRBN) and then degraded by the proteasome.
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 (By similarity). Interacts with AP1M2 (PubMed:15985462).
Receptor for extracellularly released ATP acting as a ligand-gated ion channel that plays multiple role in immunity and central nervous system physiology (PubMed:15985462, PubMed:24762105). 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 (By similarity). Upon activation, drives microglia motility via the PI3K/Akt pathway (PubMed:12917686).
Widespread distribution in the brain. Strongly expressed in microglial cells (PubMed:12917686). Also expressed in epithelial cells (PubMed:8598206).
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.
Belongs to the ELO family. ELOVL6 subfamily.
Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that elongates fatty acids with 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs. Catalyzes the synthesis of unsaturated C16 long chain fatty acids and, to a lesser extent, C18:0 and those with low desaturation degree. May participate in the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
The reaction is stimulated by the presence of HSD17B12, the enzyme catalyzing the second step of the elongation cycle.
Defects in Atrn (isoform 1) are the cause of the autosomal recessive phenotype zitter (zi), which is characterized by progressive hypomyelination and vacuolation in the central nervous system resulting in early-onset tremor and progressive flaccid paresis of the hind limb. This is due to an 8-bp deletion at the splice donor site of intron 12, which results in aberrant and unstable transcripts.
Involved in the initial immune cell clustering during inflammatory response and may regulate chemotactic activity of chemokines (By similarity). 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.
Interaction with integrins is heparin- and cell-type-dependent and promotes cell adhesion.
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 (By similarity). CCN1-mediated gene regulation is dependent on heparin-binding (By similarity). Down-regulates the expression of alpha-1 and alpha-2 subunits of collagen type-1 (By similarity). Promotes cell adhesion and adhesive signaling through integrin alpha-6/beta-1, cell migration through integrin alpha-1/beta-5 and cell proliferation through integrin alpha-v/beta-3 (By similarity).
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)) (By similarity). Interacts with RAB5IF (By similarity). 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. 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 (By similarity).
Component of the MMS22L-TONSL complex, a complex at least composed of MMS22L and TONSL/NFKBIL2. Interacts with the MCM complex, the FACT complex and the RPA complex. Interacts with MCM5; the interaction is direct. Binds histones, with a strong preference for histone H3.1 (histones H3.1 and H3-4/H3.1t). Interacts (via ANK repeats) with histone H4; specifically binds histone H4 lacking methylation at 'Lys-20' (H4K20me0). May interact with DNAJC9; the interaction seems to be histone-dependent.
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. The MMS22L-TONSL complex is required to maintain genome integrity during DNA replication. 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. Following recruitment to DSBs, the TONSL-MMS22L complex promotes recruitment of RAD51 filaments and subsequent homologous recombination. Within the complex, TONSL acts as histone reader, which recognizes and binds newly synthesized histones following their replacement by histone chaperones. Specifically binds histone H4 lacking methylation at 'Lys-20' (H4K20me0) and histone H3.1.
The ANK repeats mediate the interaction with the MCM complex and histones, while the LRR repeats mediate the interaction with MMS22L.
Binds (via the PDZ domain) to isoform 2A of SYNJ2 (via the unique motif in the C-terminus) (PubMed:10357812). 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 (PubMed:15878399). Interacts with DLL1; enhances DLL1 protein stability, and promotes notch signaling in endothelial cells (By similarity).
Regulates endocytosis of activin type 2 receptor kinases through the Ral/RALBP1-dependent pathway and may be involved in suppression of activin-induced signal transduction.
Belongs to the potassium channel family. A (Shaker) (TC 1.A.1.2) subfamily. Kv1.5/KCNA5 sub-subfamily.
Expressed equally in atrium, ventricle, aorta and skeletal muscle. Weaker expression in brain.
Expression regulated by cAMP in a tissue-specific manner. In primary cardiac cells, levels increase by 6-fold, and in GH3 cells, levels decrease 5-6-fold.
Homotetramer and heterotetramer of potassium channel proteins. Interacts with DLG1, which enhances channel currents (PubMed:11709425). Forms a ternary complex with DLG1 and CAV3 (PubMed:15277200). Interacts with KCNAB1 (By similarity). Interacts with UBE2I (By similarity).
The N-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 (PubMed:2361015, PubMed:15618540). 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:15618540). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (PubMed:15618540). Homotetrameric channels display rapid activation and slow inactivation. May play a role in regulating the secretion of insulin in normal pancreatic islets (By similarity).
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. 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.
Guanine nucleotide exchange factor (GEF) which may activate RAB8A and RAB8B (PubMed:12221131). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:12221131). Mediates the release of GDP from RAB8A and RAB8B but not from RAB3A or RAB5 (By similarity). 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 (By similarity).
Interacts with the N-terminal region of SSX2 (By similarity). Interacts with the GDP-bound forms of RAB8A and RAB8B (By similarity). The interaction with RAB8A is prevented by phosphorylation of RAB8A at 'Thr-72' (By similarity). Interacts with the GDP-bound forms of RAB3A and RAB3D (PubMed:7532276). Interacts with DCDC1 (By similarity) (PubMed:7532276). Interacts (via the N-terminal region) with TRAPPC14; this interaction mediates RAB3IP association with the TRAPP II complex (By similarity).
Ubiquitously expressed. Expressed at highest level in testis.
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.
Homodimer. Interacts with KPNA1 and KPNA4.
The first 10 amino acids are essential for nuclear localization.
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 (By similarity).
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM13 from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IB subfamily.
Has fucosyltransferase activity toward biantennary N-glycan acceptors. Does not fucosylate GlcNAc residue within type 2 lactosamine unit.
Highly expressed in the brain and lung and present in lower levels in all other tissues tested.
Homodimer and homotetramer via the coiled coil regions (PubMed:11283256). Interacts tightly with GTP-bound but not GDP-bound CDC42 (By similarity). 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 (PubMed:25107909). Interacts (via AGC-kinase C-terminal domain) with FAM89B/LRAP25 (via LRR repeat) (PubMed:25107909). Forms a tripartite complex with FAM89B/LRAP25 and LIMK1 (By similarity).
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:9418861). Regulates actin cytoskeletal reorganization via phosphorylation of PPP1R12A 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: PPP1R12C, LIMK1 and LIMK2. May play a role in TFRC-mediated iron uptake. 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 (By similarity).
Has guanylyl cyclase on binding to the beta-1 subunit.
A proteolytic cleavage generates a new N-terminus that functions as a tethered ligand.
Receptor for activated thrombin or trypsin coupled to G proteins that stimulate phosphoinositide hydrolysis. May play a role in platelets activation.
Binds the snake venom phospholipase complex taipoxin.
Desaturase has a half-life of only 4 hours.
Detected in liver (at protein level) (PubMed:2892838). Detected in adipose tissue. Detected in liver when rats are kept on a fat-free diet, but not when their food contains unsaturated fatty acids.
Stearoyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates (PubMed:2892838, PubMed:7947684). 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:2892838, PubMed:7947684). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids. Plays an important role in lipid biosynthesis. Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (By similarity). Plays an important role in body energy homeostasis (By similarity). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (PubMed:7947684). Required for normal development of sebaceous glands. Required for the biosynthesis of normal levels of Delta-9 unsaturated fatty acids and 1-alkyl-2,3-diacylglycerol in the Harderian gland. Required for normal production of meibum, an oily material that prevents drying of the cornea (By similarity).
Required for 60S pre-ribosomal subunits export to the cytoplasm.
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.
Plays a role in the cellular response to hydrogen peroxide and in the maintenance of mitochondrial integrity under conditions of cellular stress (By similarity). Involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway (By similarity).
Expression in the hippocampus is induced by long-lasting long-term potentiation.
Component of the pre-catalytic and catalytic spliceosome complexes. Component of the postcatalytic spliceosome P complex. Interacts with PDCD6; the interaction induces translocation of PDCD6 in the cytoplasm. Interacts with PPIL1 (By similarity).
Required for pre-mRNA splicing as component of the activated spliceosome. 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.
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.
Regulator of rDNA transcription. Acts in cooperation UBF/UBTF and positively regulates RNA polymerase I transcription (By similarity).
The sequence is derived from an EMBL/GenBank/DDBJ third party annotation (TPA) record where an error has been made in the annotation of the N-terminal region.
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 (By similarity). 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.
Expressed at high levels in testes, moderate levels in muscle, heart, and brain, and low levels in liver and kidney. Upon fasting, increased levels were seen in muscle, heart, liver, and kidney.
Belongs to the AAA ATPase family. BCS1 subfamily.
Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P) (By similarity). 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 (By similarity). Negatively regulates the phagocytosis of large particles by reducing phagosomal phosphatidylinositol 4,5-bisphosphate accumulation during cup formation (By similarity).
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). 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 (By similarity).
Highly expressed in intestine, kidney and stomach. Also expressed in testis and lung.
N-glycosylated; N-glycosylation of Asn-67 and Asn-391 is required for a proper thiamine pyrophosphate uptake.
Belongs to the gastrin/cholecystokinin family.
Binds to CCK-A receptors in the pancreas and CCK-B receptors in the brain.
Sulfation of Tyr-97 is essential for receptor activation.
The precursor is cleaved by proteases to produce a number of active cholecystokinins.
The shortest form (CCK8) is predominantly found in the brain, whereas the larger ones are found in the intestine.
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.
Belongs to the bacterial ribosomal protein bL35 family.
Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine (By similarity). Catalyzes the conversion of phosphatatidylethanolamine and does not act on phosphatidylcholine (By similarity). 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).
High expression in heart, aorta media and bladder.
Homodimer. Interacts with MLLT7/FOXO4. Interacts with SRF, its association does not depend on specific DNA sequences for ternary complex formation (By similarity). Interacts (via C-terminal) with EP300 (via the CREB-binding domain). Interacts with HDAC4 and HDAC5 (By similarity). Interacts with MEF2C (By similarity).
Phosphorylation regulates negatively transcriptional activity.
Smooth muscle cells (SM) and cardiac muscle cells-specific transcriptional factor which uses the canonical single or multiple CArG boxes DNA sequence. Acts as a cofactor of serum response factor (SRF) with the potential to modulate SRF-target genes (By similarity). Plays a crucial role in cardiogenesis, urinary bladder development, and differentiation of the smooth muscle cell lineage (myogenesis) (By similarity).
The C-terminal region contains a general transcription activation domain. The N-terminal region, comprising a basic and a Gln-rich domain, confers transcriptional potency and specificity by mediating association with the MADS box of SRF. The basic domain may be required for nuclear localization. The SAP domain is important for transactivation and ternary complex formation (By similarity).
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.
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.
Interacts (when farnesylated) with GPR31.
Interacts with SOS1 (By similarity). Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane (By similarity). Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14. Interacts with (when farnesylated) with GPR31 (By similarity). Interacts with RAP1GDS1 (By similarity).
Palmitoylated at Lys-182, Lys-184 and Lys-185. Lysine-depalmitoylation by SIRT2 promotes its localization to endomembranes in endocytic pathways.
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (By similarity). Plays an important role in the regulation of cell proliferation (PubMed:3110778). 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 (By similarity).
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). 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.
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 pre-initiation 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. 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 a 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.
Heterotrimer composed of an alpha, a beta and a gamma chain (By similarity). Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5 (By similarity). Interaction with METAP2 protects EIF2S1 from inhibitory phosphorylation (PubMed:1346232). Interacts with ABCF1 (By similarity). Associates with ribosomes (By similarity). Interacts with DDX3X in an RNA-independent manner (By similarity).
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 (By similarity). Substrate for at least 4 kinases: EIF2AK1/HRI, EIF2AK2/PKR, EIF2AK3/PERK and EIF2AK4/GCN2. 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.
Inhibited by extracellular acidification, zinc, bupivacaine and phenytoin. Activated by protein kinase A.
Strongest expression in heart. Moderate expression in lung and brain. Low levels in liver, kidney and skeletal muscle.
pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward.
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 (By similarity).
Has deubiquitinating activity towards 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. Deubiquitinates 'Lys-48'-linked polyubiquitination of RPS7 leading to its stabilization.
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.
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. 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. 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). 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. 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. 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. The NLRP6 inflammasome plays a central role in the maintenance of epithelial integrity and host defense against microbial infections in the intestine. 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. 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 (By similarity). Required to prevent infection by the apicomplexan parasite Cryptosporidium in enterocytes by promoting GSDMD-dependent release of IL18. 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. Essential for gut mucosal self-renewal and proliferation. Regulate mucus secretion in an inflammasome- and autophagy-dependent manner to prevent invasion by enteric bacteria,. During systemic bacterial infections, the NLRP6 inflammasome negatively regulates neutrophil recruitment and neutrophil extracellular traps (NETs) formation. May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism (By similarity).
Defects in Nlrp6 may be a cause of salt-sensitive hypertension.
Detected in several tissues (PubMed:7489366). Expressed in renal epithelial cells in medullary thick ascending limb of Henle, as well as in salivary gland apical epithelium (at protein level). Isoform 1 is widely expressed. Isoform 2 is primarily expressed in kidney (at protein level) (PubMed:18413781).
Homomultimer; forms the NLRP6 inflammasome polymeric complex, a filament composed of homopolymers in response to pathogens and other damage-associated signals. 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). 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. 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. 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. Interacts with DHX15.
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.
Strongly up-regulated in the intestine in late gestation.
The poly-Lys disordered region (350-354) mediates the formation of liquid-liquid phase separation (LLPS), an essential step for nucleation and formation of the NLRP6 inflammasome complex.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA4 subfamily.
Detected in cerebellum (at protein level).
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. Isoform 3 interacts with PRKCABP. Found in a complex with GRIA1, GRIA2, GRIA3, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with CACNG5 and PRKCG.
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.
Expressed in spleen, thymus, liver and lung.
Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.
Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the pro-inflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle.
Highly expressed in testis and brain. Expressed at intermediate level in heart, liver and kidney. Weakly expressed in spleen and lung and absent in muscle.
Identified in the spliceosome C complex (By similarity). Interacts with ERK signaling proteins MAP2K1/MEK1, MAP2K2/MEK2, LAMTOR3, ARAF/Raf-1, MAPK1/ERK2 and MAPK3/ERK1 (By similarity). Interacts with EGLN3/PHD3.
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 (By similarity). 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. May also be involved in pre-mRNA splicing.
Associates with IL31RA to form the IL31 receptor. Binds IL31 and activates STAT1, STAT3 and STAT5. Capable of transducing OSM-specific signaling events (By similarity). The OSM/OSM-R system is pivotal in the differentiation of oval cells into hepatocytes, thereby promoting liver regeneration.
Heterodimer composed of OSMR and IL6ST (type II OSM receptor). Heterodimer with IL31RA to form the IL31 receptor (By similarity).
Widely expressed. Expressed at high levels in the liver, skin and spleen. In the liver it is expressed exclusively in the oval cells.
Ear specific. Expressed in the cochlea and vestibule, but not in the cochlear nerve, cochlear nucleus, spinal chord, muscle, cerebral cortex, cerebellum, diencephalon and olfactory bulb. In the cochlea, expressed in fibrocytes of the spiral limbus, spiral ligament and suprastrial zone. In the vestibule, expressed in cells located to the stroma below the macular and crista sensory epithelia and in the subepithelial layer of the walls of semicircular canals and maculae.
May be essential for the survival of the neurosensory epithelium of the inner ear.
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 involved specifically cells of the immune system. May play a role in regulatory T-cells (Treg) development.
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 (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 (By similarity).
Expression on T-cells is drastically induced by phorbol myristate acetate (PMA) and Ca-ionophore or the engagement of CD3 and CD28.
Strongly expressed in the spleen and lung. Lower expression seen in liver, kidney and testis.
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 (By similarity).
Homodimer and homooligomer. Interacts with FGF2 and RAP80. Does not interact with FGF1 or FGF2 isoform 24 kDa. Interacts with microtubules (By similarity).
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.
Arg-707 and Arg-713 are dimethylated, probably to asymmetric dimethylarginine (By similarity).
Cleaved at Asp-94 by CASP3 during T-cell apoptosis, resulting in a loss of DNA- and chromatin-binding activities.
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. 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. 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). Required for the topoisomerase TOP2A protein stability and activity in a RNA-dependent manner (PubMed:20554522). Plays a role as a RNA polymerase II (Pol II) holoenzyme transcription regulator. 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. 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. Positively regulates CBX5-induced transcriptional gene silencing and retention of CBX5 in the nucleus. Negatively regulates glucocorticoid-mediated transcriptional activation. Key regulator of transcription initiation and elongation in embryonic stem cells upon leukemia inhibitory factor (LIF) signaling. Involved in the long non-coding RNA H19-mediated Pol II transcriptional repression. Participates in the circadian regulation of the core clock component BMAL1 transcription. Plays a role in the regulation of telomere length. Plays a role as a global pre-mRNA alternative splicing modulator by regulating U2 small nuclear ribonucleoprotein (snRNP) biogenesis. Plays a role in mRNA stability. Component of the CRD-mediated complex that promotes MYC mRNA stabilization. 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). Plays a role in mitotic cell cycle regulation. Involved in the formation of stable mitotic spindle microtubules (MTs) attachment to kinetochore, spindle organization and chromosome congression. Phosphorylation at Ser-58 by PLK1 is required for chromosome alignement and segregation and progression through mitosis. Contributes also to the targeting of AURKA to mitotic spindle MTs (By similarity). Binds to double- and single-stranded DNA and RNA, poly(A), poly(C) and poly(G) oligoribonucleotides (PubMed:20554522). Binds to chromatin-associated RNAs (caRNAs) (By similarity). Associates with chromatin to scaffold/matrix attachment region (S/MAR) elements in DNA (PubMed:8509422). Associates with chromatin in a chromatin-associated RNAs (caRNAs)-dependent manner. Binds to the Xist RNA. Binds the long non-coding H19 RNA. Binds to SMN1/2 pre-mRNAs at G/U-rich regions. Binds to small nuclear RNAs (snRNAs). Binds to the 3'-UTR of TNFA mRNA. 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). Also negatively regulates embryonic stem cell differentiation upon LIF signaling. 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. Phosphorylated on Ser-58 by PLK1 and dephosphorylated by protein phosphatase 2A (PP2A) in mitosis.
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. ATP hydrolysis is required to cycle from an oligomeric to monomeric state to compact chromatin. Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1. Identified in the spliceosome C complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Associates with heterogeneous nuclear ribonucleoprotein (hnRNP) particles. Associates (via middle region) with the C-terminal domain (CTD) RNA polymerase II (Pol II) holoenzyme; this association occurs in a RNA-independent manner. 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. Associates with the telomerase holoenzyme complex. Associates with spindle microtubules (MTs) in a TPX2-dependent manner. 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. Interacts with AURKA. Interacts (via C-terminus) with CBX5; this interaction is, at least in part, RNA-dependent. Interacts with CR2. Interacts with CRY1. Interacts (via C-terminus) with EP300; this interaction enhances DNA-binding to nuclear scaffold/matrix attachment region (S/MAR) elements. Interacts with ERBB4. Interacts with GEMIN5. Interacts with IGF2BP1. Interacts with IGF2BP2 and IGF2BP3. Interacts with NCL; this interaction occurs during mitosis. Interacts (via C-terminus) with NR3C1 (via C-terminus). Interacts with PLK1; this interaction induces phosphorylation of HNRNPU at Ser-58 in mitosis. Interacts with POU3F4. Interacts with SMARCA4; this interaction occurs in embryonic stem cells and stimulates global Pol II-mediated transcription (By similarity). 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 (PubMed:20554522). Interacts with TPX2; this interaction recruits HNRNPU to spindle microtubules (MTs). Interacts with UBQLN2 (By similarity). 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 (By similarity).
The SAP domain is necessary for specific binding to nuclear scaffold/matrix attachment region (S/MAR) elements in DNA. The RNA-binding RGG-box region is necessary for its association with inactive X chromosome (Xi) regions and to chromatin-associated RNAs (caRNAs). Both the DNA-binding domain SAP and the RNA-binding RGG-box region are necessary for the localization of Xist RNA on the Xi. The ATPase and RNA-binding RGG-box regions are necessary for oligomerization.
Homodimer. Interacts (when binding to resveratrol) with PARP1; interaction stimulates the poly-ADP-ribosyltransferase activity of PARP1.
Resveratrol strongly inhibits the tyrosine--tRNA ligase activity.
The nuclear localization signal, which mediates localization to the nucleus, is also important for interacting with tRNA(Tyr), suggesting that it is sterically blocked when tRNA(Tyr) is bound.
Tyrosine--tRNA ligase that catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr). Also acts as a positive regulator of poly-ADP-ribosylation in the nucleus, independently of its tyrosine--tRNA ligase activity. Activity is switched upon resveratrol-binding: resveratrol strongly inhibits the tyrosine--tRNA ligase activity and promotes relocalization to the nucleus, where YARS1 specifically stimulates the poly-ADP-ribosyltransferase activity of PARP1.
Belongs to the aconitase/IPM isomerase family.
Bifunctional iron sensor that switches between 2 activities depending on iron availability (By similarity). Iron deprivation, promotes its mRNA binding activity through which it regulates the expression of genes involved in iron uptake, sequestration and utilization (PubMed:16144863). 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:16144863).
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).
May play a role in fatty acid biosynthesis and insulin sensitivity.
Expressed in goblet cells of the intestines, and colon, in paraventricular hypothalamus and supraoptic nuclei. Weakly expressed in gastric epithelial cells (at protein level). Expressed by goblet cells of small and large intestinal epithelia, kidney and stomach. Expressed in the paraventricular hypothalamus, arcuate nucleus and amygdala of the brain. Weakly expressed in gastric epithelial cells.
Involved in the maintenance and repair of the intestinal mucosa. Promotes the mobility of epithelial cells in healing processes (motogen) (By similarity).
Up-regulated by hypoxia in gastric epithelial cells. Up-regulated by hypoxia-inducible factor 1 alpha (HIF1A).
Belongs to the nucleoporin NSP1/NUP62 family.
Component of the RNA exosome complex. 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 (via C-terminus region) with SETX (via N-terminus domain); the interaction enhances SETX sumoylation (By similarity).
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 (By similarity).
The six exosome core subunits containing a RNase PH-domain are not phosphorolytically active.
Palmitoyltransferase that could catalyze the addition of palmitate onto protein substrates including the D(2) dopamine receptor DRD2.
The C-terminal di-lysine motif confers endoplasmic reticulum localization.
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.
Homodimer (PubMed:2642907). 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 (By similarity).
Plays a role in vesicular protein sorting.
Expressed in the brain (at protein level) (PubMed:22632720). Expressed in carotid arteries and the aorta, mainly in aortic SMCs (PubMed:28062493).
Expression in SMCs and carotid arteries is up-regulated upon injury or by PDGFB.
Involved in transforming growth factor beta (TGF-beta)-induced smooth muscle differentiation. TGF-beta induces expression and nuclear translocation of OLFM2 where it binds to SRF, causing its dissociation from the transcriptional repressor HEY2/HERP1 and facilitating binding of SRF to target genes. Plays a role in AMPAR complex organization. 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 (PubMed:28062493).
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 (PubMed:22632720). Interacts with GRIA2 (By similarity). Interacts with OLFM1 and OLFM3 (By similarity). Interacts with SRF; the interaction promotes dissociation of SRF from the transcriptional repressor HEY2 (By similarity). Interacts with RUNX2 (PubMed:28062493).
Down-regulated by caloric restriction. Up-regulated by insulin and IGF1.
Enhances the STK11/LKB1-induced cell growth suppression activity. Negative regulator of amino acid starvation-induced autophagy.
Expressed in hypothalamus, hippocampus, cerebrum cortex and cerebellum.
Interacts with STK11/LKB1 (By similarity). Interacts with IRS4.
Belongs to the carbon-nitrogen hydrolase superfamily. BTD/VNN family.
Cytoplasmic potassium channel subunit that modulates the characteristics of the channel-forming alpha-subunits. Modulates action potentials via its effect on the pore-forming alpha subunits (Probable). Promotes expression of the pore-forming alpha subunits at the cell membrane, and thereby increases channel activity (By similarity). Mediates closure of delayed rectifier potassium channels by physically obstructing the pore via its N-terminal domain and increases the speed of channel closure for other family members (PubMed:8183366, PubMed:15618540, PubMed:18222921). Promotes the closure of KCNA1, KCNA2 and KCNA5 channels (PubMed:10064591, PubMed:10650996, PubMed:16504945). Accelerates KCNA4 channel closure (PubMed:8183366). Accelerates the closure of heteromeric channels formed by KCNA1 and KCNA4 (PubMed:16504945). Accelerates the closure of heteromeric channels formed by KCNA2, KCNA5 and KCNA6 (PubMed:15618540). Enhances KCNB1 and KCNB2 channel activity (By similarity). Binds NADPH; this is required for efficient down-regulation of potassium channel activity. Has NADPH-dependent aldoketoreductase activity (PubMed:18222921). Oxidation of the bound NADPH strongly decreases N-type inactivation of potassium channel activity (PubMed:18222921, PubMed:21436029).
Detected in brain (PubMed:9334400). Detected in hippocampus, in the middle third of the molecular layer of the dentate gyrus and in the mossy fiber zone of the CA3 region (PubMed:9334400). Detected in globus pallidus and pars reticulata of the substantia nigra (at protein level) (PubMed:9334400). Specifically expressed in the nervous system (PubMed:8183366). Detected in mesenteric arteries (PubMed:15618540).
Homotetramer (PubMed:18222921). Interaction with tetrameric potassium channel alpha subunits gives rise to a heterooctamer (Probable). Identified in potassium channel complexes containing KCNA1, KCNA2, KCNA4, KCNA5, KCNA6, KCNAB1 and KCNAB2 (PubMed:9334400, PubMed:16504945). Interacts with KCNA1 (PubMed:10064591). Interacts with the dimer formed by GNB1 and GNG2; this enhances KCNA1 binding (PubMed:10064591). Interacts with KCNA4 (By similarity). Interacts with KCNB2 and KCNA5 (By similarity). Interacts with SQSTM1 (PubMed:10477520). Part of a complex containing KCNA1, KCNA4 and LGI1; interaction with LGI1 inhibits down-regulation of KCNA1 channel activity (PubMed:16504945).
The N-terminal domain of the beta subunit mediates closure of delayed rectifier potassium channels by physically obstructing the pore.
Beta-oxidation of fatty acids. The highest activity concerns the C6 to C10 chain length substrate.
May interact with YIPF5. Interacts with C9orf72; the interaction mediates recruitment of RAB1A to the ATG1/ULK1 kinase complex. Interacts with GDI1; this promotes dissociation from membranes.
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:21303926). 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:21303926). 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. Regulates the level of CASR present at the cell membrane (By similarity). Plays a role in cell adhesion and cell migration, via its role in protein trafficking (By similarity). Plays a role in autophagosome assembly and cellular defense reactions against pathogenic bacteria (By similarity). Plays a role in microtubule-dependent protein transport by early endosomes and in anterograde melanosome transport (By similarity).
Interacts with EPHA8 (By similarity). Isoform 2 interacts with COIL. Isoform 3 interacts with DLG4.
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 is brain specific and highly enriched in the postsynaptic densities (PSDs), especially in cortical, striatal and hippocampal PSDs.
Nuclear translocation of isoform 3 requires an NMDAR-dependent proteolytic cleavage. A 35 kDa N-terminal form shuttles to the nucleus.
High expression in soft palate. Weak expression in kidney, liver, lung and brain. No expression detected in heart, testis, skeletal muscle amd spleen.
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 (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-18 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.
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 (By similarity). Selenium-binding protein which may be involved in the sensing of reactive xenobiotics in the cytoplasm. May be involved in intra-Golgi protein transport (PubMed:10799528, PubMed:17377489).
In liver, by 3,4,5,3',4'-pentachlorobiphenyl and 3-methylcholanthrene (at protein level).
In vivo target of mycophenolic acid, the active metabolite of the immunosuppressant mycophenolate mofetil.
Present in liver and colon (at protein level).
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:7809169). 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 (By similarity). Has no apparent specificity with regard to the acyl compositions of diacylglycerol (By similarity). Specifically expressed in the cerebellum where it controls the level of diacylglycerol which in turn regulates the activity of protein kinase C gamma. Through protein kinase C gamma, indirectly regulates the dendritic development of Purkinje cells, cerebellar long term depression and ultimately cerebellar motor coordination (By similarity).
Expressed specifically in brain (PubMed:7809169). Highly expressed in cerebellar Purkinje cells (at protein level) (PubMed:7809169).
The activity is calcium-dependent (PubMed:7809169). Requires phosphatidylserine for maximal activity (By similarity).
G proteins are composed of 3 units; alpha, beta and gamma (By similarity). The alpha chain contains the guanine nucleotide binding site (By similarity). Interacts with UBXD5 (By similarity). Interacts with HAX1 (By similarity). Interacts (in GTP-bound form) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane (PubMed:12176367). Interacts with RGS22 (By similarity). Interacts with ARHGEF1. Interacts (in GTP-bound form) with ARHGEF11 (via RGS domain) (By similarity). Interacts (in GTP-bound form) with ARHGEF12 (via RGS domain) (By similarity). Interacts (in GTP-bound form) with CTNND1 (By similarity). Interacts with GAS2L2 (By similarity).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:12176367). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG) (By similarity). 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 (By similarity). Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (By similarity).
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.
Heterodimer with ADAM2/fertilin subunit beta.
In the testis, expressed at all stages of development.
Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite.
Consists of at least two heavy chains and a number of intermediate and light chains. Interacts with BICD2 (By similarity). Interacts with CFAP45 and CFAP52 (By similarity).
May cause the redistribution of PAPOLB from the cytosol to the endoplasmic reticulum.
Associates with the mitochondrial contact site and cristae organizing system (MICOS) complex. May associate with the endoplasmic reticulum membrane protein complex (EMC).
Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization. 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. Through its interaction with the EMC (endoplasmic reticulum membrane protein complex), could regulate mitochondrial lipid homeostasis and thereby mitochondrial fission.
Widely expressed. Highly expressed in hindbrain, spinal cord and brain coronal sections containing corpus callosum, fornix, optic chiasm, thalamus, hypothalamus, midbrain, pons and cerebellum.
Identified in a complex that contains SEL1L, OS9, FAF2/UBXD8, UBE2J1/UBC6E and AUP1 (By similarity). Interacts with the cytoplasmic tail of ITGA2B, ITGA1, ITGA2, ITGA5, ITGAV and ITGAM (By similarity). Interacts (via C-terminus) with UBE2G2; the interaction recruits UBE2G2 to lipid droplets (By similarity). Interacts with ubiquitin ligases AMFR/gp78 and RNF139/TRC8; this promotes interaction of UBE2G2 with AMFR and RNF139 (By similarity). Interacts with apolipoprotein APOB (By similarity).
Plays a role in the translocation of terminally misfolded proteins from the endoplasmic reticulum lumen to the cytoplasm and their degradation by the proteasome (By similarity). Plays a role in lipid droplet formation (By similarity). Induces lipid droplet clustering (By similarity). 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 (By similarity). Also required for the degradation of INSIG1, SREBF1 and SREBF2 (By similarity). Plays a role in regulating assembly and secretion of very low density lipoprotein particles and stability of apolipoprotein APOB (By similarity).
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.
Expressed in brain, eye, olfactory epithelium, spleen and heart. Expressed in the basal layer, consisting of neural precursor cells and immature sensory neurons of the olfactory epithelium, but not in the mature receptor cells.
Homodimer. Interacts with PARP1, SMAD1 and SMAD4 (By similarity). Interacts with EBF1. Interacts with CEP290 (By similarity).
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 (By similarity).
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. Interacts (via N-terminal ectodomain) with APP, forming a 1:1 stoichiometric complex, including with isoforms APP695, APP751 and APP770. Also interacts with APP C-terminal fragment C99 and with Abeta40. Interacts with beta-secretase BACE1/BACE; this interaction may affect BACE1-binding to APP and hence reduce BACE1-dependent APP cleavage. Interacts with LRPAP1/RAP. Interacts (via C-terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS domain). Interacts with PACS1. 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. Interacts with neurotensin/NTS. Interacts (via the N-terminal ectodomain) with PDGFB homodimer. Interacts (via N-terminal ectodomain) with the uPA receptor PLAUR. Interacts with uPA/PLAU and PAI1/SERPINE1, either individually or in complex with each other, leading to endocytosis. Also interacts with PAI1/SERPINE1 in complex with tPA/PLAT. Interacts (via C-terminus) with AP-1 and AP-2 complexes (By similarity). Interacts with BMPR1A and BMPR1B (By similarity). Interacts with lipoprotein lipase LPL; this interaction is optimal in slightly acidic conditions (By similarity). Interacts (via N-terminal ectodomain) with GDNF (via propeptide) and GDNF receptor alpha-1/GFRA1, either individually or in complex with each other (PubMed:21994944, PubMed:23333276). Also interacts with other GDNF receptor alpha family members, including GFRA2, GFRA3 and GFRA4. Interacts with the insulin receptor INSR; this interaction strongly increases the surface exposure of INSR. Interacts (via cytosolic C-terminus) with STK39/SPAK. Interacts (via N-terminal ectodomain) with the heterodimeric complex CRLF1-CLC; within this complex, the interaction is mediated predominantly by the CRLF1 moiety. Interacts with CNTFR, as well as with the tripartite signaling complex formed by CRLF1, CLC and CNTFR. Interacts (via N-terminal ectodomain) with IL6; this interaction leads to IL6 internalization and lysosomal degradation. Binding of SOLRL1 secreted N-terminal ectodomain to IL6 may increase IL6 trans signaling. Interacts with secreted IL6R; this interaction leads to IL6R internalization. Also interacts with transmembrane IL6R; this interaction does not seem to affect subcellular location. Interacts with APOE (By similarity). Interacts with apolipoprotein E-rich beta-VLDL (By similarity). Interacts with APOA5; this interaction leads to APOA5 internalization and is abolished by heparin. Interaction with APOA5 results in enhanced binding to chylomicrons. Interacts with ROCK2 (By similarity). Interacts (via cytosolic C-terminus) with PPP3CB/calcineurin A beta (PubMed:25967121). Interacts with NTRK2/TRKB (By similarity). Interacts (via cytosolic C-terminus) with HSPA12A in an ADP-dependent manner; this interaction affects SORL1 internalization and subcellular localization (By similarity). Interacts (via N-terminal ectodomain) with ERBB2/HER2 (By similarity).
Belongs to the VPS10-related sortilin family. SORL1 subfamily.
Highly expressed in the cerebral cortex, the pyramidal cells of the CA region of the hippocampus, the granular cells of the dentate gyrus, the Purkinje cell layer of the cerebellum and the piriform cortex. Lower levels were detected over the mitral cell layer of the olfactory bulb, the nuclei of the amygdala, the nucleus reticularis of the thalamus and several hypothalamic nuclei. In the brainstem weak expression in the pontine nuclei. In the central nervous system, expression is restricted to neurons (PubMed:9510025). Expressed in intimal smooth muscle cell after vascular injury (PubMed:17332490).
Phosphorylation at Ser-2207 facilitates the interaction with GGA1.
Sorting receptor that directs several proteins to their correct location within the cell. Along with AP-1 complex, involved Golgi apparatus - endosome sorting. 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. May also sort newly produced amyloid-beta peptides to lysosomes for catabolism. Does not affect APP trafficking from the endoplasmic reticulum to Golgi compartments. 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 (By similarity). 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 (By similarity). Sorting receptor for lipoprotein lipase LPL. Promotes LPL localization to endosomes and later to the lysosomes, leading to degradation of newly synthesized LPL. 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. 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 (By similarity). 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 (PubMed:25967121). 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. By acting on the migration of intimal smooth muscle cells, may accelerate intimal thickening following vascular injury (By similarity). Stimulates proliferation and migration monocytes/macrophages. 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 (By similarity). 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. Might regulate IL6 signaling, decreasing cis signaling, while up-regulating trans signaling (By similarity).
Within the Golgi apparatus, the propeptide may be cleaved off by FURIN or a furin-like protease. After cleavage, the propeptide interacts with the mature protein N-terminus, preventing the association with other ligands. At the cell surface, partially subjected to proteolytic shedding that releases the ectodomain in the extracellular milieu. The shedding may be catalyzed by ADAM17/TACE. 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.
Acetylated following deubiquitination by VCPIP1, leading to recruitment to chromatin and DNA damage sites.
Autocatalytically cleaved in response to double-stranded DNA-binding: autocatalytic cleavage takes place in trans and leads to inactivation.
DNA-binding activates the protease activity: single-stranded DNA-binding specifically activates ability to cleave covalent DNA-protein cross-links (DPCs). In contrast, double-stranded DNA-binding specifically activates autocatalytic cleavage, and subsequent inactivation.
DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. 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. Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis. Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4 (By similarity). Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs. SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs (By similarity). Involved in recruitment of VCP/p97 to sites of DNA damage. Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation. Does not activate CHEK1 in response to DNA damage. May also act as a 'reader' of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis (By similarity).
Homodimer. Interacts (VIA PIP-box) with PCNA (when ubiquitinated). Interacts (via its SHP-box) with VCP/p97. Interacts with RAD18. Interacts with KCTD13 and POLD3.
Monoubiquitinated; monoubiquitination promotes exclusion from chromatin. Deubiquitinated by VCPIP1: deubiquitination is required for subsequent acetylation and recruitment to chromatin and DNA damage sites.
Phosphorylation by CHEK1 promotes recruitment to chromatin.
The PIP-box mediates the interaction with PCNA, while the UBZ4-type zinc finger mediates binding to 'Lys-48'- and 'Lys-63'-linked polyubiquitin.
Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (By similarity). 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. Involved in the import of PTS1- and PTS2-type containing proteins (By similarity).
Interacts (via SH3 domain) with PEX14 (via SH3-binding motif); forming the PEX13-PEX14 docking complex. Interacts with PEX19.
Belongs to the eukaryotic ribosomal protein eL32 family.
At rest, the N- and C-terminal domains interact, as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain. Upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain. Fully calcium-saturated calmodulin then leaves the N-terminal domain, binding solely to the C-terminal domain, and the whole autoinhibitory complex dissociates, resulting in activation of adenylate cyclase. As local calcium concentrations decrease, the calmodulin becomes calcium free and binds once more to the N-terminal domain, whereupon the whole system returns to rest with the re-association of the autoinhibitory complex (PubMed:8163524, PubMed:8557635, PubMed:19305019). In non-excitable cells, activated by capacitative calcium entry (CCE) through store-operated channels, namely through interaction with ORAI1 and STIM1; membrane raft and caveolae localization and membrane integrity are indispensable (PubMed:19158400, PubMed:11744699, PubMed:19171672, PubMed:22494970, PubMed:20410303). CCE-mediated adenylate cyclase activity is decreased by AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-regulated by AKAP9 and the mitochondrially targeted AKAP1 (PubMed:20410303). In excitable cells, activated during membrane depolarization through L-type voltage-gated calcium channels (VGCC), leading to calcium entry; the L-type alpha subunit is sufficient (PubMed:24086669, PubMed:25381556). Activated via stimulation of the GLP1R (PubMed:25381556). Synergistically activated by calcium/calmodulin and GNAS (PubMed:13680124). Stimulated by forskolin (PubMed:16186630, PubMed:13680124). Inhibited by PKA directly bound to AKAP5 at membrane raft (PubMed:22976297, PubMed:21771783). Inhibition by acute activation of OPRM1 and activation by chronic activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by G beta-gamma dimer (PubMed:16186630).
Brain (PubMed:13680124, PubMed:8557635). Expressed in insulin-producing cells (PubMed:13680124).
Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion (PubMed:8163524, PubMed:24086669, PubMed:22494970, PubMed:21046358, PubMed:13680124, PubMed:25381556). Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation (PubMed:8163524). Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment (PubMed:21046358, PubMed:13680124, PubMed:25381556). Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells (PubMed:16741924).
EC50 is approximately 4 times more sensitive to stimulation by calcium/calmodulin than isoform 1 and 2.
Homodimer; via transmembrane domain (PubMed:19158400, PubMed:11856299). Monomer (PubMed:19158400). Heterodimer (PubMed:11856299). Oligemer; via transmembrane domain (PubMed:11856299). Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity through PKA phosphorylation (PubMed:22976297). Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory effects of PKA on adenylate cyclase activity; interaction is dependent of catalytically active PPP2CA; antagonizes interaction with calmodulin (PubMed:22976297, PubMed:16258073). Interacts with AKAP5 (palmitoylated form); promotes the phosphorylation of ADCY8 after store-operated calcium entry (SOCE) stimulation at membrane raft (PubMed:21771783, PubMed:20410303). Interacts with ORAI1; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events (PubMed:22494970). Interacts with STIM1 (PubMed:22494970). Interacts with actin; interaction is calcium independent; interaction is affected by calcium-calmodulin; interaction controls the distribution and regulation of ADCY8 (PubMed:22399809). Interacts with calmodulin; at rest, interacts via N-terminal domain; upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain forming an autoinhibitory complex; fully calcium-saturated calmodulin leaves the N-terminal domain, binding solely to the C-terminal domain leading to dissociation of autoinhibitory complex and resulting in activation of adenylate cyclase; antagonizes interaction with PPP2CA; interaction is calcium dependent (PubMed:19305019, PubMed:16258073, PubMed:22399809). Interacts with PPP2R5D (PubMed:22976297).
N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity.
Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8.
Reduces by glucose (PubMed:21046358). Up-regulated during vascular smooth muscle cell de-differentiation by IL1B (PubMed:16741924).
The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain. The two transmembrane clusters are necessary and suficient for the plasma membrane targeting and oligomers assembly (PubMed:11856299). The N-terminal and C-terminal domains interact at rest as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain; the binding is specifically inhibited by fully calcium-saturated calmodulin, resulting in activation of AC8 (PubMed:19305019).
Consists of two distinct domains, a catalytic domain and a coenzyme-binding domain.
Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols (By similarity). Is active with D-sorbitol (D-glucitol) leading to the C2-oxidized product D-fructose (PubMed:6862079). Is a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol, which constitutes an important alternate route for glucose metabolism. May play a role in sperm motility by using sorbitol as an alternative energy source for sperm motility (By similarity).
Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols. Is active with D-sorbitol (D-glucitol) leading to the C2-oxidized product D-fructose. Is a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol, which constitutes an important alternate route for glucose metabolism. May play a role in sperm motility by using sorbitol as an alternative energy source for sperm motility.
PubMed:8223590 reports a cDNA predicted to encode a protein with an extended N-terminus but there is no further evidence for the existence of such a protein.
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.
Single-stranded DNA-binding protein that preferentially binds to the sterol regulatory element (SRE) sequence 5'-GTGCGGTG-3', and thereby mediates transcriptional repression (By similarity). Has a role as transactivator of the Myc promoter (By similarity). Binds single-stranded RNA in a sequence-specific manner (PubMed:7788528). Binds G-rich elements in target mRNA coding sequences (By similarity). Prevents G-quadruplex structure formation in vitro, suggesting a role in supporting translation by resolving stable structures on mRNAs (By similarity).
E3 ubiquitin ligase that plays important roles in the regulation of neuronal apoptosis, selective autophagy or cell proliferation. Stimulates the degradation of kinetochore ZW10 interacting protein ZWINT in a proteasome-dependent manner, leading to negative regulation of cell proliferation. Inhibits autophagic degradation of diverse known targets while contributing to autophagy of midbodies. Autophagy-inhibitory activity involves MCL1, which TRIM17 assembles into complexes with the key autophagy regulator BECN1 (By similarity). Controls neuronal apoptosis by mediating ubiquitination and degradation of MCL1 to initiate neuronal death. In addition, regulates NFAT transcription factors NFATC3 and NFATC4 activities by preventing their nuclear localization, thus inhibiting their transcriptional activities. Decreases TRIM41-mediated degradation of ZSCAN2 thereby stimulating alpha-synuclein/SNCA transcription in neuronal cells (By similarity). Prevents the E3 ubiquitin-ligase activity of TRIM28 and its interaction with anti-apoptotic BCL2A1, blocking TRIM28 from ubiquitinating BCL2A1 (By similarity).
Expressed almost exclusively in the testis.
Interacts (via coiled coil) with TRIM44 (via coiled coil). Interacts with TRIM28; this interaction prevents TRIM28 activity on BCL2A1 (By similarity). Interacts with TRIM41; this interaction prevents TRIM41 activity on ZSCAN2 (By similarity). Interacts with BECN1 (By similarity). Interacts with NFATC3 and NFATC4; these interactions prevent NFATC3 and NFATC4 nuclear localization (By similarity).
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.
Strongly expressed in testis. Also expressed in lung, brain and thymus.
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.
Major sphingomyelin synthase at the Golgi apparatus. 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. Does not use free phosphorylcholine or CDP-choline as donor. 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 (By similarity). Plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1 (PubMed:21980337).
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. May play an important role in linking the actin cytoskeleton to the plasma membrane at the synaptic junction.
Brain, and widely expressed in neural tissue. Highly concentrated in synapses of developed neurons. In developing neurons, concentrated in the lamellipodia of the growth cone.
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, TGN38 and p70-S6K.
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.
Belongs to the connexin family. Gamma-type subfamily.
Catalyzes the reduction of saturated and unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols. It plays an essential role in the production of ether lipids/plasmalogens which synthesis requires fatty alcohols. In parallel, it is also required for wax monoesters production since fatty alcohols also constitute a substrate for their synthesis.
Interacts with PEX19; PEX19 mediates the targeting of FAR1 to peroxisomes.
Acts as a transcriptional activator or repressor. 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. 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. It may interact with additional basic-zipper proteins that determine a subtype of Maf-responsive element binding (By similarity).
Expressed in lens cells at 12 dpc. Expressed in the cartilage of ribs and limbs, in the eyes and spinal cord at 15 dpc. Expressed in the outer equatorial epithelium and lens fibers at 16 dpc (at protein level). Expressed throughout the lens fiber cells at 13 and 16 dpc; not detected in the epithelium of the lens. In the eyes, confined to the lens; not detected in the retina at 15 dpc. In spinal cord, expressed in the dorsal and ventral part of the dorsal horn at 15 dpc. Predominantly expressed in post-mitotic cells.
Expressed in the muscle, uterus, intestine, kidney, liver and skin. Expressed in the lens epithelial and fiber cells.
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. The phosphorylation status can serve to either stimulate or inhibit transcription (By similarity).
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is triggered by glucocorticoids (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). Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). Interacts with TP53 (By similarity). Interacts with IER5 (By similarity). Interacts with MFHAS1; the interaction is direct (By similarity). Interacts with PABIR1/FAM122A (By similarity). Interacts with CRTC3 (By similarity).
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.
Calcium-regulated non-lysosomal thiol-protease.
Predominantly expressed in stomach and small intestine, although low levels of expression in other organs.
Binds RAB27A that has been activated by GTP-binding.
May act as Rab effector protein and play a role in vesicle trafficking. Binds phospholipids (By similarity).
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 (By similarity). 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 (By similarity). 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:21209459). Thus, plays a role in regulation of VLCFAs and energy metabolism namely, in the degradation and biosynthesis of fatty acids by beta-oxidation (PubMed:21209459). However,the actual function of ABCD2 in vivo is still unclear (By similarity).
Expression is high in the liver before weaning and very low in adult rats; the reverse developmental regulation is observed in the brain.
Homodimers (PubMed:28258215). Homotetramers (PubMed:28258215). The minimal functional unit is a homodimer but the major oligomeric form in peroxisomal membrane is a homotetramer. Forms heterotetramers with ABCD1 (PubMed:28258215). Forms heterodimers with ABCD1 (PubMed:21209459). Forms heterodimers with ABCD3 (By similarity). In addition to tetramers, some larger molecular assemblies are also found but represented only a minor fraction (PubMed:28258215). Interacts with PEX19; facilitates ABCD2 insertion into the peroxisome membrane (By similarity).
Acetylated (PubMed:30193097). Lysine acetylation by p300/EP300 is increased on high glucose conditions and promotes ubiquitination by UBR5; 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 (By similarity).
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:4186849, PubMed:30193097, PubMed:26322521, PubMed:26709450, PubMed:28345895, PubMed:31461616). Regulates cataplerosis and anaplerosis, the processes that control the levels of metabolic intermediates in the citric acid cycle (PubMed:30193097). 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 (By similarity). 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 (By similarity).
In eukaryotes there are two isozymes: a cytoplasmic one and a mitochondrial one.
Phosphoenolpyruvate carboxykinase activity is regulated by acetylation and glucose levels (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) (PubMed:30193097). 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 (By similarity). Phosphoenolpyruvate carboxykinase activity is inhibited by 3-mercaptopicolinate (PubMed:26322521). Phosphoenolpyruvate carboxykinase activity is inhibited by 3-[(carboxymethyl)thio]picolinate (CMP), which acts as a competitive inhibitor at the oxaloacetate/phosphoenolpyruvate-binding site (PubMed:31461616). Phosphorylation at Ser-90 reduces the binding affinity to oxaloacetate and converts the enzyme into an atypical protein kinase using GTP as donor (By similarity).
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 (By similarity).
Regulated by cAMP, dexamethasone, glucagon and by insulin. Dexamthasone, glucagon and cAMP increase levels, insulin decreases levels.
Ubiquitination by UBR5 leads to proteasomal degradation.
Plays role in pre-mRNA splicing as core component of spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes. Is also a component of the minor U12 spliceosome. As part of the U7 snRNP it is involved in histone pre-mRNA 3'-end processing.
Although related to other DMRT proteins, it does not contain a canonical DM DNA-binding domain.
Interacts with SKI (By similarity). Interacts (via LRR repeat) with CDC42BPA (via AGC-kinase C-terminal domain) and CDC42BPB (via AGC-kinase C-terminal domain) (PubMed:25107909). Interacts (via LRR repeat) with LIMK1 (via LIM zinc-binding domains). Forms a tripartite complex with CDC42BPA, CDC42BPB and LIMK1 (By similarity).
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.
Negative regulator of hepatic phosphatidylinositol 3-kinase (PI3K) activity.
Detected in brain and testis (at protein level). Ubiquitous.
Implicated in endocytosis. May recruit other proteins to membranes with high curvature (By similarity).
Interacts with ARC, SYNJ1 and DNM1. Interacts with PDCD6IP (By similarity). Interacts with BIN2.
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.
Interacts with SRPK1. Interacts with HSP70 (HSPA1A or HSPA1B).
Suppresses polyglutamine (polyQ) aggregation of ATXN3 in neuronal cells.
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 (By similarity). Interacts with ATG9A (By similarity).
Belongs to the PI3/PI4-kinase family. Type II PI4K subfamily.
Detected in adult brain, especially in neurons in the cerebellum, brain cortex, dorsal root ganglion and spinal cord (at protein level).
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 (PubMed:11244087). Palmitoylated by ZDHHC3 and ZDHHC7 in the CCPCC motif. Palmitoylation is cholesterol-dependent, and required for TGN localization (By similarity).
Ubiquitinated by ITCH; this does not lead to proteasomal degradation.
Homodimer. May undergo minor heretodimerization with DIO1 and DIO2.
It is uncertain whether Met-1 or Met-27 is the initiator.
Neonatal skin, placenta, skeletal muscle and cerebral cortex.
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.
In the brain, expressed in the central amygdala, hippocampus, area postrema, nucleus of the tractus solitary and cerebellum.
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:25332973, PubMed:12403838). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (PubMed:9506976, PubMed:12403838). 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).
Contains an active site 4-methylidene-imidazol-5-one (MIO), which is formed autocatalytically by cyclization and dehydration of residues Ala-Ser-Gly.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (PubMed:9405631, PubMed:12954101). Interacts (via PH domain) with GTP-bound RALA and RALB (By similarity) (PubMed:15920473). Interacts with SH3BP1; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (By similarity).
Highly expressed in olfactory mucosa but undetectable in thymus, kidney, lung, brain, spleen and liver.
May have the capacity to recognize and bind specific classes of odorants. May act as a carrier molecule, transporting odorants across the mucus layer to access receptor sites. May serve as a primary defense mechanism by recognizing and removing potentially harmful odorants or pathogenic microorganisms from the mucosa or clearing excess odorant from mucus to enable new odorant stimuli to be received (By similarity).
Acetylation at Lys-265 and Lys-268 seems to decrease lipid kinase activity. Deacetylation of these sites by SIRT1 positively regulates the exocytosis of TSH-containing granules from pituitary cells (By similarity).
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. 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). 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 (By similarity). Required for synaptic vesicle transport (By similarity). Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis. 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:12847086). Participates in cell junction assembly. Modulates adherens junctions formation by facilitating CDH1/cadherin trafficking. Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions. Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins (By similarity). Required for uropodium formation and retraction of the cell rear during directed migration. 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 (By similarity). Negative regulator of T-cell activation and adhesion. Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor. 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 (By similarity). May compete with beta-integrins for the same binding site on TLN1 and TLN2 (By similarity). Interacts with ARF6; interaction stimulates 1-phosphatidylinositol-4-phosphate 5-kinase activity (PubMed:12847086). Interacts with AP2B1 (By similarity). Interacts with AP2M1; phosphorylation of PIP5K1C by CSK disrupts the interaction; clathrin competes with PIP5K1C (By similarity). Interacts with CDH1 (By similarity). 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 (By similarity).
Phosphorylation on Ser-672 negatively regulates binding to TLN2 and is strongly stimulated in mitosis. Phosphorylation on Tyr-671 is necessary for targeting to focal adhesions. Phosphorylation on Ser-672 and Tyr-671 are mutually exclusive. Phosphorylated by SYK and CSK. Tyrosine phosphorylation is enhanced by PTK2 signaling. Phosphorylated at Tyr-635 upon EGF stimulation. Some studies suggest that phosphorylation on Tyr-671 enhances binding to tailins (TLN1 and TLN2) (By similarity); others that phosphorylation at Tyr-671 does not directly enhance binding to tailins (TLN1 and TLN2) but may act indirectly by inhibiting phosphorylation at Ser-672.
Activated by DAG and phorbol esters. Phorbol-ester/DAG-type domains bind DAG, mediating translocation to membranes. Autophosphorylation of Ser-711 and phosphorylation of Ser-707 by PKC relieves auto-inhibition by the PH domain. Catalytic activity is further increased by phosphorylation at Tyr-718 in response to oxidative stress.
Interacts (via C-terminus) with LCK. Interacts (via N-terminus and zing-finger domain 1 and 2) with PRKCD in response to oxidative stress; the interaction is independent of PRKD2 tyrosine phosphorylation.
Phosphorylation of Ser-873 correlates with the activation status of the kinase. Ser-707 is probably phosphorylated by PKC. Phosphorylation at Ser-244 by CSNK1D and CSNK1E promotes nuclear localization and substrate targeting. Phosphorylation at Ser-244, Ser-707 and Ser-711 is required for nuclear localization. Phosphorylated at Tyr-438 by ABL1 in response to oxidative stress. Phosphorylated at Tyr-718 by ABL1 specifically in response to oxidative stress; requires prior phosphorylation at Ser-707 or/and Ser-711.
Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress-induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. May potentiate mitogenesis induced by the neuropeptide bombesin 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. In response to oxidative stress, is phosphorylated at Tyr-438 and Tyr-718 by ABL1, which leads to the activation of PRKD2 without increasing its catalytic activity, and mediates activation of NF-kappa-B. In response to the activation of the gastrin receptor CCKBR, is phosphorylated at Ser-244 by CSNK1D and CSNK1E, translocates to the nucleus, phosphorylates HDAC7, leading to nuclear export of HDAC7 and inhibition of HDAC7 transcriptional repression of NR4A1/NUR77. Upon TCR stimulation, is activated independently of ZAP70, translocates from the cytoplasm to the nucleus and is required for interleukin-2 (IL2) promoter up-regulation. During adaptive immune responses, is required in peripheral T-lymphocytes for the production of the effector cytokines IL2 and IFNG after TCR engagement and for optimal induction of antibody responses to antigens. In epithelial cells stimulated with lysophosphatidic acid (LPA), is activated through a PKC-dependent pathway and mediates LPA-stimulated interleukin-8 (IL8) secretion via a NF-kappa-B-dependent pathway. During TCR-induced T-cell activation, interacts with and is activated by the tyrosine kinase LCK, which results in the activation of the NFAT transcription factors. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane and in polarized cells is involved in the transport of proteins from the TGN to the basolateral membrane. Plays an important role in endothelial cell proliferation and migration prior to angiogenesis, partly through modulation of the expression of KDR/VEGFR2 and FGFR1, two key growth factor receptors involved in angiogenesis. In secretory pathway, is required for the release of chromogranin-A (CHGA)-containing secretory granules from the TGN. Downstream of PRKCA, plays important roles in angiotensin-2-induced monocyte adhesion to endothelial cells.
Component of the DNA mismatch repair (MMR) complex composed at least of MCM9, MCM8,MSH2, MSH3, MSH6, PMS1 and MLH1. Heterodimer consisting of MSH2-MSH6 (MutS alpha) or MSH2-MSH3 (MutS beta). Both heterodimers form a ternary complex with MutL alpha (MLH1-PMS1). Interacts with MCM9; the interaction recruits MCM9 to chromatin. Interacts with MCM8. Interacts with EXO1. 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 ATR. Interacts with SLX4/BTBD12; this interaction is direct and links MutS beta to SLX4, a subunit of different structure-specific endonucleases. Interacts with SMARCAD1.
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. 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.
May play a role in intracellular immune modulation by activating NF-kappaB response and attenuating Toll-like-receptor response.
Endothelins are endothelium-derived vasoconstrictor peptides.
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.
Activated by Ca(2+)/calmodulin. Must be phosphorylated to be maximally active. Activated by CAMKK1.
Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. In vitro, isoform 1 and isoform 2 phosphorylate CREB1, SYN1/synapsin I. Phosphorylates and activates CAMK1.
Isoform 1 and isoform 2 are phosphorylated by CAMKK1.
Isoform 1 is expressed in liver, heart, lung, kidney, spleen and testis. Isoform 2 is predominantly expressed in cerebrum and cerebellum.
Homodimer; disulfide-linked. May form heterodimers with FEZ1. Interacts with synaptotagmin (By similarity).
Involved in axonal outgrowth and fasciculation.
May be involved in several stages of intracellular trafficking.
The PX domain mediates specific binding to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns(P3)).
Interacts with KNTC1 and ZW10. These interactions appear weak and may be transient or indirect. Interacts with dynein intermediate chain and dynactin (DCTN1) (By similarity). Interacts with the catalytically active form of USP45 (By similarity).
Monoubiquitinated with'Lys-48' linkage (By similarity). Deubiquitinated by USP45 (By similarity).
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. 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) (By similarity). Plays a role in cell migration (By similarity).
In the mitochondria, together with PHB, forms large ring complexes (prohibitin complexes) in the inner mitochondrial membrane (IMM) and functions as chaperone protein that stabilizes mitochondrial respiratory enzymes and maintains mitochondrial integrity in the IMM, which is required for mitochondrial morphogenesis, neuronal survival, and normal lifespan. The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner.Also regulates cytochrome-c oxidase assembly (COX) and mitochondrial respiration. Binding to sphingoid 1-phosphate (SPP) modulates its regulator activity. Has a key role of mitophagy receptor involved in targeting mitochondria for autophagic degradation. Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6.
In the nucleus, serves as transcriptional co-regulator. Acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases. Functions as an estrogen receptor (ER)-selective coregulator that potentiates the inhibitory activities of antiestrogens and represses the activity of estrogens. Competes with NCOA1 for modulation of ER transcriptional activity.
In the plasma membrane, is involved in IGFBP6-induced cell migration (By similarity). Cooperates with CD86 to mediate CD86-signaling in B lymphocytes that regulates the level of IgG1 produced through the activation of distal signaling intermediates. Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity).
LC3-interaction region (LIR) is required for interaction with MAP1LC3B/LC3-II and for Parkin-mediated mitophagy.
Phosphorylated. Tyrosine phosphorylation is indirectly stimulated by IGFBP6.
Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors and sex steroid hormones in the nucleus.
The mitochondrial prohibitin complex consists of two subunits (PHB1 and PHB2), assembled into a membrane-associated ring-shaped supercomplex of approximately 1 mDa (PubMed:11302691). Interacts with ESR1, HDAC1 and HDAC5 (By similarity). Interacts with ZNF703. Interacts with STOML2. Interacts with ARFGEF3 (By similarity). Interacts with SPHK2. Interacts with COX4I1; the interaction associates PHB2 with COX (By similarity). Interacts with MAP1LC3B (membrane-bound form LC3-II); the interaction is direct and upon mitochondrial depolarization and proteasome-dependent outer membrane rupture. Interacts with IGFBP6 (via C-terminal domain). Interacts with CLPB (By similarity). Interacts with CD86 (via cytoplasmic domain); the interactions increases after priming with CD40. Interacts with AFG3L2. Interacts with DNAJC19 (By similarity).
Interacts with PRMT5. Interacts with FBXO10. Interacts with FBXO11.
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.
Belongs to the bacterial ribosomal protein bL17 family.
Specifically expressed in the germ line and not in the somatic cells of the testis, reaching its peak at the pachytene stage of the meiotic prophase. Detected in pachytene spermatocytes and round spermatids (at protein level).
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 (By similarity).
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. Fructose 2,6-bisphosphate acts as competitive inhibitor. Strongly inhibited by Ca(2+) (By similarity).
Higher levels where found in testes followed by brain, adrenal gland, pituitary gland, ovary, liver and kidney. Low expression was found in muscle.
Interacts (via effector domain) with RALBP1; during mitosis, recruits RALBP1 to the mitochondrion where it promotes DNM1L phosphorylation and mitochondrial fission (PubMed:7623849). Interacts with EXOC2/Sec5 and EXOC8/Exo84; binding to EXOC2 and EXOC8 is mutually exclusive. Interacts with Clostridium exoenzyme C3. Interacts with RALGPS1. Interacts with LPAR1 and LPAR2. Interacts with GRK2 in response to LPAR1 activation. RALA and GRK2 binding to LPAR1 is mutually exclusive (By similarity). Interacts with CDC42 (PubMed:7623849).
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. Acts as a GTP sensor for GTP-dependent exocytosis of dense core vesicles. 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 (By similarity). The RALA-exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling (By similarity). 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 (By similarity). 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 (By similarity).
Phosphorylated. Phosphorylation at Ser-194 by AURKA/Aurora kinase A, during mitosis, induces RALA localization to the mitochondrion where it regulates mitochondrial fission.
Belongs to the RecA family. DMC1 subfamily.
May participate in meiotic recombination, specifically in homologous strand assimilation, which is required for the resolution of meiotic double-strand breaks.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. GTPBP1 subfamily.
Detected in pineal gland (at protein level).
Interacts with EXOSC2/RRP4, EXOSC3/RRP40, EXOSC5/RRP46, HNRNPD, HNRNPR and SYNCRIP. Identified in a complex with HNRNPD, HNRNPL, HNRNPQ, HNRNPR, HNRNPU and AANAT mRNA, but does not bind mRNA by itself.
Promotes degradation of target mRNA species. Plays a role in the regulation of circadian mRNA stability. Binds GTP and has GTPase activity.
AM and PAMP are potent hypotensive and vasodilatator agents.
Expressed in adrenal glands, lung, kidney, heart, spleen, duodenum and submandibular glands.
Expressed in a wide range of tissues (but not the heart or skeletal muscle), the expression is specific for certain actin-rich cell types within these tissues. Expression is prominent in the cortical regions of ion-transporting duct cells in the pancreas, in the salivary parotid gland and in certain F-actin-rich cells in the distal tubule/collecting duct. In primary cultures of gastric fibroblasts, expression is mainly within the tips of lamellipodia and at the leading edges of membrane ruffles.
Interacts with F-actin. Interacts with ANKRD54. Interacts with KBTBD10 (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.
Belongs to the eukaryotic cobalamin transport proteins family.
Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the CBLIF-cobalamin complex is internalized via receptor-mediated endocytosis (By similarity).
Arg-182 is dimethylated, probably to asymmetric dimethylarginine.
Expressed in brain, spleen, lung, liver, kidney, testis and heart. Weakly expressed in skeletal muscle (at protein level).
Homomultimer (By similarity). Found in the supraspliceosome complex (PubMed:19282290) Identified in the spliceosome C complex (By similarity). Interacts with KHDRBS3 (By similarity). Forms a complex with ILF2, ILF3, YLPM1, KHDRBS1, NCOA5 and PPP1CA (By similarity). Interacts with SAFB/SAFB1 (By similarity). Interacts with ERAP1; the interaction is RNA-independent (By similarity). Interacts with CLK2, KHDRBS2, SAFB, TRA2B and YTHDC1 (PubMed:19282290). Interacts with PPIA/CYPA (By similarity).
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 SMN. 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.
G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis. Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system.
Ligand-binding promotes phosphorylation of serine residues in the C-terminal cytoplasmic domain. Phosphorylation is important for receptor endocytosis after ligand-binding (By similarity).
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins (PubMed:7908909). Interacts at microtubules with CABP1 (via EF-hands 1 and 2) but not with calmodulin (PubMed:15095872). Interacts with FYCO1 (via C-terminus). Interacts with TP53INP1 and TP53INP2. Interacts with TBC1D25. Directly interacts with SQSTM1; this interaction leads to MAP1LC3B recruitment to inclusion bodies containing polyubiquitinated protein aggregates and to inclusion body degradation by autophagy (By similarity). Interacts with ATG4B (PubMed:19322194). Interacts with MAPK15 and BNIP3. Interacts with MAPB1, KEAP1, PCM1, OFD1, CEP131, and TECPR2. Interacts with TBC1D5. Found in a complex with UBQLN1 and UBQLN2. Interacts with UBQLN4 (via STI1 1 and 2 domains). Interacts with UBQLN1 in the presence of UBQLN4. Interacts with ATG13. Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3 (By similarity). Interacts with PLCL1; the interaction inhibits autophagosome formation (PubMed:23399561). Interacts with TRIM16 (By similarity). Interacts with CRY1 and PER2 (By similarity). Interacts with the reticulophagy receptor TEX264 (By similarity). Membrane-bound form LC3-II interacts with PHB1 and PHB2; the interaction takes place upon Parkin-mediated mitochondrial damage (By similarity). Interacts with PJVK; the interaction is direct (By similarity). Interacts with KBTBD6 and KBTBD7; the interaction is direct (By similarity). Interacts with AMBRA1 (via LIR motif) (By similarity). Interacts with JMY; the interaction results in the activation of JYM's nucleation activity in the cytoplasm (By similarity). Interacts with MOAP1 (via LIR motif) (By similarity). Interacts with TAX1BP1 (By similarity).
Abundant only in neurons. Detected in testes.
Phosphorylation by PKA inhibits conjugation of phosphatidylethanolamine (PE). Interaction with MAPK15 reduces the inhibitory phosphorylation and increases autophagy activity.
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:11060023, PubMed:16183633, PubMed:16874114). 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. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms. In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy. ATG4B constitutes the major protein for proteolytic activation (By similarity). ATG4D is the main enzyme for delipidation activity (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. Promotes primary ciliogenesis by removing OFD1 from centriolar satellites via the autophagic pathway. 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. Upon nutrient stress, directly recruits cofactor JMY to the phagophore membrane surfaces and promotes JMY's actin nucleation activity and autophagosome biogenesis during autophagy.
Heteromer. Composed of TAMALIN, CYTH2 and at least one GRM1. Also interacts with CYTH3, GRM2, GRM3 and GRM5.
Plays a role in intracellular trafficking and contributes to the macromolecular organization of group 1 metabotropic glutamate receptors (mGluRs) at synapses.
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 (Probable). FA2H is stereospecific for the production of (R)-2-hydroxy fatty acids (By similarity). Plays an essential role in the synthesis of galactosphingolipids of the myelin sheath (PubMed:17901466). Responsible for the synthesis of sphingolipids and glycosphingolipids involved in the formation of epidermal lamellar bodies critical for skin permeability barrier (By similarity). Participates in the synthesis of glycosphingolipids and a fraction of type II wax diesters in sebaceous gland, specifically regulating hair follicle homeostasis. Involved in the synthesis of sphingolipids of plasma membrane rafts, controlling lipid raft mobility and trafficking of raft-associated proteins (By similarity).
Detected at low levels in sciatic nerve from newborns. Levels increase strongly during the first 3 weeks, and decrease thereafter to reach a low, constitutive level in 4 week olds. Expressed at a low, constitutive level in adults.
Detected in oligodendrocytes (at protein level). Detected in sciatic nerve.
The N-terminal cytochrome b5 heme-binding domain is essential for catalytic activity.
The histidine box domains may contain the active site and/or be involved in metal ion binding.
Up-regulated in sciatic nerve during myelination. Up-regulated in differentiating cultured Schwann cells.
Homooligomer. Interacts with DYSF (By similarity). Interacts with DLG1 and KCNA5; forms a ternary complex (PubMed:15277200). Interacts with DAG1 (via its C-terminal); the interaction prevents binding of DAG1 with DMD. Interacts with TRIM72. Interacts with MUSK; may regulate MUSK signaling. Interacts with BVES. Interacts with CAVIN1, CAVIN2 and CAVIN4 (By similarity).
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. Mediates the recruitment of CAVIN2 and CAVIN3 proteins to the caveolae.
Sumoylation with SUMO3 by PIAS4 may reduce agonist-induced internalization and desensitization of adrenergic receptor ABRD2.
Part of the SNAPc complex composed of 5 subunits: SNAPC1, SNAPC2, SNAPC3, SNAPC4 and SNAPC5. SNAPC2 interacts with TBP and SNAPC4 (By similarity).
Monomer. Found in a complex with GRSF1, DDX28, DHX30 and FASTKD5. Associates with the 16S mitochondrial rRNA (16S mt-rRNA). Forms a regulatory protein-RNA complex, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mt-rRNA.
Plays an important role in assembly of the mitochondrial large ribosomal subunit. 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. May play a role in mitochondrial apoptosis.
Component of the nuclear pore complex that has a direct role in nuclear protein import. Actively displaces NLSs from importin-alpha, and facilitates disassembly of the importin-alpha:beta-cargo complex and importin recycling. Interacts with regulatory proteins of cell cycle progression including CDKN1B. This interaction is required for correct intracellular transport and degradation of CDKN1B.
Does not interact with TPR (By similarity). Interacts with Importin alpha-2, Importin beta, Importin beta-2, NUP153, Ran binding protein 7, CDKN1B and itself.
Highly expressed in testis, intermediate levels in kidney, liver, spleen and low basal levels in somatic cells. Expression in testis undergoes changes and subcellular localization during germ cell differentiation.
Belongs to the eukaryotic RPA43 RNA polymerase subunit family.
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. 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). 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).
Inhibited by N-hydroxy-N'-(4-n-butyl-2-methylphenyl formamidine)(HET0016) with an IC(50) of 38 nM.
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. Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid (By similarity).
Expressed in brain, lung, kidney and testis with highest levels in brain and testis.
Forms pentamers. 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 (By similarity). 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). 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.
Belongs to the pseudouridine synthase TruD family.
Expressed in brain, kidney (outer medullary collecting duct) and liver with weak expression in thymus and heart.
Forms a complex with CASK and APBA1 or CASKIN1. 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. Forms a tripartite complex composed of DLG1, MPP7 and LIN7 (LIN7A or LIN7C) (By similarity). Interacts with MAPK12 (By similarity).
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.
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.
Phosphorylated by PKA. Phosphorylated on serine in skeletal muscle at rest or upon lipolytic stimulation.
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.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues. Preferentially acts on mannose-linked GlcNAc. Also able to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin. Also acts on core 2 mucin-type oligosaccharide and N-acetyllactosamine oligomer with a lower efficiency. Has weak or no activity toward keratan sulfate and oligosaccharides containing the Galbeta1-4GlcNAc. Catalyzes 6-O-sulfation of beta-benzyl GlcNAc but not alpha- or beta-benzyl GalNAc (By similarity).
It is uncertain whether Met-1 or Met-23 is the initiator.
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 (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.
The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].
Interacts (via N-terminal extracellular domain) with PTHLH and PTH (PubMed:1313566). Homodimer in the absence of bound ligand. Peptide hormone binding leads to dissociation of the homodimer (By similarity).
Receptor for parathyroid hormone and for parathyroid hormone-related peptide. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system.
Expressed in cortical astrocytes and glioma cells. Expression is up-regulated by TGFB1.
Forms part of the large latent transforming growth factor beta precursor complex; removal is essential for activation of complex. Interacts with SDC4. Interacts (via C-terminal domain) with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner.
May play an integral structural role in elastic-fiber architectural organization and/or assembly.
Although transmembrane domains are strongly predicted, they may rather represent hydrophobic globular domains associated with microtubules.
Exclusively expressed in spermatids. Not present in mature sperm. Localized with both the manchette and the axoneme in step 10-11 spermatids. Detected on manchette microtubules of step 12 spermatids. Associates with the tail in steps 18-19 spermatids and epididymal sperm.
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 (By similarity). May assist the organization and assembly of outer dense fibers (ODFs), a specific structure of the sperm tail (PubMed:10373309).
Self-associates. Interacts with ODF1. May associate with microtubules (PubMed:10373309). Interacts with SUN3 and SYNE1; suggesting the formation of a LINC complexs; a SUN domain-based heterotrimer of SPAG4 and SUN3 may associate with SYNE1 (By similarity). Interacts with SEPT12 and LMNB1; during spermatogenesis (By similarity).
Testis specific. Exclusively expressed in spermatids.
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.
Belongs to the cytochrome c oxidase subunit 6c family.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa4.2/KCNT2 sub-subfamily.
Detected in brain, and at low levels in heart. Detected in brainstem, including auditory neurons such as the medial nucleus of the trapezoid body. Detected in the olfactory bulb, red nucleus, facial nucleus, pontine nucleus, oculomotor nucleus, substantia nigra, deep cerebellar nuclei, vestibular nucleus, and the thalamus. Detected in hippocampal CA1, CA2, and CA3 regions, the dentate gyrus, supraoptic nucleus, hypothalamus, dorsal root ganglion, and cortical layers II, III, and V. Detected in striatum cholinergic interneurons.
Outward rectifying potassium channel. Produces rapidly activating outward rectifier K(+) currents. Activated by high intracellular sodium and chloride levels (PubMed:14684870, PubMed:29069600). Channel activity is inhibited by ATP and by inhalation anesthetics, such as isoflurane (PubMed:17699666). Inhibited upon stimulation of G-protein coupled receptors, such as CHRM1 and GRM1 (By similarity).
Phosphorylated by protein kinase C. Phosphorylation inhibits channel activity (By similarity).
Can form disulfide-bonded heterodimer with NKG2 family members KLRC1 and KLRC2. KLRD1-KLRC1 heterodimer interacts with peptide-bound MHC-E-B2M heterotrimeric complex. KLRD1 plays a prominent role in directly interacting with MHC-E. KLRD1-KLRC1 interacts with much higher affinity with peptide-bound MHC-E-B2M than KLRD1-KLRC2. Interacts with the adapter protein TYROBP/DAP12; this interaction is required for cell surface expression and cell activation.
Immune receptor involved in self-nonself discrimination. In complex with KLRC1 or KLRC2 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule MHC-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia and non-classical MHC class Ib molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self. Primarily functions as a ligand binding subunit as it lacks the capacity to signal.
KLRD1-KLRC1 acts as an immune inhibitory receptor. Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions. 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. 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. In MHC-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. Upon MHC-E-peptide binding, transmits intracellular signals through KLRC1 immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHIP-1 and INPPL1/SHIP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules.
KLRD1-KLRC2 acts as an immune activating receptor. On cytotoxic lymphocyte subsets recognizes MHC-E loaded with signal sequence-derived peptides from non-classical MHC class Ib MHC-G molecules, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy. Regulates the effector functions of terminally differentiated cytotoxic lymphocyte subsets, and in particular may play a role in adaptive NK cell response to viral infection. Upon MHC-E-peptide binding, transmits intracellular signals via the adapter protein TYROBP/DAP12, triggering the phosphorylation of proximal signaling molecules and cell activation.
Acetylated. Acetylation occurs in pancreatic beta cells in response to stimulation by incretin hormones in a histone acetyltransferase (HAT)/histone deacetylase (HDAC)-dependent signaling pathway, promoting beta cell survival (PubMed:21818121).
Belongs to the potassium channel family. B (Shab) (TC 1.A.1.2) subfamily. Kv2.1/KCNB1 sub-subfamily.
Down-regulated by angiotensin II in a NFATC3-dependent manner (PubMed:15322114).
Expressed in brain (PubMed:1740690, PubMed:1961744, PubMed:8508921, PubMed:7623158, PubMed:12954870). Expressed in the hippocampus, cerebral cortex, cerebellum, thalamus, hypothalamus, olfactory bulb, corpus striatum and medial hebenula (PubMed:8463836, PubMed:10414301, PubMed:16319318). Expressed in pancreatic islets (PubMed:12403834). Expressed in heart and skeletal muscle (PubMed:1740690, PubMed:19219384, PubMed:10414301). Levels remain constant throughout postnatal development (PubMed:17192433). Expressed in neocortical pyramidal neurons and inhibitory interneurons (PubMed:1961744, PubMed:9522360, PubMed:10618149, PubMed:12832499, PubMed:17192433, PubMed:17379638, PubMed:19014551, PubMed:20202934, PubMed:24477962). Expressed in the superior cervical ganglion (SCG) neurons (PubMed:12451110). Expressed in globus pallidus neurons (PubMed:10414968). Expressed in pancreatic beta cells (PubMed:11463864, PubMed:22411134). Expressed in cardiomyocytes (PubMed:17965280). Expressed in arterial smooth muscle, alveolar epithelium and parenchyma (at protein level) (PubMed:9362476, PubMed:9616203, PubMed:15322114). Expressed in brain, heart, lung, liver, colon, kidney and adrenal gland (PubMed:8508921, PubMed:9362476, PubMed:19074135). Expressed in pyramidal cells of the cerebral cortex, in Purkinje and granule cells of the cerebellum (PubMed:8463836). Expressed in CA1-CA3 pyramidal cells, dentate granule cells and interneurons of the hippocampus (PubMed:7623158, PubMed:10024359). Expressed in pulmonary artery (PA) smooth muscle cells (PubMed:9362476).
Expressed in embryonic brain at 14 dpc, and thereafter (at protein level) (PubMed:8508921). Expressed in embryonic brain at 14 dpc, and thereafter (PubMed:8508921).
Homotetramer or heterotetramer with KCNB2 (PubMed:20202934). Heterotetramer with non-conducting channel-forming alpha subunits such as KCNF1, KCNG1, KCNG3, KCNG4, KCNH1, KCNH2, KCNS1, KCNS2, KCNS3 and KCNV1 (PubMed:8670833, PubMed:8980147, PubMed:9362476, PubMed:9079713, PubMed:9305895, PubMed:9696692). Channel activity is regulated by association with ancillary beta subunits such as AMIGO1, KCNE1, KCNE2 and KCNE3 (PubMed:12954870, PubMed:19219384). Self-associates (via N-terminus and C-terminus); self-association is required to regulate trafficking, gating and C-terminal phosphorylation-dependent modulation of the channel (PubMed:12560340, PubMed:18463252, PubMed:19690160). Interacts (via C-terminus) with STX1A (via C-terminus); this decreases the rate of channel activation and increases the rate of channel inactivation in pancreatic beta cells, induces also neuronal apoptosis in response to oxidative injury as well as pore-independent enhancement of exocytosis in neuroendocrine cells, chromaffin cells, pancreatic beta cells and from the soma of dorsal root ganglia (DRG) neurons (PubMed:12621036, PubMed:12807875, PubMed:17301173, PubMed:18167541, PubMed:19077057, PubMed:20484665, PubMed:22411134, PubMed:24928958). Interacts (via N-terminus) with SNAP25; this decreases the rate of channel inactivation in pancreatic beta cells and also increases interaction during neuronal apoptosis in a N-methyl-D-aspartate receptor (NMDAR)-dependent manner (PubMed:12403834, PubMed:12807875, PubMed:19077057). Interacts (via N-terminus and C-terminus) with VAMP2 (via N-terminus); stimulates channel inactivation rate (PubMed:18542995, PubMed:19690160, PubMed:19077057). Interacts with CREB1; this promotes channel acetylation in response to stimulation by incretin hormones (PubMed:21818121). Interacts (via N-terminus and C-terminus) with MYL12B (PubMed:24569993). Interacts (via N-terminus) with PIAS3; this increases the number of functional channels at the cell surface (PubMed:9565597). Interacts with SUMO1. Interacts (via phosphorylated form) with PTPRE; this reduces phosphorylation and channel activity in heterologous cells (By similarity).
Inhibited by 42 nM hanatoxin 1 (HaTx1), a spider venom toxin of the tarantula G. spatulata (PubMed:7576642). Inhibited by 100 nM stromatoxin 1 (ScTx1), a spider venom toxin of the tarantula S. calceata (PubMed:12065754). Modestly sensitive to millimolar levels of tetraethylammonium (TEA) and 4-aminopyridine (4-AP) (PubMed:2770868, PubMed:1875913, PubMed:8083226, PubMed:9362476). Completely insensitive to toxins such as dendrotoxin (DTX) and charybdotoxin (CTX) (PubMed:9362476).
Phosphorylated (PubMed:8083226, PubMed:15195093, PubMed:16319318, PubMed:16407566, PubMed:18463252). Differential C-terminal phosphorylation on a subset of serines allows graded activity-dependent regulation of channel gating in hippocampal neurons (PubMed:9351973, PubMed:17192433, PubMed:16917065). Ser-607 and Tyr-128 are significant sites of voltage-gated regulation through phosphorylation/dephosphorylation activities (PubMed:12615930, PubMed:17192433). Tyr-128 can be phosphorylated by Src and dephosphorylated by cytoplasmic form of the phosphatase PTPRE isoform 2 (PubMed:12615930). CDK5-induced Ser-607 phosphorylation increases in response to acute blockade of neuronal activity (PubMed:21712386). Phosphorylated on Tyr-128 by Src and on Ser-804 by MAPK14/P38MAPK; phosphorylations are necessary and sufficient for an increase in plasma membrane insertion, apoptotic potassium current surge and completion of the neuronal cell death program (PubMed:17360683, PubMed:19622611). Phosphorylated on Ser-520, Ser-607, Ser-655 and Ser-804 by CDK5; phosphorylation is necessary for KCNB1 channel clustering formation (PubMed:21712386). The Ser-607 phosphorylation state differs between KCNB1-containing clusters on the proximal and distal portions of the axon initial segment (AIS) (PubMed:24477962). Highly phosphorylated on serine residues in the C-terminal cytoplasmic tail in resting neurons (PubMed:9351973, PubMed:16917065). Phosphorylated in pancreatic beta cells in response to incretin hormones stimulation in a PKA- and RPS6KA5/MSK1-dependent signaling pathway, promoting beta cell survival (PubMed:21818121). Phosphorylation on Ser-567 is reduced during postnatal development with low levels at P2 and P5; levels then increase to reach adult levels by P14 (PubMed:17192433). Phosphorylation on Ser-457, Ser-541, Ser-567, Ser-607, Ser-655 and Ser-719 as well as the N-terminal Ser-15 are sensitive to calcineurin-mediated dephosphorylation contributing to the modulation of the voltage-dependent gating properties (PubMed:17192433, PubMed:16917065). Dephosphorylation by phosphatase PTPRE isoform 2 confers neuroprotection by its inhibitory influence on the neuronal apoptotic potassium current surge in a Zn(2+)-dependent manner (PubMed:19622611). Dephosphorylated at Ser-607 by protein phosphatase PPP1CA (PubMed:21712386). Hypoxia-, seizure- or glutamate-induced neuronal activities promote calcium/calcineurin-dependent dephosphorylation resulting in a loss of KCNB1-containing clustering and enhanced channel activity (PubMed:15195093, PubMed:16319318, PubMed:16407566, PubMed:17192433, PubMed:16917065). In response to brain ischemia, Ser-567 and Ser-607 are strongly dephosphorylated while Ser-457 and Ser-719 are less dephosphorylated (PubMed:17192433). In response to brain seizures, phosphorylation levels on Ser-567 and Ser-607 are greatly reduced (PubMed:17192433). Phosphorylated/dephosphorylated by Src or FYN tyrosine-protein kinases and tyrosine phosphatase PTPRE in primary Schwann cells and sciatic nerve tissue (By similarity).
Sumoylated on Lys-474, preferentially with SUMO1; sumoylation induces a positive shift in the voltage-dependence of activation and inhibits channel activity (PubMed:21518833). Sumoylation increases the frequency of repetitive action potential firing at the cell surface of hippocampal neurons and decreases its frequency in pancreatic beta cells (PubMed:21518833). Desumoylated by SENP1 (PubMed:21518833).
The N-terminal and C-terminal cytoplasmic regions mediate homooligomerization; self-association is required to regulate trafficking, gating and C-terminal phosphorylation-dependent modulation of the channel (PubMed:12560340, PubMed:18463252, PubMed:19690160). The N-terminal cytoplasmic region is important for interaction with other channel-forming alpha subunits and with ancillary beta subunits (PubMed:12954870, PubMed:19219384). The C-terminus is necessary and sufficient for the restricted localization to, and clustering within, both in soma and proximal portions of dendrite of neurons and in lateral membrane of non-neuronal polarized cells (PubMed:8978827, PubMed:10719893). The C-terminus is both necessary and sufficient as a mediator of cholinergic and calcium-stimulated modulation of channel cell membrane clustering localization and activity in hippocampal neurons (PubMed:16407566).
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system. Contributes to the regulation of the action potential (AP) repolarization, duration and frequency of repetitive AP firing in neurons, muscle cells and endocrine cells and plays a role in homeostatic attenuation of electrical excitability throughout the brain (PubMed:10024359, PubMed:10618149, PubMed:12451110, PubMed:17379638, PubMed:19276663, PubMed:23878373). Also plays a role in the regulation of exocytosis independently of its electrical function (PubMed:20484665). 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. Homotetrameric channels mediate a delayed-rectifier voltage-dependent outward potassium current that display rapid activation and slow inactivation in response to membrane depolarization (PubMed:2770868, PubMed:2206531, PubMed:1875913, PubMed:8083226, PubMed:8978827, PubMed:9351973, PubMed:9565597, PubMed:12560340). Can form functional homotetrameric and heterotetrameric channels that contain variable proportions of KCNB2; channel properties depend on the type of alpha subunits that are part of the channel (PubMed:20202934). Can also form functional heterotetrameric channels with other alpha subunits that are non-conducting when expressed alone, such as KCNF1, KCNG1, KCNG3, KCNG4, KCNH1, KCNH2, KCNS1, KCNS2, KCNS3 and KCNV1, creating a functionally diverse range of channel complexes (PubMed:8670833, PubMed:8980147, PubMed:9362476, PubMed:9079713, PubMed:9305895, PubMed:9696692). Heterotetrameric channel activity formed with KCNS3 show increased current amplitude with the threshold for action potential activation shifted towards more negative values in hypoxic-treated pulmonary artery smooth muscle cells (PubMed:9362476). Channel properties are also modulated by cytoplasmic ancillary beta subunits such as AMIGO1, KCNE1, KCNE2 and KCNE3, slowing activation and inactivation rate of the delayed rectifier potassium channels (PubMed:12954870, PubMed:19219384). 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. Major contributor to the slowly inactivating delayed-rectifier voltage-gated potassium current in neurons of the central nervous system, sympathetic ganglion neurons, neuroendocrine cells, pancreatic beta cells, cardiomyocytes and smooth muscle cells (PubMed:9362476, PubMed:9616203, PubMed:10024359, PubMed:10414968, PubMed:10618149, PubMed:11463864, PubMed:12451110, PubMed:12127166, PubMed:12403834, PubMed:12621036, PubMed:12807875, PubMed:12832499, PubMed:12954870, PubMed:15322114, PubMed:15195093, PubMed:16407566, PubMed:17301173, PubMed:17379638, PubMed:18463252, PubMed:18167541, PubMed:19276663, PubMed:20484665, PubMed:21518833, PubMed:22411134, PubMed:23878373). Mediates the major part of the somatodendritic delayed-rectifier potassium current in hippocampal and cortical pyramidal neurons and sympathetic superior cervical ganglion (CGC) neurons that acts to slow down periods of firing, especially during high frequency stimulation (PubMed:10618149, PubMed:12451110, PubMed:16319318, PubMed:17379638, PubMed:19276663, PubMed:23878373, PubMed:16917065). Plays a role in the induction of long-term potentiation (LTP) of neuron excitability in the CA3 layer of the hippocampus (By similarity). Contributes to the regulation of glucose-induced action potential amplitude and duration in pancreatic beta cells, hence limiting calcium influx and insulin secretion (PubMed:11463864). Plays a role in the regulation of resting membrane potential and contraction in hypoxia-treated pulmonary artery smooth muscle cells (PubMed:9616203). May contribute to the regulation of the duration of both the action potential of cardiomyocytes and the heart ventricular repolarization QT interval (By similarity). Contributes to the pronounced pro-apoptotic potassium current surge during neuronal apoptotic cell death in response to oxidative injury (PubMed:12832499, PubMed:16273079, PubMed:17360683, PubMed:19077057, PubMed:19622611, PubMed:24928958). May confer neuroprotection in response to hypoxia/ischemic insults by suppressing pyramidal neurons hyperexcitability in hippocampal and cortical regions (PubMed:16319318). Promotes trafficking of KCNG3, KCNH1 and KCNH2 to the cell surface membrane, presumably by forming heterotetrameric channels with these subunits (By similarity). Plays a role in the calcium-dependent recruitment and release of fusion-competent vesicles from the soma of neurons, neuroendocrine and glucose-induced pancreatic beta cells by binding key components of the fusion machinery in a pore-independent manner (PubMed:11463864, PubMed:17301173, PubMed:18167541, PubMed:20484665, PubMed:22411134).
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:16908527, PubMed:21990363). Plays an important role in hepatic triglyceride metabolism (PubMed:18349115).
Homohexamer and homotrimer (PubMed:19136561). Identified in a complex that contains at least CPT1A, ACSL1 and VDAC1 (PubMed:21622568). Also identified in complexes with ACSL1 and VDAC2 and VDAC3.
Nuclease required for the repair of DNA interstrand cross-links (ICL). 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.
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+).
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. Nucleotide-binding opens the substrate binding pocket and flips the active site from inside the hydrophobic core into a catalytically competent, solvent-exposed posture.
Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration. Its substrate specificity is unclear: does not show any protein kinase activity. Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway, as suggested by its ability to bind coenzyme Q lipid intermediates. Shows an unusual selectivity for binding ADP over ATP.
Autoinhibited by the N-terminal domain, containing the KxGQ motif, that completely occludes the typical substrate binding pocket. Nucleotide-binding relieves inhibition.
Homodimer; homodimerizes via its transmembrane region. Interacts with the multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9.
Interacts with SEPTIN2; this interaction impedes tubulin-binding. Interacts with TRAF3IP1 (By similarity). Interacts with KNSTRN (By similarity).
Non-neuronal microtubule-associated protein. Promotes microtubule assembly (By similarity).
Phosphorylation on Ser-761 negatively regulates MAP4 activity to promote 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.
Homodimer in cis. Does not appear to form trans-homodimers. Interacts with ITGB3; the interaction inhibits ITGAV:ITGB3 heterodimer formation.
RGD motif 2 (but not RGD motif 1) is involved in integrin ITGAV:ITGB3 binding.
Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3. Mediates heterophilic cell-cell interactions in vitro. Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38. Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes. Stimulates formation of primary cilia in chondrocytes. Enhances expression of genes involved in the hedgehog signaling pathway in chondrocytes, including the hedgehog signaling molecule IHH; may also promote signaling via the PTHLH/PTHrP pathway. Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis. Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells. Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK. May play a role in the maturation and maintenance of the blood-brain barrier.
Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Responsible for the release of glucagon from proglucagon in pancreatic A cells (By similarity).
Catalytic subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. Interacts with histones H4 and H2A.
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.
Histone acetyltransferase that plays a role in different biological processes including cell cycle progression, glucose metabolism, histone production or DNA damage repair. Coordinates histone production and acetylation via H4 promoter binding. Acetylates histone H4 at 'Lys-5' (H4K5ac) and 'Lys-12' (H4K12ac) and, to a lesser extent, histone H2A at 'Lys-5' (H2AK5ac).
Histone acetyltransferase that plays a role in different biological processes including cell cycle progression, glucose metabolism, histone production or DNA damage repair. Coordinates histone production and acetylation via H4 promoter binding. Acetylates histone H4 at 'Lys-5' (H4K5ac) and 'Lys-12' (H4K12ac) and, to a lesser extent, histone H2A at 'Lys-5' (H2AK5ac). 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. Promotes homologous recombination in DNA repair by facilitating histone turnover and incorporation of acetylated H3.3 at sites of double-strand breaks. In addition, acetylates other substrates such as chromatin-related proteins. Acetylates also RSAD2 which mediates the interaction of ubiquitin ligase UBE4A with RSAD2 leading to RSAD2 ubiquitination and subsequent degradation.
Phosphorylated by AMPK at Ser-190; phosphorylation increases HAT1 activity.
Probably involved in membrane protein trafficking.
Together with PI4K2A and the type III PI4Ks (PIK4CA and PIK4CB) it contributes to the overall PI4-kinase activity of the cell. This contribution may be especially significant in plasma membrane, endosomal and Golgi compartments. The phosphorylation of phosphatidylinositol (PI) to PI4P is the first committed step in the generation of phosphatidylinositol 4,5-bisphosphate (PIP2), a precursor of the second messenger inositol 1,4,5-trisphosphate (InsP3). Contributes to the production of InsP3 in stimulated cells and is likely to be involved in the regulation of vesicular trafficking.
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.
Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network.
Interacts with AP4B1 and AP4E1; the interaction is direct and mediates the association of TEPSIN with the adapter-like complex 4 (AP-4), a heterotetramer composed of AP4B1, AP4E1, AP4M1 and AP4S1.
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.
Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation. Involved in the regulation of both caspase-dependent apoptosis and caspase-independent cell death. In the skin, it plays a predominant role in suppressing caspase-dependent apoptosis in response to UV stress in a range of dermal cell types.
Expressed in many regions of the adult brain.
Expressed predominantly in liver and kidney.
Heterodimer; with RXRA. This heterodimerization is required for DNA binding and transactivation activity. Interacts with NCOA3 coactivator (By similarity). Interacts with CITED2; the interaction stimulates its transcriptional activity (PubMed:15051727). 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 (By similarity). 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 (By similarity).
Interacts with GATA4 and NKX2-5 (By similarity). Interacts with NR0B2 (By similarity). Interacts with CLOCK and BMAL1 (By similarity). Interacts with IFI204 (By similarity). Interacts with NEDD9/HEF1 (By similarity).
Phosphorylated in vitro by CDK1, PKA and PKC.
The bHLH domain is essential for its repressor activity towards the CLOCK-BMAL1 heterodimer.
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. Restricts the CLOCK and BMAL1 localization to the cytoplasm. Plays a role in both the input and output pathways of the circadian clock: in the input component, is involved in modulating the magnitude of photic entrainment and in the output component, contributes to the regulation of a variety of liver clock-controlled genes involved in lipid metabolism (By similarity).
Dimer of identical or non-identical chains, which can be either B (brain type) or M (muscle type). With MM being the major form in skeletal muscle and myocardium, MB existing in myocardium, and BB existing in many tissues, especially brain.
Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate). Creatine kinase isoenzymes play a central role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, brain and spermatozoa.
Except for the WW domain, the protein is intrinsically disordered.
Interacts with POU3F2/Brn-2, ATXN1, TXNL4A, HTT and AR. Interaction with ATXN1 correlates positively with the length of the polyglutamine tract. Interacts with RNA polymerase II large subunit in a phosphorylation-dependent manner. Forms a ternary complex with ATXN1 mutant and phosphorylated RNA polymerase II. Interacts (via C-terminus) with TXNL4A and CD2BP2. Interacts (via WW domain) with ATN1 and SF3B1, and may interact with additional splice factors. Interacts (via WW domain) with WBP11; Leading to reduce interaction between PQBP1 and TXNL4A. Interacts with CAPRIN1. Interacts with DDX1. Interacts with SFPQ. Interacts with KHSRP.
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. Interacts with splicing-related factors via the intrinsically disordered region and regulates alternative splicing of target pre-mRNA species. 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. May be involved in ATXN1 mutant-induced cell death. The interaction with ATXN1 mutant reduces levels of phosphorylated RNA polymerase II large subunit. Involved in the assembly of cytoplasmic stress granule, possibly by participating in the transport of neuronal RNA granules. Also acts as an innate immune sensor of infection by retroviruses, by detecting the presence of reverse-transcribed DNA in the cytosol. 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.
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.
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) (By similarity). Interacts (GDP-bound form preferentially) with DENND10 (By similarity).
High levels in eye, intestine, lung, pancreas and spleen, and low or absent in brain, liver, heart, kidney, and skeletal muscle.
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. Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA methyltransferase RlmE family. TRM7 subfamily.
Methylates the 2'-O-ribose of nucleotides at positions 32 and 34 of the tRNA anticodon loop of substrate tRNAs.
Belongs to the Mediator complex subunit 28 family.
Forms a ternary complex with NF2/merlin and GRB2. Binds to actin (By similarity). Component of the Mediator complex, which is probably 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 complex containing NF2/merlin that participates in cellular signaling to the actin cytoskeleton downstream of tyrosine kinase signaling pathways (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 preinitiation complex with RNA polymerase II and the general transcription factors.
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). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains. 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 (By similarity). Regulates the IL1-mediated translocation of NCOR1 out of the nucleus (By similarity). Involved in heart development (By similarity).
Degraded in a lysosome-dependent manner following interactiuon with TRIM38.
Interacts with MAP3K7 and TRAF6. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2. Binds 'Lys-63'-linked polyubiquitin chains (By similarity). Interacts with NCOR1 and HDAC3 to form a ternary complex (By similarity). Interacts (via C-terminal) with NUMBL (via PTB domain). Interacts (via the C-terminus) with DYNC2I2 (via WD domains). Interacts with RBCK1. Interacts with TRIM5 (By similarity). Interacts with TRIM38 (via B30.2/SPRY domain), leading to its translocation to lysosomes and degradation (By similarity).
The RanBP2-type zinc finger (NZF) mediates binding to two consecutive 'Lys-63'-linked ubiquitins.
Ubiquitinated; following IL1 stimulation or TRAF6 overexpression. Ubiquitination involves RBCK1 leading to proteasomal degradation.
Endonuclease that catalyzes the cleavage of RNA on the 3' side of pyrimidine nucleotides. Acts on single-stranded and double-stranded RNA (By similarity).
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+). Critical component of the visual transduction cascade, controlling the calcium concentration of outer segments during light and darkness. Light causes a rapid lowering of cytosolic free calcium in the outer segment of both retinal rod and cone photoreceptors and the light-induced lowering of calcium is caused by extrusion via this protein which plays a key role in the process of light adaptation.
The uncleaved signal sequence is required for efficient membrane targeting and proper membrane integration and topology.
Brain. Expression in the pituitary is restricted to the anterior lobe. Expression in the hypothalamus is observed in the neuronal cells and neurons of arcuate nucleus, supraoptic nucleus and median eminence (at protein level).
Neuroendocrine protein of the granin family that regulates the biogenesis of secretory granules.
ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (By similarity). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate). 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).
Expressed in lung, ileum, colon and liver. Higher in liver of Eisai hyperbilirubinemic rats.
Strongly up-regulated under conditions of cholestasis.
Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers (PubMed:9516481). May play a role in SDF1A-stimulated chemotaxis (By similarity).
Higher levels of expression found in adult liver than in fetal liver.
Predominantly expressed in normal liver. High levels also found in regenerating liver. Very low levels found in heart and testis.
Increases glutamate release in the striatum and decreases GABA concentration in the striatum.
Increases glutamate release in the striatum.
Met-enkephalin-Arg-Phe neuropeptide acts as a strong ligand of Mu-type opioid receptor OPRM1 (PubMed:8624732). Met-enkephalin-Arg-Phe-binding to OPRM1 in the nucleus accumbens of the brain increases activation of OPRM1, leading to long-term synaptic depression of glutamate release (By similarity).
Neuropeptide that competes with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress.
Processed by ACE to generate Met-enkephalin in the nucleus accumbens of the brain.
Proenkephalin-A is cleaved by CTSL to generate Met-enkephalin.
Interacts with PLA2R1; this interaction mediates PLA2G10 clearance and inactivation.
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids 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. Contributes to phospholipid remodeling of very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. Hydrolyzes LDL phospholipids releasing unsaturated fatty acids that regulate macrophage differentiation toward foam cells. Efficiently hydrolyzes and inactivates platelet activating factor (PAF), a potent lipid mediator present in oxidized LDL (By similarity). 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. Secreted by gut epithelium, hydrolyzes dietary and biliary phosphatidylcholines in the gastrointestinal lumen. 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. May participate in hair follicle morphogenesis by regulating phosphatidylethanolamines metabolism at the outermost epithelial layer and facilitating melanin synthesis. By releasing lysophosphatidylcholines (LPCs) at sperm acrosome, controls sperm cell capacitation, acrosome reaction and overall fertility. 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. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane. 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 (By similarity). May play a role in maturation and activation of innate immune cells including macrophages, group 2 innate lymphoid cells and mast cells (By similarity).
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 teethRequired 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).
Osteostatin is a potent inhibitor of osteoclastic bone resorption.
PTHrP interacts with PTH1R (via N-terminal extracellular domain).
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 (By similarity).
Belongs to the bacterial ribosomal protein bL33 family.
ATP-dependent RNA helicase. Required for mRNA export and translation regulation during spermatid development (By similarity).
By gonadotropin in Leydig cells. Inhibited by flutamine.
Expressed in pubertal and adult animals but not in immature animals.
Isoform 1 is expressed in germ cells. Isoform 2 is highly expressed in Leydig cells and weakly expressed in the pituitary and hypothalamus. Isoform 3 is weakly expressed only in germ cells.
May start at Met-200 rather than Met-190.
Phosphorylated on threonine residues. The phosphorylated form is found in the cytoplasm but not in the nucleus.
Association to the cytoskeleton through a N-terminal leucine rich-domain (between AA 190-218).
Interacts with ESR1, PBX1, PBX2 and PBX3. Interacts with TEX11 (By similarity).
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 (By similarity).
The C-terminal domain (AA 443-731) contains a nuclear export signal.
Alpha-helical parts of the C-terminal intracellular region mediate heterodimeric interaction with GABBR2. 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.
At 17 dpc during embryonic development, highly expressed in brain regions including the striatum, olfactory bulb, septal nuclei, lateral habenula, pyramidal CA1-CA2 cell layers of the hippocampus and in the neuroepithelial cells of the ventricular zone. On the day of birth, expressed in the regions of the brain including hippocampus, thalamic nuclei, cortex and cerebellum.
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:9872315, PubMed:9872317, PubMed:9872744). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:9872317, PubMed:10658574). 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:9872315, PubMed:9872744, PubMed:10924501). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:9069281, PubMed:10457184, PubMed:9872315, PubMed:9872744, PubMed:10924501, PubMed:10692480). Calcium is required for high affinity binding to GABA (PubMed:10692480). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9872744). 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:9872744, PubMed:10924501, PubMed:10692480). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (By similarity).
Heterodimer of GABBR1 and GABBR2 (PubMed:9872315, PubMed:9872317, PubMed:9872744). Homodimers may form, but are inactive (PubMed:9872317). Interacts (via C-terminus) with ATF4 (via leucine zipper domain) (PubMed:10924501). Interacts with JAKMIP1 (PubMed:14718537).
Ubiquitously expressed in tissues including the forebrain, cerebellum, eye, atrium, ventricle, lung, stomach, small intestine, colon, liver, spleen, kidney, urinary bladder and skeletal muscle (PubMed:9875211). Expressed at low levels in testis, and more highly in brain regions (PubMed:9069281). Expression is high the brain regions including cerebral cortical layers, with higher expression in VIb than in the II-V layers, pyramidal CA1-CA3 cell layers and granular cell layers of the hippocampus, granular cell layers of the dentate gyrus, including the caudate, putamen, nucleus accumbens and olfactory tubercle, the granular layer cell layers of the medial habenula, in the cerebellum, predominantly in Purkinje cells, and in the granule cell layer (PubMed:9069281, PubMed:9872315 PubMed:9872744, PubMed:10727622). Also expressed in areas of the brain including the medial geniculate nucleus, substantia nigra, pars compacta, the ventral tegmental area, and in several thalamic, amygdaloid and hypothalamic nuclei, such as the arcuate nucleus of the hypothalamus and mammilary bodies of the hypothalamus (PubMed:9069281, PubMed:9872744). Expressed in the amacrine cell of the retina (PubMed:10924501). Isoform 1A: Expressed in the brain, spinal cord, stomach, testis, adrenal gland, pituitary, spleen and prostate (PubMed:10658574). Isoform 1B: Expressed in the brain, spinal cord, stomach, testis, kidney and liver (PubMed:10658574). Expressed in Isoform 1C: Ubiquitously expressed (PubMed:9875211). Isoform 1D: Expressed in the forebrain, cerebellum, eye, kidney and urinary bladder (PubMed:9875211). Isoform 1E: Ubiquitously expressed with high expression the pyramidal CA1-CA3 cell layers of the hippocampus, the granule cell layers of the dentate gyrus and olfactory tubercle, the whole cortex, and Purkinje cells of the cerebellum (PubMed:10457184). Moderate expression in the granule cell layer of the cerebellum (PubMed:10457184).
A secreted form is produced by caspase-mediated proteolytic cleavage.
Expressed in the heart, liver, brain, spleen, lung, kidney, testis and skeletal muscle.
Catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation through the ubiquitin-proteasome system. 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. Essential for the formation of radiation-induced foci, timely DNA repair and for response to replication stress. Promotes the recruitment of TP53BP1 and BRCA1 at DNA damage sites.
Monomer. Interacts with GAN (via BTB domain) (By similarity).
There are two active sites within the E1 molecule, allowing it to accommodate two ubiquitin moieties at a time, with a new ubiquitin forming an adenylate intermediate as the previous one is transferred to the thiol site.
Endothelins are endothelium-derived vasoconstrictor peptides (By similarity). Probable ligand for G-protein coupled receptors EDNRA and EDNRB which activates PTK2B, BCAR1, BCAR3 and, GTPases RAP1 and RHOA cascade in glomerular mesangial cells (By similarity). Also binds the DEAR/FBXW7-AS1 receptor (PubMed:9508787).
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 (By similarity).
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9. In the complex, it probably interacts directly with COPS3, COPS4 and COPS7 (COPS7A or COPS7B).
Expressed in skeletal muscle, cardiac muscle and skin.
Expression in cardiomyocytes is higher in adult as compared with neonatal.
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.
Repressed by adrenergic agents (phenylephrine, isoproterenol, dobutamine and clenbuterol), forskolin and phorbol myristate acetate (at transcriptional levels) (PubMed:22143674). No change in expression with endothelin-1 (PubMed:22143674).
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 the brain. Expressed in cerebellum, olfactory bulb, cerebral cortex, hippocampus and brain stem.
Receptor that may have an important role in cell/cell signaling during nervous system formation.
Belongs to the universal ribosomal protein uL4 family.
High levels in liver and lung, moderate levels in spleen, brain, heart, kidney, jejunum and testis. Up-regulated in 3Y1 cells upon growth arrest.
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. 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.
Homodimer (By similarity). 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 (By similarity). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (By similarity). The closed form interacts (via the middle domain and TPR repeat-binding motif) with co-chaperone TSC1 (via C-terminus) (By similarity). Interacts with TOM34 (By similarity). Interacts with TERT; the interaction, together with PTGES3, is required for correct assembly and stabilization of the TERT holoenzyme complex (By similarity). Interacts with CHORDC1 and DNAJC7 (By similarity). Interacts with STUB1 and UBE2N; may couple the chaperone and ubiquitination systems (By similarity). Interacts (via TPR repeat-binding motif) with PPP5C (via TPR repeats); the interaction is direct and activates PPP5C phosphatase activity (By similarity). Following LPS binding, may form a complex with CXCR4, GDF5 and HSPA8 (By similarity). Interacts with KSR1 (By similarity). Interacts with co-chaperone CDC37 (via C-terminus); the interaction inhibits HSP90AA1 ATPase activity (By similarity). May interact with NWD1 (By similarity). Interacts with FNIP1 and FNIP2; the interaction inhibits HSP90AA1 ATPase activity (By similarity). Interacts with co-chaperone AHSA1 (phosphorylated on 'Tyr-223'); the interaction activates HSP90AA1 ATPase activity and results in the dissociation of TSC1 from HSP90AA1 (By similarity). Interacts with FLCN in the presence of FNIP1 (By similarity). Interacts with HSP70, STIP1 and PTGES3 (By similarity). Interacts with SGTA (via TPR repeats) (PubMed:15708368). Interacts with SMYD3; this interaction enhances SMYD3 histone-lysine N-methyltransferase (By similarity). Interacts with TTC1 (via TPR repeats) (By similarity). Interacts with HSF1 in an ATP-dependent manner (By similarity). Interacts with MET; the interaction suppresses MET kinase activity (By similarity). Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity (By similarity). Interacts with HIF1A, KEAP1 and RHOBTB2 (By similarity). Interacts with HSF1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities. Interacts with STUB1 and SMAD3 (By similarity). Interacts with HSP90AB1; interaction is constitutive (By similarity). 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. Interacts with PDCL3 (PubMed:27496612). Interacts with TOMM70; the interaction is required for preprotein mitochondrial import. Interacts with TOMM70, IRF3 and TBK1; the interactions are direct and mediate the association of TOMM70 with IRF3 and TBK1 (By similarity). 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. Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation. After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state. Co-chaperone TSC1 promotes ATP binding and inhibits HSP90AA1 ATPase activity. Binding to phosphorylated AHSA1 promotes HSP90AA1 ATPase activity. Inhibited by geldanamycin, Ganetespib (STA-9090) and SNX-2112.
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. Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle. Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70. 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. In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes. Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation. Mediates the association of TOMM70 with IRF3 or TBK1 in mitochondrial outer membrane which promotes host antiviral response.
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.
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. 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. May require the presence of the HDE element located at the histone pre-RNA 3'-end to avoid non-specific cleavage.
Inhibitory regulator of the Ras-cyclic AMP pathway. May bind inositol tetrakisphosphate (IP4) and phospholipids.
Widely expressed. Higher expression in brain, placenta, and kidney.
Homodimer (By similarity). Interacts with GLMN. 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 (By similarity). Associates with tubulin (PubMed:17435176). Interacts with MAPT/TAU (PubMed:20133804). 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 (By similarity).
Immunophilin protein with PPIase and co-chaperone activities (By similarity). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90) (By similarity). Plays a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. May have a protective role against oxidative stress in mitochondria (By similarity). Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. The PPIase activity controls neuronal growth cones via regulation of TRPC1 channel opening.
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.
Widely detected in the brain (at protein level).
Extensively phosphorylated on serine residues in the RS domain.
Found in a pre-mRNA splicing complex with SRSF4/SFRS4, SRSF5/SFRS5, SNRNP70, SNRPA1, SRRM1 and SRRM2. Interacts (via RS domain) with PHF5A (via N-terminus) (By similarity).
May be required for progression through G1 and entry into S phase of cell growth. May play a regulatory role in pre-mRNA splicing. Autoregulates its own expression. Plays a role in constitutive splicing and can modulate the selection of alternative splice sites (By similarity). Could play an important role in development and differentiation in the spleen and thymus.
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 (By similarity).
Phosphorylated on tyrosines following cross-linking of BCR in B-cells, high affinity IgG receptor (FCGR1) in myeloid cells, or high affinity IgE receptor (FCER1) in mast cells; which induces the recruitment of GRB2.
When phosphorylated, interacts with GRB2. May also interact with SOS1, GAB1 and CBL (By similarity).
May function in erythrocyte differentiation.
Belongs to the KIF-binding protein family.
Interacts with KIF1B. Interacts with STMN2.
Required for organization of axonal microtubules, and axonal outgrowth and maintenance during peripheral and central nervous system development.
Expressed in brain structures, particularly in hippocampus, cortex, and cerebellum (at protein level). Expressed in astrocytes and hippocampal neurons (at protein level) (PubMed:25355561). Expressed in peritoneal mast cells (PubMed:28082679).
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) (By similarity). 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).
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.
Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (By similarity). Dephosphorylates and activates transcription factor NFATC1 (By similarity). Dephosphorylates and inactivates transcription factor ELK1 (By similarity). Dephosphorylates DARPP32 (By similarity). 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).
Expressed in kidney (at protein level) (PubMed:25967121). Expressed in hippocampal presynaptic termini (at protein level) (PubMed:23699505).
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 (PubMed:25967121). Interacts with SORL1 (PubMed:25967121). 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) (By similarity).
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 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.
In muscle, parvalbumin is thought to be involved in relaxation after contraction. It binds two calcium ions.
Heterodimer of a type I and a type II keratin. KRT17 associates with KRT6 isomers (KRT6A or KRT6B). Interacts with TRADD and SFN (By similarity).
Phosphorylation at Ser-44 occurs in a growth- and stress-dependent fashion in skin keratinocytes, it has no effect on filament organization.
Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair. Required for the correct growth of hair follicles, in particular for the persistence of the anagen (growth) state. Modulates the function of TNF-alpha in the specific context of hair cycling. Regulates protein synthesis and epithelial cell growth through binding to the adapter protein SFN and by stimulating Akt/mTOR pathway. Involved in tissue repair. May be a marker of basal cell differentiation in complex epithelia and therefore indicative of a certain type of epithelial 'stem cells'. Acts as a promoter of epithelial proliferation by acting a regulator of immune response in skin: promotes Th1/Th17-dominated immune environment contributing to the development of basaloid skin tumors. May act as an autoantigen in the immunopathogenesis of psoriasis, with certain peptide regions being a major target for autoreactive T-cells and hence causing their proliferation.
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.
Interacts with DRG1; the interaction forms a polysomal DRG1-DFRP1/ZC3H15 complex which provides protein stability to DRG1 possibly by blocking poly-ubiquitination. Associates with microtubules.
Protects DRG1 from proteolytic degradation. Stimulates DRG1 GTPase activity likely by increasing the affinity for the potassium ions.
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). Interacts with CSRP3 (PubMed:9234731). Interacts with NUPR1 (By similarity).
Induces fibroblasts to differentiate into myoblasts. Acts as a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation.
Methylation at Lys-104 by EHMT2/G9a inhibits myogenic activity.
Phosphorylated by CDK9. This phosphorylation promotes its function in muscle differentiation (By similarity).
Ubiquitinated on the N-terminus; which is required for proteasomal degradation.
Binds medium- and long-chain acyl-CoA esters and may function as an intracellular carrier of acyl-CoA esters.
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 (By similarity).
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.
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9. In the complex, it probably interacts directly with COPS1, COPS4, COPS5, COPS6 and COPS7 (COPS7A or COPS7B). Specifically interacts with the ligand binding domain of the thyroid receptor (TR). Does not require the presence of thyroid hormone for its interaction. Interacts with CUL1 and CUL2. Interacts with IRF8/ICSBP1 and with nuclear receptors NR2F1 and NR0B1 (By similarity). Interacts with NIF3L1 (PubMed:12522100).
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 spermatocytes and spermatides.
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.
Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. May also dephosphorylate proteins phosphorylated on Ser, Thr, and Tyr residues (By similarity).
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.
Acts as guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters.
Detected in brain, throughout the gray matter. Detected at low levels in heart and skeletal muscle.
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.
Exhibits night/day variations with an up to 150-fold increased expression at night. Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway. Down-regulated by light-induced proteasomal degradation. In the retina, 10-fold increased expression at night.
Highly expressed at night in pinealocytes and in the retina. Expressed at very low levels in the hindbrain and midbrain.
Monomer (By similarity). Interacts with several 14-3-3 proteins, including YWHAB, YWHAE, YWHAG and YWHAZ, preferentially when phosphorylated at Thr-29 (By similarity). Phosphorylation on Ser-203 also allows binding to YWHAZ, but with lower affinity (By similarity). The interaction with YWHAZ increases affinity for arylalkylamines and acetyl-CoA and protects the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation (By similarity).
cAMP-dependent phosphorylation on both N-terminal Thr-29 and C-terminal Ser-203 regulates AANAT activity by promoting interaction with 14-3-3 proteins.
Sialomucin that may play a key role in hematopoiesis. May be involved in cell adhesion. Promotes myogenesis by enhancing CXCR4-dependent cell motility. Positively regulates myoblast migration and promotes myoblast fusion into myotubes (By similarity).
Ubiquitous. Expressed at highest levels in the liver, kidney, lung and intestine.
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 (By similarity).
Belongs to the DEAD box helicase family. DDX52/ROK1 subfamily.
Required for efficient ribosome biogenesis. 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.
Expressed after injury in the carotid arteries (at protein level). Expressed in brain, lung, and after injury in fibroblasts of the adventitia and the neointima of the arteries.
Its overexpression in smooth muscle cell lines increases their migratory ability and inhibits collagen type I expression. May act as a negative regulator of collagen matrix deposition.
Strongly induced in carotid arteries after injury (balloon catheter injury model). By various growth factor (BMP4, TGFB1) in NIH 3T3 cell line.
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 (By similarity).
Essential component of the apolipoprotein B mRNA editing enzyme complex which is responsible for the postranscriptional editing of a CAA codon for Gln to a UAA codon for stop in APOB mRNA. Binds to APOB mRNA and is probably responsible for docking the catalytic subunit, APOBEC1, to the mRNA to allow it to deaminate its target cytosine. The complex also seems to protect the edited APOB mRNA from nonsense-mediated decay (By similarity).
Isoforms 1 and 2 are widely expressed while isoforms 3 and 4 are restricted to liver and small intestine.
Part of the apolipoprotein B mRNA editing complex with APOBEC1. Found in a complex with APOBEC1 and CELF2/CUGBP2. Interacts APOBEC1. Interacts with TNPO2; TNPO2 may be responsible for transport of A1CF into the nucleus. Interacts with SYNCRIP. Interacts with CELF2/CUGBP2 (By similarity).
The RRM domains are necessary but not sufficient for binding to APOB mRNA. Additional residues in the pre-RRM and C-terminal regions are required for RNA-binding and for complementing APOBEC1 activity (By similarity).
Essential for gene silencing: has a role in the structure of silenced chromatin. Plays a role in the developing brain (By similarity).
Controls the flux of glucose into the hexosamine pathway. Most likely involved in regulating the availability of precursors for N- and O-linked glycosylation of proteins. Regulates the circadian expression of clock genes BMAL1 and CRY1 (PubMed:10898949). Has a role in fine tuning the metabolic fluctuations of cytosolic UDP-GlcNAc and its effects on hyaluronan synthesis that occur during tissue remodeling (By similarity).
Homotetramer, may also exist as homodimers.
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). 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.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site.
Multifunctional cytokine mainly produced by T-cells that plays a regulatory role in immune response, tissue homeostasis, host defense, and oncogenesis. Possesses antiviral functions and induces the type I intereferon response during influenza infection. Signals through two receptor complexes IL20RA/IL20RB or IL20RB/IL22RA1. In turn, stimulates the JAK1-STAT3 and MAPK pathways and promotes the secretion of pro-inflammatory mediators including IL8 and MMP1 (By similarity). 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-99 promotes proteasomal degradation.
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. Interacts with CTCFL, PRMT5 and SNRPD3 (By similarity).
Autophosphorylated. Autophosphorylation is not required for catalytic activity.
Interacts with Nkx1-2. Interacts with FAS and DAXX. Probably part of a complex consisting of HIPK3, FAS and FADD. Interacts with UBL1/SUMO-1 (By similarity). Interacts with and stabilizes ligand-bound androgen receptor (AR).
Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors.
Expressed in the brain (at protein level) (PubMed:22632720, PubMed:26660156). In brain, expressed in the neocortex and enriched in the hippocampus but only modestly expressed in the cerebellum (PubMed:26660156). Expressed throughout the hippocampus but is most highly expressed in the CA1 region and the stratum lacunosum-moleculare of the CA2 region (PubMed:26660156).
Expression is low at postnatal day 0, increases at postnatal day 7, peaks at postnatal days 14 and 21 and decreases at 2 months of age.
Required to maintain a pool of extrasynaptic AMPA-regulated glutamate receptors (AMPAR) which is necessary for synapse development and function. Regulates basal AMPAR function and synaptic transmission during development but is dispensable at mature hippocampal synapses. Plays a role in regulating basal phosphorylation levels of glutamate receptor GRIA1 and promotes GRIA1 and GRIA2 cell surface expression.
Interacts with HSPA5; the interaction is direct (By similarity). 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 (By similarity). Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra (PubMed:16462600). Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (PubMed:16462600). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death (By similarity). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (By similarity). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (By similarity). Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells (By similarity). 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 (By similarity).
The N-terminal region may be responsible for neurotrophic activity while the C-terminal region may play a role in the ER stress response.
Interacts with XRN2; the interaction is direct.
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. 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. May also act on O-phospho-D-serine.
Nucleolar protein that acts as a modulator of rRNA synthesis. Plays a central role during organogenesis (By similarity).
May function during cartilage development and maintenance.
May possess two intramolecular disulfide bonds.
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 (By similarity).
In cyliated cells, dynein axonemal particle-specific protein required for deployment of ODA to the axoneme. Interacts with outer dynein arm (ODA) subunits.
Mitochondrial membrane carrier protein that mediates the import of NAD(+) into mitochondria. Mitochondrial NAD(+) is required for glycolysis and mitochondrial respiration. Compared to SLC25A52, SLC25A51-mediated transport is essential for the import of NAD(+) in mitochondria.
Down-regulated by PGE2 and in ischemic kidney.
Glycosylated. Glycosylation is necessary for proper targeting of the transporter to the plasma membrane (By similarity).
Highly expressed in kidney; in the particular segment of the proximal tubule and to a lower extent in brain. Found preferentially in the cortex and outer medulla and weakly in the inner medulla.
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (By similarity). Also mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS), 9-(2-phosphonylmethoxyethyl) guanine (PMEG), 9-(2-phosphonylmethoxyethyl) diaminopurine (PMEDAP), ochratoxin (OTA), acyclovir (ACV), 3'-azido-3-'deoxythymidine (AZT), cimetidine (CMD) and edaravone sulfate. Mediates the sodium-independent uptake of p-aminohippurate (PAH), cidofovir, adefovir, 2,4-dichloro-phenoxyacetate (2,4-D), hippurate (HA), indoleacetate (IA), indoxyl sulfate (IS) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). PAH uptake is inhibited by p-chloromercuribenzenesulphonate (PCMBS), diethyl pyrocarbonate (DEPC), indomethacin, sulindac, diclofenac, carprofen, okadaic acid, benzothiazolylcysteine (BTC), S-chlorotrifluoroethylcysteine (CTFC), cysteine S-conjugates S-dichlorovinylcysteine (DCVC), furosemide, steviol, phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, benzylpenicillin, bumetamide, losartan, phenol red, urate and alpha-ketoglutarate (By similarity). PAH uptake is inhibited by glutarate and probenecid.
Multiple cysteine residues are necessary for proper targeting to the plasma membrane.
Binds opioids in the presence of acidic lipids; probably involved in cell contact.
Belongs to the ferroportin (FP) (TC 2.A.100) family. SLC40A subfamily.
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. Interacts with HAMP; this interaction promotes SLC40A1 rapid ubiquitination.
Major iron transporter that plays a key role in balancing cellular and systemic iron levels (By similarity). Transports iron from intestinal, splenic, and hepatic cells into the blood to provide iron to other tissues. 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 (By similarity).
May be involved in iron transport and iron homeostasis.
Polyubiquitinated by RNF217; leading to proteasomal degradation (By similarity). Ubiquitination is necessary for its internalization by hepcidin/HAMP (By similarity).
Cilium- and flagellum-specific protein that plays a role in axonemal structure organization and motility (By similarity). Involved in the regulation of the size and morphology of cilia. Required for axonemal microtubules polyglutamylation (By similarity).
Interacts with AIP1. Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). Interacts with type I receptor ACVR1 (By similarity). Interacts with BMP7 (By similarity).
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. Mediates induction of adipogenesis by GDF6.
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.
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 (PubMed:7831323, PubMed:7831324, PubMed:10679020). May well act as a vesicular anchor by interacting with the target membrane and holding the vesicular and target membranes in proximity (PubMed:7831323, PubMed:7831324, PubMed:10679020).
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 (PubMed:7831323). Interacts with MIF (By similarity). Interacts with GM130/GOLGA2; interaction is disrupted upon phosphorylation of GM130/GOLGA2 by CDK1 at the onset of mitosis (PubMed:9150144, PubMed:9753325, PubMed:10744704, PubMed:10769027).
Phosphorylated in a cell cycle-specific manner; phosphorylated in interphase but not in mitotic cells. Dephosphorylated protein associates with the Golgi membrane; phosphorylation promostes dissociation (By similarity).
Detected on hippocampus neurons, especially at inhibitory synapses. Detected in retina, in the outer and inner plexiform layer. Detected in pancreas, in islet of Langerhans beta cells (at protein level). Expressed in brain, spinal cord and dorsal root ganglion. Detected in brain, and at lower levels in pancreas islet beta cells.
Interacts with NRXN1, NRXN2 and NRXN3 (PubMed:8576240, PubMed:18334216, PubMed:20624592). Interacts (via its C-terminus) with DLG4/PSD-95 (via PDZ domain 3) (By similarity). Interacts with PATJ (PubMed:9647694). Interacts with GPHN (PubMed:19755106). Interacts with MDGA1 and MDGA2 (PubMed:23248271). 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 (PubMed:28279354). Interacts with LHFPL4; leading to mutual regulation of the protein level and synaptic clustering (PubMed:29742426, PubMed:28279354). Interacts with GABRA1 (PubMed:28279354).
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.
Homodimer (PubMed:1730632). Homodimerizes after import into the mitochondrion (By similarity).
S-nitrosylation at Cys-237 in liver improves catalytic efficiency.
Very long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats (PubMed:8034667, PubMed:1730632). 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:8034667, PubMed:1730632). Among the different mitochondrial acyl-CoA dehydrogenases, very long-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 12 to 24 carbons long primary chains (PubMed:1730632).
Inhibits TIFA-mediated TRAF6 activation possibly by inducing a conformational change in TIFA.
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 (By similarity).
External component of the CIA complex. In the CIA complex, interacts directly with CIAO1 and MMS19.
Transcriptional repressor that binds the GZF1 responsive element (GRE) (consensus: 5'-TGCGCN[TG][CA]TATA-3'). May be regulating VSX2/HOX10 expression.
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 (By similarity).
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (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:22627129). Also plays an important role in the biosynthesis of complex lipids. Can also phosphorylate 1-alkyl-2-acylglycerol in vitro as efficiently as diacylglycerol provided it contains an arachidonoyl group (By similarity). Also involved in the production of alkyl-lysophosphatidic acid, another bioactive lipid, through the phosphorylation of 1-alkyl-2-acetyl glycerol (PubMed:22627129).
Stimulated by calcium and phosphatidylserine (By similarity). Activated by sphingosine (PubMed:22627129).
Component of a complex at least composed of ELL, SNF8/EAP30, VPS25/EAP20 and VPS36/EAP45 (By similarity). Component of the endosomal sorting complex required for transport II (ESCRT-II), composed of SNF8, VPS36 and 2 copies of VPS25. Interacts with CFTR; the interaction requires misfolded CFTR. Interacts (via C-terminal half) with the ESCRT-III subunit CHMP6 (via N-terminal half) (By similarity).
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 (By similarity). The ESCRT-II complex may also play a role in transcription regulation, possibly via its interaction with ELL.
Activated by ATP (PubMed:18937505, PubMed:9111008). Inhibited by calcium-activated calmodulin (PubMed:11118454, PubMed:18937505). Inhibited by bromoenol lactone (BEL) (PubMed:18937505).
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:18937505, PubMed:9111008). 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. Can further hydrolyze lysophospholipids carrying saturated fatty acyl chains (lysophospholipase activity) (PubMed:18937505). Upon oxidative stress, contributes to remodeling of mitochondrial phospholipids in pancreatic beta cells, in a repair mechanism to reduce oxidized lipid content (PubMed:24648512). Preferentially hydrolyzes oxidized polyunsaturated fatty acyl chains from cardiolipins, yielding monolysocardiolipins that can be reacylated with unoxidized fatty acyls to regenerate native cardiolipin species. Hydrolyzes oxidized glycerophosphoethanolamines present in pancreatic islets, releasing oxidized polyunsaturated fatty acids such as hydroxyeicosatetraenoates (HETEs) (PubMed:24648512). 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:18937505). 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 (By similarity). 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. 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).
Expressed in pancreatic beta-cells (PubMed:9111008). Expressed in skeletal muscle (at protein level) (PubMed:18937505).
Has two putative calmodulin binding domains, the 1-9-14 and IQ motifs (PubMed:11118454). 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 (PubMed:11118454).
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.
Hepatic stellate cells and endothelial cells (at protein level). Highly expressed in adrenal gland, small intestine, testis and eye. Lower levels of expression are observed in liver, heart, lung, skin, mammary tissue and skeletal muscle.
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.
Transfers the acyl group from the sn-1 position of phosphatidylcholine to all-trans retinol, producing all-trans retinyl esters (PubMed:3410848). Retinyl esters are storage forms of vitamin A (By similarity). LRAT plays a critical role in vision (By similarity). 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 (By similarity). Required for the survival of cone photoreceptors and correct rod photoreceptor cell morphology (By similarity).
Cytochromes P450 are a group of heme-thiolate monooxygenases.
Belongs to the ABC transporter superfamily. ABCF family. EF3 subfamily.
Displays an antiviral effect against flaviviruses such as west Nile virus (WNV) in the presence of OAS1B.
Lacks transmembrane domains and is probably not involved in transport.
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 (PubMed:12138115). 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 (By similarity). 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).
Exclusively expressed in polymorphonuclear leukocytes.
Phosphorylated by GRK6 upon leukotriene B4 binding; which promotes desensitization.
Receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response.
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.
High levels in liver and kidney. Also detected in heart, retina, ovary. Lung, testis and brain.
Inhibited by o-methylbenzoylalanine (OMBA).
Inhibited by thiol reagents and heavy metal ions.
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein Transport via Transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif. May also play a role in extracellular calcium homeostasis (By similarity).
Interacts with LEPR (By similarity). Interacts with RAB13.
Negatively regulates leptin receptor (LEPR) cell surface expression, and thus decreases response to leptin (By similarity). 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.
Involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
Homodimer, and heterodimer with DDX39A. Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex; TREX seems to have dynamic structure involving ATP-dependent remodeling; in the complex bridges ALYREF/THOC4 and the THO complex, and, in a ATP-dependent manner, ALYREF/THOC4 and SARNP/CIP29. Component of the spliceosome. Interacts directly with U2AF2. Interacts with RBM8A, RNPS1 and SRRM1, FYTTD1/UIF, THOC1, MX1 and POLDIP3. Interacts with LUZP4.
Involved in nuclear export of spliced and unspliced mRNA. Assembling component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. May undergo several rounds of ATP hydrolysis during assembly of TREX to drive subsequent loading of components such as ALYREF/THOC and CHTOP onto mRNA. Also associates with pre-mRNA independent of ALYREF/THOC4 and the THO complex. Involved in the nuclear export of intronless mRNA; the ATP-bound form is proposed to recruit export adapter ALYREF/THOC4 to intronless mRNA; its ATPase activity is cooperatively stimulated by RNA and ALYREF/THOC4 and ATP hydrolysis is thought to trigger the dissociation from RNA to allow the association of ALYREF/THOC4 and the NXF1-NXT1 heterodimer. Involved in transcription elongation and genome stability.
Splice factor that is required for the first ATP-dependent step in spliceosome assembly and for the interaction of U2 snRNP with the branchpoint. Has both RNA-stimulated ATP binding/hydrolysis activity and ATP-dependent RNA unwinding activity. Even with the stimulation of RNA, the ATPase activity is weak. Can only hydrolyze ATP but not other NTPs. The RNA stimulation of ATPase activity does not have a strong preference for the sequence and length of the RNA. However, ssRNA stimulates the ATPase activity much more strongly than dsRNA. Can unwind 5' or 3' overhangs or blunt end RNA duplexes in vitro. The ATPase and helicase activities are not influenced by U2AF2; the effect of ALYREF/THOC4 is reported conflictingly with [] reporting a stimulatory effect.
The helicase C-terminal domain mediates interaction with ALYREF/THOC4.
Dual specificity phosphatase able to dephosphorylate phosphotyrosine, phosphoserine and phosphothreonine residues within the same substrate, with a preference for phosphotyrosine as a substrate (By similarity). Involved in the modulation of intracellular signaling cascades. In skeletal muscle regulates systemic glucose homeostasis by activating, AMPK, an energy sensor protein kinase. Affects MAP kinase signaling though modulation of the MAPK1/2 cascade in skeletal muscle promoting muscle cell differentiation, development and atrophy (By similarity).
Homodimer (By similarity). Interacts with PRKAA2 (By similarity).
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.
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. Interacts with RTN1; RTN2; RTN3 and RTN4; the interaction leads to inhibition of amyloid precursor protein processing (By similarity). Interacts with SNX6. Interacts with PCSK9. Interacts with NAT8 and NAT8B. Interacts with BIN1 (By similarity). 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 (By similarity). Interacts with NRDC AND NRG1 (By similarity).
N-Glycosylated (By similarity). 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 (By similarity). 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. Monoubiquitinated and 'Lys-63'-linked polyubitinated. Deubiquitnated by USP8; inhibits lysosomal degradation.
Belongs to the Cob(I)alamin adenosyltransferase family.
Small GTPase required for proper nuclear import of RNA polymerase II (RNAPII). May act at an RNAP assembly step prior to nuclear import.
Expressed at highest levels in brain and testis, followed by skin, kidney, liver and spleen. Isoforms 2, 3, 4, 5, 6 and 7 may be specifically expressed in muscle tissues, including heart and skeletal muscle (extensor digitorum longus) (at protein level) (PubMed:11796721).
May be a constituent of a NFASC/NRCAM/ankyrin G complex. Interacts with RHBG. Directly interacts with DMD and betaDAG1; this interaction does not interfere with DMD-binding and is required for DMD and betaDAG1 retention at costameres. Interacts (via N-terminal ANK repeats) with SCHIP1 isoform 7 (via C-terminus); this interaction is required for the localization at axon initial segments (AISs) and nodes of Ranvier (NRs) (By similarity). Interacts with PLEC and FLNC (PubMed:21223964). Isoform 7 interacts with PLEC and FLNC through its muscle-specific C-terminal sequence. Interacts with KCNA1; this inhibits channel activity (By similarity). Interacts (via ANK repeats) with IQCJ-SCHIP1; required for IQCJ-SCHIP1 localization at axon initial segments (AIS) and nodes of Ranvier (By similarity). Interacts with SCHIP1 (By similarity). Interacts with SCN5A (By similarity).
Membrane-cytoskeleton linker. May participate in the maintenance/targeting of ion channels and cell adhesion molecules at the nodes of Ranvier and axonal initial segments. In skeletal muscle, required for costamere localization of DMD and betaDAG1 (By similarity). Regulates KCNA1 channel activity in function of dietary Mg(2+) levels, and thereby contributes to the regulation of renal Mg(2+) reabsorption (By similarity).
The 76 amino-acid long sequence from Asp-1060 to Val-1135 is encoded by a muscle-specific exon.
The 76 amino-acid long sequence from Asp-1077 to Val-1152 is encoded by a muscle-specific exon.
The 76 amino-acid long sequence from Asp-1710 to Val-1785 is encoded by a muscle-specific exon.
The 76 amino-acid long sequence from Asp-1888 to Val-1963 is encoded by a muscle-specific exon.
The 76 amino-acid long sequence from Asp-864 to Val-939 is encoded by a muscle-specific exon.
The 76 amino-acid long sequence from Asp-881 to Val-956 is encoded by a muscle-specific exon.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A3 subfamily.
Brain (PubMed:1948034, PubMed:1765147). Expressed in the substantia nigra and ventral tegmental area, regions that contain dopaminergic cell bodies (PubMed:1765147).
Homooligomer; disulfide-linked (By similarity). Interacts with PRKCABP and TGFB1I1 (By similarity). Interacts (via N-terminus) with SYNGR3 (via N-terminus) (By similarity). Interacts with SLC18A2 (By similarity). Interacts with TOR1A (ATP-bound); TOR1A regulates SLC6A3 subcellular location (By similarity). Interacts with alpha-synuclein/SNCA (By similarity). Interacts with SEPTIN4 (By similarity).
Inhibited by mazindol, cocaine, desipramine, GBR 12783 dihydrochloride, GBR 12909 dihydrochloride and nomifensine.
Mediates sodium- and chloride-dependent transport of dopamine (PubMed:1948035, PubMed:1948034, PubMed:1765147, PubMed:1502198, PubMed:8125921). Also mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (PubMed:8125921). Regulator of light-dependent retinal hyaloid vessel regression, downstream of OPN5 signaling (By similarity).
Belongs to the SLC43A transporter (TC 2.A.1.44) family.
Embryonic pancreas and adrenal glands (at protein level).
May have a role in neuroendocrine differentiation. Inhibits adipocyte differentiation.
Monomer (By similarity). Interacts with SH3RF2 (PubMed:22128169).
Pancreas and adrenal glands (at protein level).
Interacts with TRPC3 (By similarity). Interacts with BAG5 and HSPA8; the interaction with HSPA8 is increased in the presence of BAG5 (By similarity). Junctophilin-2 N-terminal fragment: Interacts with MEF2C (By similarity).
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. 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. Necessary for proper intracellular Ca(2+) signaling in cardiac myocytes via its involvement in ryanodine receptor-mediated calcium ion release. Contributes to the construction of skeletal muscle triad junctions.
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).
The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, by interacting with phospholipids. Has affinity for phosphatidylserine, and phosphorylated phosphatidylinositols including PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,5)P2 and PtdIns(3,4,5)P3.
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.
In contrast to other members of the family, lacks the conserved Ser at position 243 which is replaced by a Pro residue, suggesting it is inactive.
Down-regulated by doxorubicin (adriamycin), in vitro.
Interacts with TTN/titin (By similarity). Interacts with YBX1.
May play an important role in endothelial cell activation. May act as a nuclear transcription factor that negatively regulates the expression of cardiac genes.
ADP-ribosylation at Arg-125 is necessary and sufficient to activate P2RX7 and gate the channel.
Functional P2XRs are organized as homomeric and heteromeric trimers. Interacts with LAMA3, ITGB2, ACTB, ACTN4, SVIL, MPP3, HSPA1, HSPCB, HSPA8, PIK230 and PTPRB (By similarity). Interacts (via C-terminus) with EMP2 (By similarity).
Palmitoylation of several cysteines in the C-terminal cytoplasmic tail is required for efficient localization to cell surface.
Phosphorylation results in its inactivation.
Receptor for ATP that acts as a ligand-gated ion channel. Responsible for ATP-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Could function in both fast synaptic transmission and the ATP-mediated lysis of antigen-presenting cells.
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 (By similarity).
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. Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.2/SCN2A subfamily.
Expressed in brain (at protein level) (PubMed:10827969). Expressed in cerebellar granule neurons (at protein level) (PubMed:28029095).
Heterooligomer of a large alpha subunit and a smaller beta subunit. Heterooligomer with SCN2B or SCN4B; disulfide-linked (PubMed:26894959). Heterooligomer with SCN1B or SCN3B; non-covalently linked. Interacts with NEDD4L. Interacts with CALM. Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the scorpion toxin BMK M1 (PubMed:20678086).
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. Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By similarity).
Phosphorylation at Ser-1506 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.
Sumoylated at Lys-38. Sumoylation is induced by hypoxia, increases voltage-gated sodium current and mediates the early response to acute hypoxia in neurons (PubMed:28029095). Sumoylated SCN2A is located at the cell membrane (PubMed:28029095).
Stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents.
Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity.
Belongs to the aerobic coproporphyrinogen-III oxidase family.
Involved in the heme biosynthesis. Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX (By similarity).
Expressed in hippocampal neuronal synaptic termini (at protein level) (PubMed:23699505). Expressed predominantly in post-mitotic neurons of the central and peripheral nervous system.
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 PTK2/FAK1 (By similarity). Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. The complex p35/CDK5 interacts with CLOCK (By similarity). 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 (By similarity).
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 (By similarity).
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 (PubMed:23699505). 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 (By similarity).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ2 subfamily.
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.
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 and cesium (By similarity).
Prominently expressed in the central nervous system. Also found in other excitable tissues such as heart and skeletal muscle.
S-nitrosylation increases the open probability and inward rectifying currents.
May be involved in vesicle transport between the ER and the Golgi complex.
Inhibited by aprotinin, leupeptin, benzamidine, SERPINA1, SPINT1 and SPINT2.
Belongs to the complex I subunit 6 family.
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids. Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of saturated and unsaturated fatty acids (PubMed:10620324, PubMed:10869363, PubMed:15618658). May act as a major omega-hydroxylase for dodecanoic (lauric) acid in kidney (PubMed:10620324, PubMed:10869363, PubMed:15618658). At preglomerular arteries, may participate 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:15618658). Can also catalyze the oxidation of the penultimate carbon (omega-1 oxidation) of fatty acids with lower efficiency, displaying a preference for the (R)-stereoisomer (PubMed:10869363). 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:10620324, PubMed:10869363, PubMed:15618658).
Activated by cytochrome b5 and phosphatidylserine.
Expressed at proximal straight tubules and preglomerular arteries of the outer medulla as well in the cortex regions of kidney (at protein level).
APOD occurs in the macromolecular complex with lecithin-transport and binding of bilin. Appears to be able to transport a variety of ligands in a number of different contexts.
Expressed in liver, kidney, bladder, adrenal, cerebrum, duodenum, testis, lung, spleen, pancreas, heart and skin.
Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Gly/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes mono-, di- or tri-methylation of the exposed alpha-amino group of the Ala, Gly or Ser residue in the [Ala/Gly/Ser]-Pro-Lys motif and mono- or di-methylation of Pro in the Pro-Pro-Lys motif. Some of the substrates may be primed by NTMT2-mediated monomethylation. Catalyzes the trimethylation of the N-terminal Gly in CENPA (after removal of Met-1). Responsible for the N-terminal methylation of KLHL31, MYL2, MYL3, RB1, RCC1, RPL23A and SET. Required during mitosis for normal bipolar spindle formation and chromosome segregation via its action on RCC1.
Belongs to the cyclic nucleotide-gated cation channel (TC 1.A.1.5) family. CNGA2 subfamily.
Heterotetramer composed of two subunits of CNGA2, one of CNGA4 and one of CNGB1b. The complex forms the cyclic nucleotide-gated (CNG) channel of olfactory sensory neurons (By similarity).
Odorant signal transduction is probably mediated by a G-protein coupled cascade using cAMP as second messenger. The olfactory channel can be shown to be activated by cyclic nucleotides which leads to a depolarization of olfactory sensory neurons.
The C-terminal coiled-coil domain mediates trimerization of CNGA subunits.
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).
Exocrine pancreas-specific. Expressed in azaserine-induced pancreatic tumors (at protein level). Expressed in AR42J cells but not in ARIP, DSL6A, or DSL6B cells. Down-regulation is associated with the change of an azaserine-induced acinar cell carcinoma to a ductal phenotype.
Expressed from day 12 of gestation in pancreatic structures.
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.
Interacts with importin alpha, RXR and RARA.
Sumoylated in response to retinoic acid binding, sumoylation is critical for dissociation from ER and subsequent nuclear translocation.
Transports retinoic acid to the nucleus. Regulates the access of retinoic acid to the nuclear retinoic acid receptors (By similarity).
An autoinhibitory domain is present in the N-terminal region of the protein.
Autophosphorylated when activated by CDC42/p21.
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 (By similarity).
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 RAF 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 (By similarity).
Acts as a transcriptional activator or repressor. 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. Involved either as an oncogene or as a tumor suppressor, depending on the cell context (By similarity). Required for the transcriptional activation of HOXB3 in the rhombomere r5 in the hindbrain (By similarity).
Expressed at low levels in a variety of tissues, including liver, muscle and spleen. Strongly expressed in hypertrophic chondrocytes of the femur epiphysis, while expression is very weak in immature proliferating chondrocytes (at protein level).
Expressed in the cartilage of ribs and limbs, in the eyes and spinal cord at 15 dpc (at protein level). Expressed in the lens epithelium at 13 and 16 dpc; not detected in the fiber cells of the lens. In the eyes, confined in the equator of the lens; not detected in the retina at 15 dpc. In spinal cord, expressed in the ventral part of the dorsal horn and the ventral horn at 15 dpc. Predominantly expressed in postmitotic cells.
Homodimer or heterodimer with other bHLH-Zip transcription factors. Forms homodimers and heterodimers with FOS, FOSB and FOSL2, but not with JUN proteins (JUN, JUNB and JUND). Binds DNA as a homodimer or a heterodimer. Interacts with the intracellular cytoplasmic domain of LRP1 (LRPICD); the interaction results in a moderate reduction of MAFB transcriptional potential. Interacts with PAX6; the interaction is direct. Interacts with ETS1 and LRP1 (By similarity).
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.
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. Also interacts with UPF2 and HNRPD. Interacts with METTL3. Interacts with DDX3X (By similarity).
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. 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.
The RRM domain mediates interaction with EIF3J.
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.
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.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE9 subfamily.
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. 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. 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 (By similarity). In brain, involved in cognitive function, such as learning and long-term memory (PubMed:18674549, PubMed:22070409, PubMed:22328573).
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:18674549). Specifically inhibited by PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) (PubMed:22070409).
Widely expressed in brain: highly expressed in the basal forebrain, cerebellum and olfactory bulb (PubMed:11698617, PubMed:14501210). Expressed at highest level in cerebellar Purkinje cells (PubMed:14501210).
Acetylated. Acetylation at Lys-39 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 99-103, this acetylation is strongly induced by glucocorticoid treatment and enhances transactivation activity.
Acts as a dominant negative through heterodimerization with isoform 2 (PubMed:1934061). Promotes osteoblast differentiation and osteoclastogenesis (By similarity).
Binds DNA as a homodimer and as a heterodimer (PubMed:1934061). Interacts with MYB; within the complex, MYB and CEBPB bind to different promoter regions. Interacts with ATF4. Binds DNA as a heterodimer with ATF4 (By similarity). Can form stable heterodimers with CEBPA, CEBPD, CEBPE and CEBPG (PubMed:1377818, PubMed:1884998). Interacts with SIX1 (By similarity). Isoform 2 and isoform 3 also form heterodimers (PubMed:1934061). 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. Interacts with DDIT3/CHOP.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 (By similarity). 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 (PubMed:15308669).
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.
Important transcription factor regulating the expression of genes involved in immune and inflammatory responses (PubMed:8336793). Also plays a significant role in adipogenesis, as well as in the gluconeogenic pathway, liver regeneration, and hematopoiesis (PubMed:10635333). 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 (By similarity). 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 (PubMed:10635333). 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 (By similarity). 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 (PubMed:15308669).
Methylated. Methylation at Arg-3 by CARM1 and at Lys-39 by EHMT2 inhibit transactivation activity. Methylation is probably inhibited by phosphorylation at Thr-189.
O-glycosylated, glycosylation at Ser-181 and Ser-182 prevents phosphorylation on Thr-189, Ser-185 and Thr-180 and DNA binding activity which delays the adipocyte differentiation program.
Phosphorylated at Thr-189 by MAPK and CDK2, serves to prime phosphorylation at Thr-180 and Ser-185 by GSK3B and acquire DNA-binding as well as transactivation activities, required to induce adipogenesis. MAPK and CDK2 act sequentially to maintain Thr-189 in the primed phosphorylated state during mitotical cloning expansion and thereby progression of terminal differentiation (By similarity). Phosphorylation at Ser-105 enhances transactivation activity (PubMed:8336793). Phosphorylation at Ser-277 in response to calcium increases transactivation activity. Phosphorylated at Thr-189 by RPS6KA1 (By similarity).
Sumoylated by polymeric chains of SUMO2 or SUMO3 (By similarity). Sumoylation at Lys-134 is required for inhibition of T-cells proliferation. In adipocytes, sumoylation at Lys-134 by PIAS1 leads to ubiquitination and subsequent proteasomal degradation. Desumoylated by SENP2, which abolishes ubiquitination and stabilizes protein levels (By similarity).
Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures (PubMed:8627351). Interacts (phosphorylated upon activation by BDNF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by BDNF) with PLCG1 and/or PLCG2; mediates PLCG1 phosphorylation and activation. Interacts with SH2B1 and SH2B2. Interacts with NGFR; may regulate the ligand specificity of the receptor. Interacts with SORCS2; this interaction is important for normal targeting to post-synaptic densities in response to high-frequency stimulation (By similarity). Interacts (phosphorylated upon ligand-binding) with SH2D1A; regulates NTRK2. Interacts with SQSTM1 and KIDINS220. Interacts (phosphorylated upon ligand-binding) with FRS2; activates the MAPK signaling pathway. Interacts with APPL1 (By similarity). Interacts with MAPK8IP3/JIP3 and KLC1; interaction with KLC1 is mediated by MAPK8IP3/JIP3 (PubMed:21775604). Interacts with SORL1; this interaction facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling (By similarity).
Phosphorylated. Undergoes ligand-mediated autophosphorylation that is required for interaction with SHC1 and PLCG1 and other downstream effectors. Some isoforms are not phosphorylated.
Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differentiation, and synapse formation and plasticity. Receptor for BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4. Alternatively can also bind NTF3/neurotrophin-3 which is less efficient in activating the receptor but regulates neuron survival through NTRK2. Upon ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades. Through SHC1, FRS2, SH2B1, SH2B2 activates the GRB2-Ras-MAPK cascade that regulates for instance neuronal differentiation including neurite outgrowth. Through the same effectors controls the Ras-PI3 kinase-AKT1 signaling cascade that mainly regulates growth and survival. Through PLCG1 and the downstream protein kinase C-regulated pathways controls synaptic plasticity. Thereby, plays a role in learning and memory by regulating both short term synaptic function and long-term potentiation. PLCG1 also leads to NF-Kappa-B activation and the transcription of genes involved in cell survival. Hence, it is able to suppress anoikis, the apoptosis resulting from loss of cell-matrix interactions. May also play a role in neutrophin-dependent calcium signaling in glial cells.
The neuronal activity and the influx of calcium positively regulate the kinase activity and the internalization of the receptor which are both important for active signaling. Regulated by NGFR that may control the internalization of the receptor. NGFR may also stimulate the activation by BDNF compared to NTF3 and NTF4. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. The formation of active receptors dimers able to fully transduce the ligand-mediated signal, may be negatively regulated by the formation of inactive heterodimers with the non-catalytic isoforms.
Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor (By similarity).
Widely expressed in the central and peripheral nervous system. The different forms are differentially expressed in various cell types. Isoform T2 is primarily expressed in neurons.
Cochlea. Expressed at low levels in substantia nigra.
Exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons.
Cleaved by CASP8 upon death ligand binding such as tumor necrosis factor-alpha. CASP8 cleavage blocks survival-related autophagy and favors apoptosis (By similarity).
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 (By similarity).
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 (By similarity).
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.
Heparin acts as an important cofactor, producing 20 to 100-fold accelerations of SERPINA10 reactions with factor Xa and factor XIa.
In regenerating livers, it showed maximal expression 48 hours after hepatectomy, expression remaining elevated up to 2 weeks after liver removal.
Inhibits activity of the coagulation protease factor Xa in the presence of PROZ, calcium and phospholipids. Also inhibits factor XIa in the absence of cofactors (By similarity).
Has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker against S.epidermidis, S.aureus and group b streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.
Interacts with SLC40A1; this interaction promotes SLC40A1 rapid ubiquitination.
Liver-produced hormone that constitutes the main circulating regulator of iron absorption and distribution across tissues. Acts by promoting endocytosis and degradation of ferroportin/SLC40A1, leading to the retention of iron in iron-exporting cells and decreased flow of iron into plasma. Controls the major flows of iron into plasma: absorption of dietary iron in the intestine, recycling of iron by macrophages, which phagocytose old erythrocytes and other cells, and mobilization of stored iron from hepatocytes.
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. 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. Protects cells against lipotoxicity.
Densely expressed in cerebellum and at moderate levels in the amygdala, cortex, striatum, spleen, liver and pituitary.
Homodimer and heterodimer with SSTR2. Heterodimerization with SSTR2 inactivates SSTR3 receptor function.
Phosphorylated. Phosphorylation increases upon somatostatin binding.
Receptor for somatostatin-14 and -28. This receptor is coupled via pertussis toxin sensitive G proteins to inhibition of adenylyl cyclase.
Accessory component of both the DNA polymerase delta complex and the DNA polymerase zeta complex. 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. 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. 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. Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR). 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. 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.
Belongs to the DNA polymerase delta/II small subunit family.
Component of both the DNA polymerase delta and DNA polymerase zeta complexes. 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. Within Pol-delta4, directly interacts with POLD1, POLD3 and POLD4. 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. 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. Contrary to the other components of Pol-delta4, does not directly interact with PCNA. 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. Directly interacts with POLDIP2 and POLDIP3. Directly interacts with KCTD13/PDIP1; in the presence of PCNA, this interaction may stimulate DNA polymerase activity. Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3, with REV3L bearing DNA polymerase catalytic activity (By similarity). Interacts with KCTD10 (PubMed:15982757).
Part of the SNARE core complex containing STX7, VAMP8 and VTI1B. Interacts with VAMP8. Forms a SNARE complex with STX7, VTI1B 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. Interacts with HECTD3 (By similarity). Interacts with TPC1 (By similarity).
Vesicle trafficking protein that functions in the early secretory pathway, possibly by mediating retrograde transport from cis-Golgi membranes to the ER.
Widely expressed in all tissues examined.
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. Component of the WASH complex, composed of F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASHC1, WASHC2, WASHC3, WASHC4 and WASHC5. Interacts with S100B (By similarity). Interacts with S100A1. Interacts with SH3BP1; recruits CAPZA1 to forming cell junctions. Interacts with CD2AP (By similarity). Directly interacts with CRACD; this interaction decreases binding to actin (By similarity).
At 17.5 dpc, expressed in brain including hippocampus and corpus callosum (PubMed:28521134). Isoform 1: Expression begins after birth at P1-P5 stages and is maintained in adults (PubMed:9660871, PubMed:28521134). Expressed in mature neurons (PubMed:28521134). Isoform 2: Expressed at 13 dpc, 16 dpc and 18 dpc stages (PubMed:9660871, PubMed:28521134). Expression is increased at P1-P5 stages and persists at low levels in the adult brain (PubMed:9660871, PubMed:28521134). Expressed in unpolarized hippocampal neurons and throughout neuronal development (PubMed:28521134).
Interacts with calmodulin (via C-terminus); the interaction is dependent on Ca(2+) (PubMed:8700896, PubMed:11413126). Interacts (via C-terminus) with TMEM106B (via N-terminus) (PubMed:24357581). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (By similarity).
Involved in microtubule stabilization in many cell types, including neuronal cells (PubMed:8700896, PubMed:9660871, PubMed:3456161, PubMed:11413126, PubMed:28521134). Specifically has microtubule cold stabilizing activity (PubMed:3456161). Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with TMEM106B (By similarity). Regulates KIF5A-mediated axonal cargo transport (PubMed:28521134). Regulates axonal growth during neuron polarization (PubMed:28521134).
Isoform 1 is specifically expressed in adult brain. Isoform 2 is predominantly expressed in embryonic brain; expression persists at low levels in the adult brain.
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.
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.
Weakly expressed in heart, brain and testis.
Belongs to the exonuclease superfamily. TREX family.
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.
Expressed predominantly in lung, colon and spleen. Present in liver (at protein level).
Exerts both phospholipase and triglyceride lipase activities (By similarity). More active as a phospholipase than a triglyceride lipase (By similarity). 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 (By similarity). Hydrolyzes high density lipoproteins (HDL) more efficiently than other lipoproteins (By similarity).
Head to tail Homodimer. Interacts with apolipoprotein C-2 (By similarity).
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.
Mediates sodium- and bicarbonate-dependent electrogenic sodium bicarbonate cotransport, with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3.
Observed in hepatocytes and in the apical region of bile duct intrahepatic cholangiocytes of liver. Also observed in uroepithelium cells lining the outer pelvic wall of the kidney (at protein level). Highly expressed in colon, distal colon, liver, kidney and testis. Moderate expression in duodenum and stomach and weak expression in heart. In kidney, very weakly expressed in the inner medulla, but abundantly expressed in cortex and outer medulla in the medullary thick ascending and cortical thick ascending limbs of the loop of Henle.
May be involved in apoptosis regulation.
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 (By similarity).
Broadly distributed, but higher levels found in liver, spleen, intestine, lung and kidney.
Tetramer of heterotrimers consisting of exclusion domain, heavy- and light chains.
Thiol protease. Has dipeptidylpeptidase activity. Can act as both an exopeptidase and endopeptidase (By similarity).
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 (By similarity).
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.
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. In vitro also methylates unmodified 'Lys-20' (H4K20me0) of histone H4 and nucleosomes (By similarity). 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 (By similarity). 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).
Strongly down-regulated in various cancers such as hepatocarcinomas.
Serine protease inhibitor with activity toward thrombin, trypsin, and urokinase. Promotes neurite extension by inhibiting thrombin. Binds heparin.
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.
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.
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. In the CIA complex, MMS19 acts as an adapter between early-acting CIA components and a subset of cellular target iron-sulfur proteins.
Detected at low concentration in practically all the fetal tissues and its expression markedly and rapidly decreased after birth.
Homotetramer. Interacts with ATP6V1E1 (By similarity).
In vertebrates, three forms of this ubiquitous glycolytic enzyme are found, aldolase A in muscle, aldolase B in liver and aldolase C in brain.
Expressed in kidney collecting duct cells and in the nuclei of proximal convoluted tubule cells in the kidney cortex (at protein level).
Interacts (via COMM domain) with COMMD1 (via COMM domain). Interacts with NFKB1/p105. Interacts with CCDC22, CCDC93, SCNN1B, CUL3, CUL4A, CUL4B, CUL5.
May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes. May down-regulate activation of NF-kappa-B. Modulates Na(+) transport in epithelial cells by regulation of apical cell surface expression of amiloride-sensitive sodium channel (ENaC) subunits.
Splice factor that binds to the single-stranded 3'AG at the exon/intron border and promotes its utilization in the second catalytic step. Involved in the regulation of alternative splicing and the utilization of cryptic splice sites.
Expressed throughout the cell cycle independently of DNA synthesis. Levels increase from embryonic day 18 to postnatal day 10.
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 (By similarity). Interacts with ZMYND11; when trimethylated at 'Lys-36' (H3.3K36me3).
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 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 (By similarity). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (By similarity). Interacts with ASF1A, MCM2, NASP and SPT2 (By similarity).
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.
Both precursor form and mature form have thiol reductase activity.
Lysosomal thiol reductase that can reduce protein disulfide bonds. May facilitate the complete unfolding of proteins destined for lysosomal degradation. Plays an important role in antigen processing. Facilitates the generation of MHC class II-restricted epitodes from disulfide bond-containing antigen by the endocytic reduction of disulfide bonds. Facilitates also MHC class I-restricted recognition of exogenous antigens containing disulfide bonds by CD8+ T-cells or crosspresentation (By similarity).
N-glycosylated. Sugar chains contain mannose-6-phosphate (By similarity).
Synthesized as a 35 kDa precursor which is then processed into the mature 30 kDa form via cleavage of N-terminal and C-terminal propeptides. Processing of the precursor is mediated by multiple lysosomal proteases (By similarity).
Inhibitory regulator of the Ras-cyclic AMP pathway. Binds inositol tetrakisphosphate (IP4) (By similarity).
Belongs to the FIT family. FIT1 subfamily.
Plays an important role in the formation of lipid droplets (LDs), which are storage organelles at the center of lipid and energy homeostasis. Directly binds to diacylglycerol (DAGs) and triacylglycerol.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A5 subfamily.
Sodium- and chloride-dependent glycine transporter (PubMed:8226790, PubMed:25480793). Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:8226790). May be responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses (PubMed:8226790).
Specifically expressed in spinal cord, brain stem, and to a lesser extent in the cerebellum.
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). Interacts (via cytoplasmic domain) with DST (via N-terminus). Interacts with RAC1. ITGA6:ITGB4 is found in a ternary complex with NRG1 and ERBB3. ITGA6:ITGB4 is found in a ternary complex with IGF1 and IGF1R. ITGA6:ITGB4 interacts with IGF2.
Integrin alpha-6/beta-4 is a receptor for laminin. It 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. ITGA6:ITGB4 binds to IGF1 and this binding is essential for IGF1 signaling. ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling.
Palmitoylated by DHHC3 at several cysteines of the membrane-proximal region, enhancing stability and cell surface expression. Palmitoylation also promotes secondary association with tertaspanins (By similarity).
The fibronectin type-III-like domains bind BPAG1 and plectin and probably also recruit BP230.
Receptor for cysteinyl leukotrienes mediating constriction of the microvascular smooth muscle during an inflammatory response. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system (By similarity).
Involved in pinching off the separated nuclei at the cleavage furrow and in cytokinesis. Required for mitotic integrity and maintenance of chromosomal stability. Protects cells against mitotic errors, centrosomal amplification, micronucleus formation and aneuploidy. Plays a key role of midbody function involving abscission of the daughter cells during cytokinesis and appropriate chromosomal and nuclear segregation into the daughter cells.
Expression restricted to the beta-cells of pancreatic 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.
Belongs to the class-II aminoacyl-tRNA synthetase family. Type 1 subfamily.
AMP deaminase plays a critical role in energy metabolism.
Part of complex consisting of SFPQ, NONO and MATR3. Interacts with AGO1 and AGO2 (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 TFCB.
Belongs to the acetyltransferase family. GCN5 subfamily.
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 (By similarity).
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.
Highly expressed in brain, in particular in cortex, the CA2 region of the hippocampus, olfactory bulb, striatum and pons. Not detectable in the other tissues tested.
Highly expressed in cerebellum in 1 to 3 week old rats. Expression levels before and after are much lower. Expression in total brain increases slightly during development and remains at a constant high level after birth.
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 tumor suppressor (By similarity).
Phosphorylated on serine residues. Hyperphosphorylated by the cAMP-dependent kinase PKA during cell-cycle progression (By similarity).
Homohexamer. 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. Interacts with LRPPRC. Interacts with androgen receptor AR (via N-terminus). Interacts with estrogen receptor ESR1; the interaction relocalizes ESR1 to the cytoplasm. 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. Interacts with MECOM. Interacts with URI1.
Involved in gene transcription regulation. Acts in concert with the corepressor URI1 to regulate androgen receptor AR-mediated transcription. Together with URI1, associates with chromatin to the NKX3-1 promoter region. Negatively regulates the transcriptional activity of the estrogen receptor ESR1 by inducing its translocation into the cytoplasm. May act as nuclear chaperone that facilitates the formation of the NF-kappa-B enhanceosome and thus positively regulates NF-kappa-B transcription activity. Potential component of mitochondrial-associated LRPPRC, a multidomain organizer that potentially integrates mitochondria and the microtubular cytoskeleton with chromosome remodeling. Increasing concentrations of UXT contributes to progressive aggregation of mitochondria and cell death potentially through its association with LRPPRC. 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.
By streptozotocin and fasting in skeletal muscle.
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 thier 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 (By similarity).
Expressed in testis, heart, kidney and skeletal muscle. Low levels of expression are detectable in all other tissues screened.
Interacts with and stabilizes RNF123. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with HIF1A (via N-terminus) (By similarity).
Binds the telomeric double-stranded 5'-TTAGGG-3' repeat.
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.
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.
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Has GTP:AMP phosphotransferase and ITP:AMP phosphotransferase activities.
Efficient DNA binding requires dimerization with another bHLH protein. Forms homo- or heterooligomers with myogenin, E12 and ITF2 proteins. Interacts with PTF1. Interacts with RUNX1T1. Interacts with NEUROD2 (By similarity). Interacts with BHLHA9.
Isoform gamma is highly expressed in lung, kidney, spleen, and is expressed at reduced levels in heart, muscle, liver, pituitary, brain and the trigeminal ganglion. The expression of isoform alpha predominates over isoform gamma in the pituitary and the brain.
Transcriptional regulator. Involved in the initiation of neuronal differentiation. Activates transcription by binding to the E box (5'-CANNTG-3') (By similarity). May be involved in the functional network that regulates the development of the GnRH axis.
Expressed in the brain of 20 dpc embryos.
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 (By similarity). Plays a role in axon guidance (By similarity). 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 (By similarity). Involved in invasive growth and cell migration. May participate in cytokinesis (By similarity).
Phosphorylation at Ser-522 enhances CRMP1-mediated alteration of FLNA ternary structure and FLNA dissociation from F-actin.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family. YchF/OLA1 subfamily.
Hydrolyzes ATP, and can also hydrolyze GTP with lower efficiency. Has lower affinity for GTP.
Activated by trypsin cleavage in the duodenum. Can also be activated by thrombin or autocatalytically.
Secretory calcium-dependent phospholipase A2 that primarily targets dietary phospholipids in the intestinal tract (PubMed:1420353, PubMed:17158102). Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) with preference for phosphatidylethanolamines and phosphatidylglycerols over phosphatidylcholines (PubMed:1420353, PubMed:17158102). May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism and inflammation in the intestinal tract (PubMed:14998370). Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines (PubMed:14998370). May act in an autocrine and paracrine manner (By similarity). Has anti-helminth activity in a process regulated by gut microbiota. Upon helminth infection of intestinal epithelia, directly affects phosphatidylethanolamine contents in the membrane of helminth larvae, likely controlling an array of phospholipid-mediated cellular processes such as membrane fusion and cell division while providing for better immune recognition, ultimately reducing larvae integrity and infectivity (By similarity).
Sulfate transporter. May play a role in endochondral bone formation.
Interacts with HUS1, HUS1B, RAD1, RAD9A and RAD17.
Homodimer; in the catalytically active form. Monomer in the secreted form.
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:2709006). 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. Acts as a neurotrophic factor, neuroleukin, for spinal and sensory neurons. It is secreted by lectin-stimulated T-cells and induces immunoglobulin secretion (By similarity).
Phosphorylation at Ser-185 by CK2 has been shown to decrease enzymatic activity and may contribute to secretion by a non-classical secretory pathway.
Belongs to the POU transcription factor family. Class-4 subfamily.
Expressed in the heart, brain and spinal cord (PubMed:8835784, PubMed:18368538). Expressed in cardiomyocytes (at protein level) (PubMed:18368538). Expressed in brain and spinal cord (PubMed:8835784, PubMed:18368538). Expressed in dorsal root ganglion (RGD) neurons (PubMed:8835784).
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. Functions either as activator or repressor modulating the rate of target gene transcription through RNA polymerase II enzyme in a promoter-dependent manner. 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.
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.
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 (By similarity). Interacts with DBF4 (By similarity). Interacts with POLQ (By similarity).
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 (By similarity).
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.
Belongs to the eIF4E-binding protein family.
Belongs to the eukaryotic ribosomal protein eS8 family.
Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs.
Enhances Ca(2+)-mediated inhibition of inositol 1,4,5-triphosphate receptor (ITPR) Ca(2+) release.
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. Interacts with STAC, STAC2 and STAC3 (via their SH3 domains) (By similarity). Interacts with CALM (By similarity).
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.
Belongs to the carnosine N-methyltransferase family.
Expressed at higher level in skeletal muscle compared to other tissues.
Homodimer. Each monomer accommodates one molecule of carnosine in its active pocket, 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.
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. 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 (By similarity).
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 (By similarity).
Efficient DNA binding requires dimerization with another bHLH protein (By similarity). Heterodimer with NPAS4 or 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. Specifically recognizes the xenobiotic response element (XRE).
Binds DNA as a homodimer and as a heterodimer (PubMed:1884998, PubMed:8367486, PubMed:12578822). Can form stable heterodimers with CEBPB, CEBPD, CEBPE and CEBPG (PubMed:1884998, PubMed:1377818). Can form stable homodimers (also isoform 2 and isoform 3 dimers) and heterodimers with CEBPB (with isoform 2 and isoform 3) and CEBPG (PubMed:1377818, PubMed:8367486). Interacts with PRDM16 (By similarity). Interacts with UBN1 (By similarity). 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 (By similarity). Interacts with RB1 (By similarity). Interacts (when phosphorylated at Ser-193) with CDK2, CDK4, E2F4 and SMARCA2 (By similarity). 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 (By similarity). Interacts (via recognition sequence) with TRIB1 (By similarity).
Can act as dominant-negative. Binds DNA and have transctivation activity, even if much less efficiently than isoform 2. Does not inhibit cell proliferation.
Directly and specifically enhances ribosomal DNA transcription interacting with RNA polymerase I-specific cofactors and inducing histone acetylation.
Isoform 2 and isoform 3 are expressed in liver (at protein level).
Isoform 2 and isoform 3 are not expressed at 1 day before birth, relative concentration of both isoforms increases with the age of the animal, reaching maximal levels in the adulthood.
Mutagenesis in position: 14: RRQR -> AAAA abolishes nucleolar localization and prevents induction of 45S pre-RNA.
Phosphorylation at Ser-193 is required for interaction with CDK2, CDK4 and SWI/SNF complex leading to cell cycle inhibition. Dephosphorylated at Ser-193 by protein phosphatase 2A (PP2A) through PI3K/AKT signaling pathway regulation. Phosphorylation at Thr-222 and Thr-226 by GSK3 is constitutive in adipose tissue and lung. In liver, both Thr-222 and Thr-226 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 V296A substitution has little effect on the binding of CEBPA to its consensus site (5'-GCAAT-3'), while greatly increasing affinity for cAMP response element (CRE) sites (5'-GTCAT-3').
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 (PubMed:8367486, PubMed:11672531, PubMed:16735515, PubMed:20176812). Binds directly to the consensus DNA sequence 5'-T[TG]NNGNAA[TG]-3' acting as an activator on distinct target genes. During early embryogenesis, plays essential and redundant functions with CEBPB (By similarity). Essential for the transition from common myeloid progenitors (CMP) to granulocyte/monocyte progenitors (GMP) (PubMed:11672531). 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 (PubMed:11672531). 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 (PubMed:11672531). Proliferation arrest also depends on a functional binding to SWI/SNF complex (By similarity). In liver, regulates gluconeogenesis and lipogenesis through different mechanisms. To regulate gluconeogenesis, functionally cooperates with FOXO1 binding to IRE-controlled promoters and regulating the expression of target genes such as PCK1 or G6PC1. To modulate lipogenesis, interacts and transcriptionally synergizes with SREBF1 in promoter activation of specific lipogenic target genes such as ACAS2. In adipose tissue, seems to act as FOXO1 coactivator accessing to ADIPOQ promoter through FOXO1 binding sites (By similarity).
Ubiquitinated by COP1 upon interaction with TRIB1.
Expressed specifically during the late G1 and S phases.
Histone binding is mediated by the concave surface of the LRR region.
Interacts with histones H3 and H4. Interacts with KLF5; this interaction induces promoter region-specific histone incorporation and inhibition of histone acetylation by ANP32B.
Multifunctional protein that is involved in the regulation of many processes including cell proliferation, apoptosis, cell cycle progression or transcription. Regulates the proliferation of neuronal stem cells, differentiation of leukemic cells and progression from G1 to S phase of the cell cycle (PubMed:11162633). As negative regulator of caspase-3-dependent apoptosis, may act as an antagonist of ANP32A in regulating tissue homeostasis (PubMed:16499868). Exhibits histone chaperone properties, able to recruit histones to certain promoters, thus regulating the transcription of specific genes. Also plays an essential role in the nucleocytoplasmic transport of specific mRNAs via the uncommon nuclear mRNA export receptor XPO1/CRM1 (By similarity). Participates in the regulation of adequate adaptive immune responses by acting on mRNA expression and cell proliferation (By similarity).
Predominantly expressed in brain. Expressed in the entire embryonic brain, whereas in the adult brain its expression is restricted to the subventricular zone where there are neural progenitor cells.
Suppression of the expression of this gene by RNAi induces apoptosis.
Belongs to the complex I NDUFA5 subunit family.
Plays a role in promoting axonal degeneration following neuronal injury by toxic insult or trauma.
Exhibits weak phospholipase activity, acting on various phospholipids, including phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine and lysophospholipids. However, in view of the small size of the putative binding pocket, it has been proposed that it may act rather as an amidase or a peptidase (By similarity).
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 (By similarity).
Heterodimer of a catalytic subunit and a regulatory subunit.
Associates with proteins harboring glycine-rich transmembrane domains and ensures their efficient localization to the cell surface.
Belongs to the dicarboxylate/amino acid:cation symporter (DAACS) (TC 2.A.23) family. SLC1A6 subfamily.
Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:14506254, 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). 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).
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). Participates in the formation of novel hepoxilin regioisomers. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Homodimer. Interacts with CDK5 (By similarity).
Present in kidney, lung, testis and placenta, very low levels in liver.
Expression observed in trophoblast giant cells (TGCs), the placenta-derived cell lineage aligned at the boundary between the uterus and placenta, at 12.5 dpc. Expressions gradually decreased during placental maturation, and the signal is no more detectable in the cells at 18.5 dpc.
Highest levels in the cecum and colon. Moderate levels present in the liver, spleen, kidney, ovary, uterus and small intestine. Low levels in the stomach, pancreas and placenta. Expressed only moderately in the placenta. Persistent expression is detected in hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female. Hypothalamic expression is sensitive to neonatal imprinting by estrogen. Expression is higher in the hypothalamus than in the brainstem and spinal cord. In the brain, metastin-like immunoreactivity is found mainly in three groups of cells: dorsomedial hypothalamic nucleus, nucleus of the solitary tract, and caudal ventrolateral medulla.
Metastasis suppressor protein. 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. 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. Intracerebroventricular administration induces an increase in serum LH and FSH levels in prepubertal male and female as well as in adult animals.
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) (By similarity). Interacts with EPN1 (By similarity). Interacts with EPS15; clathrin competes with EPS15 (By similarity). Interacts with SNAP91; clathrin competes with SNAP91 (By similarity). Interacts with CLTC; clathrin competes with EPS15, SNAP91 and PIP5K1C (PubMed:7559550). Interacts with LDLRAP1 (By similarity). Interacts with AMPH and BIN1 (By similarity). Interacts with ARF6 (GDP-bound) (By similarity). Interacts (dephosphorylated at Tyr-737) with ARRB1; phosphorylation of AP2B1 at Tyr-737 disrupts the interaction (By similarity). Interacts with SLC2A8 (By similarity). Interacts with SCYL1 and SCYL2 (By similarity). Interacts with TGFBR1 and TGFBR2 (By similarity). Interacts with PIP5K1C; clathrin competes with PIP5K1C (PubMed:19287005). Interacts with DENND1B (By similarity). Interacts with FCHO1 (PubMed:22484487). Interacts with RFTN1 (By similarity). Interacts with KIAA1107 (By similarity). 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 (By similarity).
Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. 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 (By similarity). 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 (By similarity).
Interacts with DNM1L/DLP1 through the TPR region. Interacts with MARCHF5. Interacts with MIEF1. Interacts with PEX11A, PEX11B and PEX11G.
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 (By similarity).
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.
ATP-binding cassette (ABC) transporter that plays a role in lipid homeostasis and macrophage-mediated phagocytosis (By similarity). Binds APOA1 and may function in apolipoprotein-mediated phospholipid efflux from cells (By similarity). May also mediate cholesterol efflux (By similarity). May regulate cellular ceramide homeostasis during keratinocyte differentiation (By similarity). 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 (By similarity).
Expressed in blood cells. Also detected in brain and ovary tissues (at protein level). Expressed in platelet.
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 (By similarity). 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).
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.
Belongs to the cytidine and deoxycytidylate deaminase family. ADAT2 subfamily.
Probably participates in deamination of adenosine-34 to inosine in many tRNAs.
Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen.
Expressed at highest levels in liver, lower levels in brain, kidney and heart (at protein level) (PubMed:12871948). Expressed in microvessels of the blood-brain barrier (BBB) (at protein level) (PubMed:18687783).
Monomer (By similarity). Homodimer (By similarity). Homooligomer (By similarity).
Specific thyroid hormone transmembrane transporter, that mediates both uptake and efflux of thyroid hormone across the cell membrane independently of pH or a Na(+) gradient. Major substrates are the iodothyronines T3 and T4 and to a lesser extent rT3 and 3,3-diiodothyronine (3,3'-T2) (PubMed:12871948). Acts as an important mediator of thyroid hormone transport, especially T3, through the blood-brain barrier (By similarity).
May play a role in microtubule-mediated transport or vesicle function.
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:7796908, PubMed:6783036, PubMed:2072101). Metabolizes the cysteine conjugates of certain halogenated alkenes and alkanes to form reactive metabolites. 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:8502223).
Inhibited by aminooxyacetate (in vitro).
Testis-specific (PubMed:2423516, PubMed:1706721). Expressed in pachytene spermatocytes during meiotic prophase I (PubMed:1706721).
Testis-specific histone H1 that forms less compacted chromatin compared to other H1 histone subtypes. Formation of more relaxed chromatin may be required to promote chromatin architecture required for proper chromosome regulation during meiosis, such as homologous recombination. Histones H1 act as linkers that bind to nucleosomes and compact polynucleosomes into a higher-order chromatin configuration.
The Gln-54 residue in the globular domain forms a hydrogen bond with the main chain carbonyl of Met-52 and is spatially oriented away from the nucleosome dyad axis, leading to lower affinity towards Four-way junction DNA and reconstituted 5S mononucleosomes.
This histone is a testis-specific H1 variant that appears during meiosis in spermatogenesis.
Acetylated. Deacetylated by SIRT2, thereby inhibiting Schwann cell peripheral myelination.
Adapter protein involved in asymmetrical cell division and cell polarization processes (PubMed:18550519). Seems to play a central role in the formation of epithelial tight junctions (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 (By similarity). Required for establishment of neuronal polarity and normal axon formation in cultured hippocampal neurons (By similarity). Involved in Schwann cell peripheral myelination (PubMed:21949390). Targets the phosphatase PTEN to cell junctions (PubMed:18082612).
Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3. Interacts (via PDZ 1 domain) with PARD6A, PARD6B and F11R/JAM1. Interacts with AURKA, AURKB and SIRT2 (By similarity). Interacts with PRKCI. Interacts with PRKCZ (Probable). Part of a complex with PARD6A or PARD6B, PRKCI or PRKCZ and CDC42 or RAC1. Interacts with LIMK2 and CDH5. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Directly interacts with TIAM1 and TIAM2. Interacts with ECT2 and FBF1 (By similarity). Interacts (via PDZ 3 domain) with PTEN (via C-terminus). Interacts (via coiled-coil domain) with FRMD4A (By similarity). Found in a complex with PARD3, CYTH1 and FRMD4A (By similarity). Interacts with SAPCD2 (By similarity). Interacts with PRKCA (By similarity).
Contains a conserved N-terminal oligomerization domain (NTD) that is involved in oligomerization and is essential for proper subapical membrane localization.
Isoform 1 is predominantly expressed in lung, glandular stomach, prostate, ovary and uterus. Isoform 1 is also expressed in brain, with a high expression in the cortex, hippocampus and in the striatum. Isoform 2 is predominantly expressed in intestinal epithelial cells, kidney and prostate.
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 (By similarity).
The second PDZ domain mediates interaction with membranes containing phosphoinositol lipids.
Belongs to the sarcoglycan alpha/epsilon family.
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.
Plays a role as an inducible effector molecule that mediates Fas resistance produced by surface Ig engagement in B cells.
No expression at 1 day old. Expressed at 7 days old, increased expression at 14 and 56 days old.
Retina, outer segments of photoreceptor cells.
By leukemia inhibitory factor or retinoic acid in vitro. In vivo, induced during the axonal elongation period following axotomy.
Expressed in neurons, oligodendrocytes and astrocytes. Also expressed in the mucosal cell layer of the colon. In the developing brain, isoform 1 is expressed in both neurones and oligodendroglial cells, whereas isoform 2 is restricted to oligodendroglial cells.
Probable choline transporter. May be involved in membrane synthesis and myelin production.
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 (By similarity).
Expressed in neuronal and lymphatic tissue.
Anti-terminator protein required to prevent early mRNA termination during transcription. Together with SCAF4, acts by suppressing the use of early, alternative poly(A) sites, thereby preventing the accumulation of non-functional truncated proteins. 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. Independently of SCAF4, also acts as a positive regulator of transcript elongation.
Interacts with POLR2A; via C-terminal heptapeptide repeat domain (CTD) phosphorylated at 'Ser-2' and 'Ser-5' (PubMed:8692929, PubMed:9528809). Identified in a complex with CDC5L and other spliceosomal proteins (By similarity).
Expressed in the peripheral nervous system Schwann cells (at protein level).
Up-regulated in Schwann cells by EGR2 during nerve development and after nerve injury.
Exhibits arylsulfatase activity and highly specific endoglucosamine-6-sulfatase activity. It can remove sulfate from the C-6 position of glucosamine within specific subregions of intact heparin.
Interacts (via Arg/Ser-rich domain) with LUC7L3, RBM39 and RSF1.
Plays a role in pre-mRNA splicing. Involved in both constitutive and alternative pre-mRNA splicing. May have a role in the recognition of the 3' splice site during the second step of splicing (By similarity).
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 (By similarity).
Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI(3)K) results in its targeting to the plasma membrane.
Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6 (By similarity). 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. 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 (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). Has both ATP- and GTP-dependent kinase activities. 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 (By similarity). May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation (PubMed:20204506). Required for lysosome-peroxisome membrane contacts and intracellular cholesterol transport through modulating peroxisomal PtdIns(4,5)P2 level (By similarity). 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 (By similarity). Negatively regulates insulin signaling through a catalytic-independent mechanism. PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3 (PubMed:21847559). May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size (By similarity).
Homodimer. Interacts with PIP4K2B; the interaction may regulate localization to the nucleus (By similarity). Probably interacts with PIP5K1A; the interaction inhibits PIP5K1A kinase activity (By similarity).
In rod outer segments, activated by light.
Phosphorylated in tyrosines. Phosphorylation is induced by light and increases kinase activity.
May be implicated in B-cell differentiation and lymphomagenesis.
Belongs to the helicase family. RLR subfamily.
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription.
E3 ubiquitin ligase that plays an important role in antiviral immunity by restricting different viral infections including dengue virus or vesicular stomatitis indiana virus. Ubiquitinates viral proteins such as dengue virus NS3 thereby limiting infection. Plays also a role in cataract formation together with TP53. Mechanistically, inhibits UVB-induced cell apoptosis and reactive oxygen species (ROS) production by inducing TP53 ubiquitination.
Homo-multimer; required for antiviral activity (By similarity). 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.
May have a role in promoting tumor progression. May block the TGFB1-enhanced cell growth (By similarity). Overexpression of HYAL1 suppressed the growth rate of colon carcinoma cell tumors in an experimental model.
Belongs to the sterol desaturase family.
Catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes (By similarity). 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. As an interferon-stimulated gene, has broad antiviral activities against a wide range of enveloped viruses. Its product, 25-hydroxycholesterol, activates the ER-localized enzyme ACAT to induce internalization of accessible cholesterol on the plasma membrane and restricts virus-host membranes fusion which inhibits virus replication (By similarity). In testis, production of 25-hydroxycholesterol by macrophages plays a role in Leydig cell differentiation (PubMed:11967195, PubMed:11207193).
Catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes (PubMed:11967195, PubMed:11207193). 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. May play an important role in regulating lipid metabolism by synthesizing a corepressor that blocks sterol regulatory element binding protein (SREBP) processing. In testis, production of 25-hydroxycholesterol by macrophages plays a role in Leydig cell differentiation (PubMed:11967195, PubMed:11207193). Interferon-stimulated gene which has broad antiviral activities against a wide range of enveloped viruses (By similarity).
Expressed in testicular macrophages at all stages, with the highest level in 10 day old animals.
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.
Involved in the positive regulation of histone H3-K9 dimethylation.
Disulfide-linked heterodimer with the amino acid transporter SLC7A9.
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 proximal tubule.
Predominantly expressed in kidney and intestine. In kidney localized to the apical membrane of the proximal tubules.
Expressed at late stages of spermatogenesis, from late to maturing spermatids.
High expressed in testis and weakly expressed in lung, intestine, and spleen. Not expressed in spermatogonia, spermatocytes, and round spematids in adult testis but specifically detected in elongated spermatids.
Interacts (via coiled-coil domains) with BNIP3L (via BH3 domain). Interacts (via coiled-coil domains) with BNIP3 (via BH3 domain). Colocalizes with BNIP3 and BNIP3L at the mitochondrion outer membrane.
Key regulator of mitochondrial quality that mediates the repairing or degradation of unhealthy mitochondria in response to mitochondrial damage. Mediator of mitochondrial protein catabolic process (also named MALM) by mediating the degradation of damaged proteins inside mitochondria by promoting the accumulation in the mitochondrial matrix of hydrolases that are characteristic of the lysosomal lumen. Also involved in mitochondrion degradation of damaged mitochondria by promoting the formation of vacuole-like structures (named MIV), which engulf and degrade unhealthy mitochondria by accumulating lysosomes (By similarity). 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 (By similarity). May have a role in spermatogenesis, especially in cell differentiation from late elongate spermatids to mature spermatozoa.
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 (By similarity).
The cytoplasmic C-terminal region mediates interaction with STIM1, while the N-terminal lumenal region mediates regulation of SOCE activity.
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 (By similarity).
Detected in all tissues with the highest level in liver, thymus and brain.
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.
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.
Heme oxygenase 2 activity is non-inducible.
Inhibited by metalloporphyrins such as Sn- and Zn-protoporphyrins.
Widely distributed in body with a high concentration in the brain.
Detected in brain (at protein level). Detected in brain, in synaptic layers of the cerebellum, hippocampus and cerebral cortex.
Homotetramer. Interacts with HSC70 as well as DNAJ homologs and HSP90. Interacts (via the C-terminus 302- 318 AA) with GRK5 (By similarity).
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.
Belongs to the Golgi pH regulator (TC 1.A.38) family.
Component of chromatin-associated Polycomb (PcG) complexes. Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2/RING2 MBLR, L3MBTL2 and YAF2. Interacts with CBX2 and PCGF6. Component of a PRC1-like complex. Component of repressive BCOR complex containing Polycomb group subcomplex at least composed of RYBP, PCGF1, BCOR and RNF2/RING2. Interacts with BMI1, PHC2, PCGF2, RNF2; CBX6, CBX7 and CBX8 (By similarity). Interacts with MN1 (By similarity).
Constitutes one of the E3 ubiquitin-protein ligases that mediate monoubiquitination of 'Lys-119' of histone H2A, thereby playing a central role in histone code and gene regulation. H2A 'Lys-119' ubiquitination gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. 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. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. Compared to RNF2/RING2, it does not have the main E3 ubiquitin ligase activity on histone H2A, and it may rather act as a modulator of RNF2/RING2 activity (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 tubulin--tyrosine ligase family.
Catalyzes the post-translational addition of a tyrosine to the C-terminal end of detyrosinated alpha-tubulin.
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).
Heterotetramer of two type I and two type II keratins. Associates with KRT10.
Probably contributes to terminal cornification. Associated with keratinocyte activation, proliferation and keratinization (By similarity). Required for maintenance of corneocytes and keratin filaments in suprabasal keratinocytes in the epidermis of the ear, potentially via moderation of expression and localization of keratins and their partner proteins (By similarity). Plays a role in the establishment of the epidermal barrier on plantar skin (By similarity).
Directly interacts with BCL2; this interaction prevents the formation of the anti-apoptotic BAX-BCL2 complex.
Promotes apoptosis by binding to BCL2, hence preventing the formation of protective BCL2-BAX heterodimers.
Detected in immature, proliferating, mature, columnar and hypertrophic chondrocytes from ribs, tail, vertebra and femur.
May be involved in the negative control of osteogenic differentiation of osteochondrogenic precursor cells in peripheral zones of fetal cartilage and at the cartilage-bone interface.
Proteolytically cleaved by a furin-like convertase to generate a persistent C-terminal fragment found in almost the entire cartilage matrix, and affecting osteoblast differentiation.
Component of a ribosome-associated endoplasmic reticulum (ER) translocon complex involved in multi-pass membrane protein transport into the ER membrane and biogenesis. 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. 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.
Forms a complex with NCLN/Nicalin and NOMO, resulting in a stabilization of the 3 proteins, which are otherwise quickly degraded by the proteasome. Interacts with CHRM3, CHRM1 and AVPR2. 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.
Sodium:sulfate symporter that mediates sulfate reabsorption in the kidney and small intestine (PubMed:7690140, PubMed:7816544, PubMed:8300634, PubMed:8175644). Can also mediate the transport of selenate and thiosulfate (PubMed:8175644, PubMed:8300634).
Belongs to the Mediator complex subunit 10 family.
Brain, in the lateral mammillary nuclei, the anterior pretectal nuclei, and several layers of the hippocampus.
First detected in the testis at 5 weeks. Level of expression increases up to 7 weeks and maintains even at 63 weeks.
Interacts with ULK1. May interact with RAB11A and RAB11B, but does not exhibit any GTPase-activating activity toward these proteins. Interacts with TRAPPC8.
Plays a role in the regulation of starvation-induced autophagosome formation. 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.
PubMed:15758561 detected expression at the stage of sexual maturation in testis, mainly in the spermatocytes. No expression detected in the ovary, brain, heart, lung, liver and kidney. PubMed:15200410 detected expression in brain, heart, lung, liver, spleen and kidney but not in small intestine.
NAD-dependent aldehyde dehydrogenase that catalyzes the formation of retinoic acid (By similarity). Has high activity with all-trans retinal, and has much lower in vitro activity with acetaldehyde (By similarity). 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).
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 (By similarity). 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 (By similarity). Also has an inhibitory role in some cells (By similarity). Non-covalently associates with activating receptors of the CD300 family to mediate cell activation (By similarity). 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 (By similarity). Associates with natural killer (NK) cell receptors such as the KLRD1/KLRC2 heterodimer to mediate NK cell activation (By similarity). Associates with TREM1 to mediate activation of neutrophils and monocytes (By similarity). Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (By similarity). PAssociation with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (By similarity). Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding which suppresses the release of pro-inflammatory cytokines (By similarity). 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). ositively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allosimulatory ability (By similarity). Negatively regulates B cell proliferation (By similarity). Required for CSF1-mediated osteoclast cytoskeletal organization (By similarity). Positively regulates multinucleation during osteoclast development (By similarity).
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 (By similarity). Homotrimer; disulfide-linked (By similarity). Homotetramer; disulfide-linked (By similarity). Homotrimers and homotetramers form when low levels of partner receptors are available and is competitive with assembly with interacting receptors (By similarity). They may represent alternative oligomerization states or may be intermediates in the receptor assembly process (By similarity). Binding of a metal cation aids in homooligomerization through coordination of the metal ion by the subunits of the oligomer (By similarity). Interacts with TREM1 (By similarity). Interacts with TREM2 (By similarity). Interacts with CLECSF5 (By similarity). Interacts with CD300LB and CD300C2 (By similarity). Interacts with CD300E (By similarity). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK mediating neutrophils and macrophages integrin-mediated activation (By similarity). Interacts with KLRC2 (By similarity). Interacts with CD300H (By similarity). Interacts with KLRD1 (By similarity).
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.
Succinylated. Desuccinylated by SIRT5. Succinylation, at least at Lys-83 and Lys-310, inhibits the enzymatic activity.
Decreased expression in the choroid plexus after penetrating injury in the central nervous system.
Expressed in the brain, with expression in the choroid plexus and the ventricular ependymal cells (at protein level).
Probable hormone that may attenuate cell proliferation and induce senescence of oligodendrocyte and neural precursor cells in the central nervous system (PubMed:20404145, PubMed:21349154). ECRG4-induced senescence is characterized by G1 arrest, RB1 dephosphorylation and accelerated CCND1 and CCND3 proteasomal degradation (PubMed:20404145).
Homodimer. Interacts with itself. Interacts with PPP1R3B, PPP1R3C, PPP1R3D, HIRIP5, and EPM2AIP1. Binds glycogen and Lafora bodies. Interacts with NHLRC1/malin (via the NHL repeats). Forms a complex with NHLRC1/malin and HSP70. 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. Interacts with PRDM8.
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. Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro). Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. 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. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.
The CBM20 domain mediates binding to cytoplasmic glycogen and to Lafora polyglucosan bodies.
Expressed in liver, blood plasma, serum and in platelets. Also present in fibrin clots, wound fluid from acute wounds and chronic leg ulcers.
Interacts with THBS1 (via the TSP type I repeats); the interaction blocks the antiangiogenic effect of THBS1 with CD36. 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 (By similarity). Interacts with PLG (via its Kringle domains); the interaction tethers PLG to the cell surface and enhances its activation. 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).
Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Inhibits rosette formation. Acts as an adapter protein and implicated in regulating many processes such as immune complex and pathogen clearance, 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 (By similarity).
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 (By similarity).
The His-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 (By similarity).
The cystatin domains can also bind heparan sulfate. Binding is enhanced in the presence of zinc ions (By similarity).
Adapter protein that plays a role in regulating cell-surface expression of adrenergic receptors and probably also other G protein-coupled receptors. Plays a role in NEDD4-mediated ubiquitination and endocytosis af activated ADRB2 and subsequent ADRB2 degradation. May recruit NEDD4 to ADRB2. 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.
Interacts (via PPxY motifs) with NEDD4 (via WW domains). Interacts with ADRB2. Interacts with ADRB3. Interacts with HGS (via PPxY motifs). Does not bind TXN (thioredoxin). Interacts with ITCH.
Homodimer; disulfide-linked. Interacts with DUSP14. Binds to CD80/B7-1 and CD86/B7-2/B70. Interacts with GRB2 (By similarity).
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.
Has been found in central nervous system and muscle (PubMed:8417155). Found in embryonic liver and spleen but not in adult liver (PubMed:8417155).
Homotetramer; composed of disulfide-linked homodimers. Catalytic forms H (GPI-anchor dimer) and T (asymmetric collagen-tailed), which differ in their C-terminus, account for all types of known ACHE forms (Probable). Interacts with PRIMA1. The interaction with PRIMA1 is required to anchor it to the basal lamina of cells and organize into tetramers (By similarity).
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft.
Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58 (PubMed:8707840). Interacts with NUP88 (By similarity). Interacts with NUTF2 (PubMed:8707840). Interacts with HIKESHI (By similarity). Interacts with OSBPL8 (By similarity). Interacts with CAPG (By similarity). Interacts with SAS6 and TUBG1 at the centrosome (By similarity). Interacts with MCM3AP (By similarity).
Essential component of the nuclear pore complex (PubMed:2190987, PubMed:8707840). The N-terminal is probably involved in nucleocytoplasmic transport (By similarity). The C-terminal is involved in protein-protein interaction probably via coiled-coil formation, promotes its association with centrosomes and may function in anchorage of p62 to the pore complex (By similarity). Plays a role in mitotic cell cycle progression by regulating centrosome segregation, centriole maturation and spindle orientation (By similarity). It might be involved in protein recruitment to the centrosome after nuclear breakdown (By similarity).
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.
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:12773305, PubMed:8530477). 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 (By similarity).
Expression reaches a maximum at postnatal day 7 before to significantly decrease.
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 INSC/inscuteable and FRMPD1 (By similarity). Interacts with GNAI1, GNAI2 and GNAI3 preferentially in their GDP-bound state. May also interact with GNAO1. Interacts with STK11/LKB1 and MACF1.
Isoform 4 is specifically expressed in brain by neurons and also detected in testis, liver, kidney, heart and pancreas (at protein level). Highly expressed in cerebellum and subventricular zone-olfactory bulb system. Isoform 2 and isoform 3 are specifically expressed in heart and are also detected in brain.
Minor isoform. Mutagenesis of Met-1 into Gly leads to expression of isoform 2.
Phosphorylation regulates interaction with G(i/o) alpha.
Produced by initiation at Met-62 of isoform 3. Mutagenesis of Met-1 into Gly prevents expression of this isoform. Combined mutagenesis of Gln-57, Gln-105 and Gln-129 into Ala alters the function of the GoLoco domains.
Responsible for altered neurotransmission and altered behavior like drug seeking associated with cocaine addiction. Depletion in prefrontal cortex reverses the behavioral consequences of cocaine addiction while overexpression in drug-naive animals induces addictive behavior upon acute cocaine injection.
The GoLoco domains mediate interaction with G(i/o) alpha. The GoLoco domains are essential for the GDI activity toward G(i/o) alpha.
Up-regulated in prefrontal cortex and core region of nucleus accumbens during late withdrawal from chronic cocaine administration.
Regulator of microtubule dynamic that has microtubule bundling activity (By similarity). Required for embryo implantation; possibly by regulating beta-catenin (By similarity). Also required for decidualization via regulation of beta-catenin (By similarity).
Interacts with microtubules. Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends. Interacts with CLIP2, ERC1, MAPRE3, PHLDB2 and RSN. The interaction with ERC1 may be mediated by PHLDB2. Interacts with GCC2; recruits CLASP2 to Golgi membranes (By similarity). 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. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex.
Phosphorylated by GSK3B. 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 the growing microtubule plus ends.
Two TOG regions display structural characteristics similar to HEAT repeat domains and mediate interaction with microtubules.
May be important in protein trafficking and/or protein folding and stabilization.
Calcium-dependent phospholipid-binding protein that may play a role in calcium-mediated intracellular processes.
The C2 domain 1 is not necessary for calcium-mediated translocation and association to the plasma membrane (PubMed:26175110). The C2 domain 2 is necessary for calcium-mediated translocation and association to the plasma membrane (PubMed:26175110).
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.
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. Interacts with NBDY. Interacts with Tex19.1 (By similarity). Interacts with LSM14A (By similarity). Interacts with DDX6 (By similarity).
Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO).
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 (By similarity).
Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg(2+) (By similarity).
Isoform JM-A CYT-2 and isoform JM-A CYT-1 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, which are further processed by a presenilin-dependent gamma-secretase to release the respective cytoplasmic intracellular domain E4ICD (either E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2) (By similarity).
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 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 BCL2. Interacts (phosphorylated) with STAT1 (By similarity). Interacts with CBFA2T3. Interacts (soluble intracellular domain) with STAT5A (By similarity).
Preferentially expressed in the developing nervous system. Exhibits distinct and highly regionalized patterns of expression in the adult brain, where it is mainly found in the reticular nucleus of the thalamus. Very low levels in kidney, and heart.
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 (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.
Activated through PKC-mediated hyperphosphorylation.
Component of a complex that includes at least ASF1A, CABIN1, HIRA, histone H3.3 and UBN1 (By similarity). Interacts with MEF2B (By similarity). Interacts with calcineurin.
May be required for replication-independent chromatin assembly (By similarity). May serve as a negative regulator of T-cell receptor (TCR) signaling via inhibition of calcineurin.
Widely expressed with prominent expression in neurons.
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.
A soluble form (sIL1R2) can also be produced by proteolytic cleavage at the cell surface (shedding) involving a metalloproteinase.
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 (By similarity).
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. Involved in the regulation of ciliary length.
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. Dynein-2 complex is built around two copies of cytoplasmic dynein 2 heavy chain 1 (DYNC2H1). The C-terminal region 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 (By similarity). Interacts with DYNC2H1 (via N-terminus); this interaction stabilizes the dynein-2 complex structure (PubMed:11907264).
GRF is released by the hypothalamus and acts on the adenohypophyse to stimulate the secretion of growth hormone.
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.
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.
Identified in the spliceosome C complex (By similarity). Interacts with ANKRD28 and ZIK1 (By similarity). Interacts with DDX1 (By similarity). Interacts with MDM2; this interaction leads to ubiquitination and proteasomal degradation (By similarity). Interacts with p53/TP53 (By similarity). Interacts with BRDT (By similarity). Interacts with RBM42 (PubMed:19170760). Interacts with IVNS1ABP (By similarity). Interacts with PPIA/CYPA (By similarity). Part of a transcription inhibitory ribonucleoprotein complex composed at least of the circular RNA circZNF827, ZNF827 and HNRNPL (By similarity).
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. 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 (By similarity). 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 (By similarity).
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 (By similarity).
Ubiquitinated by MDM2. Doxorubicin treatment does not affect monoubiquitination, but slightly decreases HNRNPK poly-ubiquitination (By similarity).
Expressed at high levels in several developing projection systems: in neurons of the thalamus, subplate, and lower cortical laminae in the forebrain and in the pontine nucleus, cerebellar granule cells, and Purkinje cells in the hindbrain.
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. 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.
Represents a conventional myosin. This protein should not be confused with the unconventional myosin-3 (MYO3).
Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Positively regulates microRNA (miRNA)-mediated gene silencing and is essential for P-body formation and integrity. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. Acts as a transcriptional corepressor for SNAI1- and SNAI2/SLUG-dependent repression of E-cadherin transcription. Negatively regulates the Hippo signaling pathway and antagonizes phosphorylation of YAP1. Inhibits E2F-mediated transcription, and suppresses the expression of the majority of genes with E2F1-responsive elements. Regulates osteoblast development, function, differentiation and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt receptor signaling pathway in osteoblasts. May act as a tumor suppressor by inhibiting cell proliferation (By similarity).
Interacts with SQSTM1 and RB1. Interacts with EIF4E, AGO1, AGO2, DCP2, DDX6, LATS1, LATS2, EGLN1/PHD2, EGLN2/PHD1 and EGLN3/PHD3. Interacts (via LIM zinc-binding 2) with VHL. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Found in a complex with TRAF6, PRKCZ and SQSTM1. Interacts (via LIM domains) with TRAF6. Interacts (via LIM domains) with SNAI1 (via SNAG domain), SNAI2/SLUG (via SNAG domain) and SCRT1 (via SNAG domain) (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. Positively regulates PERK-mediated and IRE1-mediated unfolded protein response signaling. Plays an essential role in VEGF-mediated release of Ca(2+) from ER stores during angiogenesis. Also plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26. 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 (By similarity).
Highly expressed in the liver and significantly in brain, lungs and kidneys.
Interacts with EIF2AK3. Interacts with ARL6IP1, isoform RTN1-A of RTN1, isoform RTN2-B of RTN2, isoform 3 of RTN3 and isoform 3 of RTN4. Interacts with RNF5. Interacts with RNF26 (By similarity). Interacts with PKD2 (By similarity).
May play a role in apoptosis. May act as a tumor suppressor (By similarity).
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.
Interacts with either CDK4 or CDK6 protein kinase to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Component of the ternary complex CCND1/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity (By similarity). Interacts directly with CDKN1B. Can form similar complexes with either CDKN1A or CDKN2A. Interacts with FBXO4 (By similarity). Interacts with UHRF2; the interaction ubiquitinates CCND1 and appears to occur independently of phosphorylation. Interacts with USP2. 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. Interacts with CDK4; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression (By similarity).
Phosphorylation at Thr-286 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex. It also plays an essential role for recognition by the FBXO31 component of SCF (SKP1-cullin-F-box) protein ligase complex following DNA damage.
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. 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. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also a substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity. Component of the ternary complex, cyclin D1/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Exhibits transcriptional corepressor activity with INSM1 on the NEUROD1 and INS promoters in a cell cycle-independent manner.
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. The DCX(AMBRA1) complex represents the major regulator of CCND1 stability during the G1/S transition (By similarity). 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. SCF-type ubiquitination is dependent on Thr-286 phosphorylation. Ubiquitinated also by UHRF2 apparently in a phosphorylation-independent manner. Ubiquitination leads to its degradation and G1 arrest. Deubiquitinated by USP2; leading to its stabilization (By similarity).
Mitochondrial GTPase involved in mitochondrial trafficking.
Becomes apparent upon completion of villus formation at 20 days gestation (2 days before birth) and is expressed by the entire epithelium of the villus.
Expressed predominantly in the intestinal epithelium in differentiated villus cells.
Heterotetramer of two type I and two type II keratins. Associates with KRT8 (By similarity).
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-233 (By similarity).
Has E3 ubiquitin-protein ligase activity.
Belongs to the bacterial ribosomal protein bL20 family.
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.
Binds calcium via the C2 domains. The calcium-bound C2 domains mediate interactions with phospholipid bilayers.
Interacts with RAB3B, RAB3C, RAB3D, RAB8A, RAB27A and RAB27B (By similarity). Interacts with RAB3A; this interaction recruits RPH3A to synaptic vesicules (PubMed:8617225, PubMed:10025402). Interacts (via C2B domain) with SNAP25 (PubMed:16203731, PubMed:28634303). Interacts with deubiquitinating enzyme CAND1; this interaction results in the deubiquitination of RPH3A (PubMed:29367474). Interacts with GRIN2A and DLG4; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (PubMed:26679993). Interacts with SNCA (By similarity).
Plays an essential role in docking and fusion steps of regulated exocytosis (PubMed:8617225, PubMed:16203731). 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 (PubMed:8617225). In the post-synaptic compartment, forms a ternary complex with GRIN2A and DLG4 and regulates NMDA receptor stability (PubMed:26679993). Also plays a role in the exocytosis of arginine vasopressin hormone (PubMed:29367474).
Ubiquitinated. Deubiquitinated by CAND1 to prevent its degradation.
Has a glutathione-disulfide oxidoreductase activity in the presence of NADPH and glutathione reductase. Reduces low molecular weight disulfides and proteins.
Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML) (PubMed:11431483).
May regulate cell proliferation and coordinate apoptosis and cell cycle progression via a novel mechanism independent of both p53/TP53 and NF-kappa-B.
Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1. Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex. Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex (By similarity).
Forms a heteromeric complex with ERLIN1. In complex with ERLIN1, interacts with RNF170. Interacts with activated ITPR1, independently of the degree of ITPR1 polyubiquitination. Interacts with SCAP, INSIG1, SREBF1 and SREBF2 under cholesterol sufficiency conditions; indicative for an association with the SCAP-SREBP-INSIG complex. Probably part of an AMFR/gp78 and INSIG1-containing ubiquitin ligase complex involved in ERAD of HMGCR. Interacts with TMUB1; TMUB1 bridges the association with AMFR. Interacts with SYVN1 and RNF139. Interacts with TMEM259 (By similarity). Interacts with TMEM41B (By similarity).
Part of a SCF (SKP1-cullin-F-box) protein ligase complex. Interacts with SKP1 and CUL1 (By similarity).
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 (By similarity).
Belongs to the UDP-glucose/GDP-mannose dehydrogenase family.
Catalyzes the formation of UDP-alpha-D-glucuronate, a constituent of complex glycosaminoglycans (By similarity). 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 (By similarity).
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.
Belongs to the cyclin family. Cyclin C subfamily.
Interacts with ARHGEF28 (By similarity). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases. 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. Binds PRKCL1, ROCK1 and ROCK2. Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN. Interacts with PLCE1 and AKAP13. Interacts with DIAPH1. Interacts (in the constitutively activated, GTP-bound form) with DGKQ. Interacts with RACK1; enhances RHOA activation. Interacts with PKP4; the interaction is detected at the midbody. Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA. Interacts with ARHGDIB (By similarity). 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 (By similarity). Interacts with RAP1GDS1; the interaction is direct and in a 1:1 stoichiometry (By similarity).
Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (By similarity). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (PubMed:18420945).
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. Inhibited by GAPs such as ARHGAP30. Inhibited by GDP dissociation inhibitors such as ARHGDIA.
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. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. 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 (By similarity). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436). 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 (By similarity). May be an activator of PLCE1 (By similarity). 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 (PubMed:21423166). 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.
Plays a role in the regulation of neuronal activity.
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 (By similarity).
The MTERF repeats form a half-donut shaped, right-handed superhelix, where the concave side displays a positively charged path for nucleic acid interaction.
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 (By similarity).
Interacts with 5-lipoxygenase (ALOX5/5LO) in a calcium-independent manner. Binds to F-actin with a stoichiometry of 1:2 (By similarity).
Belongs to the histone deacetylase family. HD type 2 subfamily.
Interacts with HDAC3. Interacts with HDAC2 and NCOR2/SMRT. Interacts with HSPA8/HSC70. Interacts with MSH2.
Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine. Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine. Histone deacetylase activity has been observed in vitro. Has also been shown to be involved in MSH2 deacetylation. The physiological relevance of protein/histone deacetylase activity is unclear and could be very weak. May play a role in the promotion of late stages of autophagy, possibly autophagosome-lysosome fusion and/or lysosomal exocytosis in neuroblastoma cells. May play a role in homologous recombination. May promote DNA mismatch repair.
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. However, histone deacetylase activity has been observed in vitro and HDAC10 has also been shown to be involved in MSH2 deacetylation.
Inhibits angiogenesis in a CD36-dependent manner.
Interacts with ELMO1 and DOCK1 (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, MAGI3 and BAIAP2 (By similarity). Interacts with PHYHIP (By similarity). Interacts with DLG4 (via PDZ domain) (By similarity). Vasculostatin-120: Interacts with CD36 (By similarity). Vasculostatin-120: Interacts with ARRB2 (By similarity). Interacts with BAIAP3; this interaction is direct (By similarity).
Phosphatidylserine receptor which enhances the engulfment of apoptotic cells (By similarity). Also mediates the binding and engulfment of Gram-negative bacteria (By similarity). Stimulates production of reactive oxygen species by macrophages in response to Gram-negative bacteria, resulting in enhanced microbicidal macrophage activity (By similarity). In the gastric mucosa, required for recognition and engulfment of apoptotic gastric epithelial cells (By similarity). Promotes myoblast fusion (By similarity). Activates the Rho pathway in a G-protein-dependent manner (By similarity). 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 dendritic localization of PARD3 and TIAM1 (PubMed:23595754). Potent inhibitor of angiogenesis in brain and may play a significant role as a mediator of the p53/TP53 signal in suppression of glioblastoma (By similarity).
Proteolytically cleaved to produce vasculostatin-40 and vasculostatin-120. Vasculostatin-40 is the major form and is produced through proteolytic cleavage by MMP14 between residues 317 and 325 with cleavage likely to be between Ser-322 and Leu-323.
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.
Belongs to the bacterial ribosomal protein bL12 family.
May play a role in cellular stress response.
Widely expressed. Highly expressed by Sertoli cells in testis (at protein level).
By HMGB1/amphoterin; in cultured hippocampal neurons.
Expressed at moderate levels in the central nervous system of stage 13-14 embryos. Highest levels at this stage in fiber tracts from dorsal root ganglia and trigeminal ganglion to the spinal cord as well as in fibers on both sides of the Purkinje cell layer of the cerebellum. Expression is down-regulated during postnatal stages P6 to P10 followed by up-regulation at the onset of myelination. High level expression in most myelinated axon tracts of the adult including cerebellum, pons, medulla, and spinal cord as well as in nonmyelinated fiber tracts in the striatum lucidum CA3 region of the hippocampus.
Homodimer, and heterodimer with AMIGO2 and AMIGO3 (PubMed:12629050). Interacts with KCNB1 (By similarity).
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 (PubMed:12629050). Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (By similarity).
The LRR repeat region mediates homodimerization.
Plays an important role in the de novo pathway and in the salvage pathway of purine nucleotide biosynthesis. Catalyzes the first commited step in the biosynthesis of AMP from IMP.
Plays an important role in the de novo pathway and in the salvage pathway of purine nucleotide biosynthesis. Catalyzes the first committed step in the biosynthesis of AMP from IMP.
H(+)-myo-inositol cotransporter (PubMed:11500374). Can also transport related stereoisomers (PubMed:11500374).
Belongs to the CMP-NeuNAc synthase family.
Catalyzes the activation of N-acetylneuraminic acid (NeuNAc) to cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-NeuNAc), a substrate required for the addition of sialic acid. Has some activity toward NeuNAc, N-glycolylneuraminic acid (Neu5Gc) or 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN).
Homotetramer; the active enzyme is formed by a dimer of dimers.
Catalyzes the decarboxylation of L-aspartate, 3-sulfino-L-alanine (cysteine sulfinic acid), and L-cysteate to beta-alanine, hypotaurine and taurine, respectively. The preferred substrate is 3-sulfino-L-alanine. Does not exhibit any decarboxylation activity toward glutamate.
Degraded during both macroautophagy and during chaperone-mediated autophagy (CMA).
Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains.
Monomer and homodimer. Heterodimer with UBQLN2. Binds CD47 (By similarity). Binds NBL1 (PubMed:9303440). Binds GABRA1, GABRA2, GABRA3, GABRA6, GABRB1, GABRB2 and GABRB3 (PubMed:11528422). 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 PSEN1 and PSEN2. 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) (By similarity). Interacts with BCL2L10/BCL-B; in the cytoplasm (By similarity).
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. 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. Plays a role in unfolded protein response (UPR) by attenuating the induction of UPR-inducible genes, DDTI3/CHOP, HSPA5 and PDIA2 during ER stress. 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. Negatively regulates the TICAM1/TRIF-dependent toll-like receptor signaling pathway by decreasing the abundance of TICAM1 via the autophagic pathway. Promotes the ubiquitination and lysosomal degradation of ORAI1, consequently down-regulating the ORAI1-mediated Ca2+ mobilization (By similarity). 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 (PubMed:22847417). Promotes the surface expression of GABA-A receptors (PubMed:11528422). Ubiquitinates BCL2L10 and thereby stabilizes protein abundance (By similarity).
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.
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 (By similarity).
Interacts with STK38 and STK38L. Associates with the SH3 domain of NEDD9. Interacts with VIM and PLXNA3. 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.
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). 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. 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 bivalent Mical/EHBP Rab binding (bMERB) domain, mediates binding to predominantly Rab8, Rab10, Rab10, Rab13 and Rab15 (in their GTP-bound forms).
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.
Heterodimer of SAE1 and UBA2/SAE2. The heterodimer corresponds to the two domains that are encoded on a single polypeptide chain in ubiquitin-activating enzyme E1. Interacts with UBE2I.
The heterodimer acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.
Belongs to the TRAFAC class YlqF/YawG GTPase family.
Expressed by developing CNS stem cells. When cortical stem cells differentiate into neurons, astrocytes, and oligodendrocytes, expression level is reduced in both dividing and postmitotic progeny.
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). May interact with p53/TP53 via its basic domain. This interaction is most probably indirect and mediated by 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.
Expressed in the deep and shallow cortices of the retina lens (at protein level).
Part of a complex required for lens intermediate filament formation composed of BFSP1, BFSP2, and CRYAA (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 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 (By similarity). Plays a role in maintenance of retinal lens optical clarity (By similarity).
Found to decrease dramatically after birth.
Autoacetylated. Autoacetylation at Lys-602 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; phosphorylation of RUNX1 enhances the interaction. Interacts with RUNX2. Interacts with p53/TP53. Interacts with PML 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 (By similarity). Acetylates p53/TP53 at 'Lys-120' and 'Lys-382' and controls its transcriptional activity via association with PML (By similarity).
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.
Receptor for the hormone galanin. The activity of this receptor is mediated by G proteins that inhibit adenylate cyclase activity.
Spinal cord, small intestine, Rin14B insulinoma cells and several brain regions, particularly ventral hippocampus, amygdala, supraoptic nucleus, hypothalamus, thalamus, lateral parabrachial nucleus and locus coeruleus.
Three cysteine residues are found in the C-terminus, at least one of which may be palmitoylated.
Belongs to the POU transcription factor family. Class-6 subfamily.
Contains two direct repeats of 7 amino acids in the N-terminus.
In the embryo, widely expressed, with highest levels in the developing brain and spinal cord. In the adult, mostly found in the brain, where it is diffusely expressed with the exception of an enrichment in layer IV of the neocortex. Also found in kidney, lung, heart, adrenal, skin, and placenta. Low levels in spleen, muscle, liver, anterior pituitary, testis and ovary.
Transcription factor that binds preferentially to a variant of the octamer motif (5'-ATGATAAT-3').
Specifically expressed in spleen and kidney.
Brefeldin A induces dissociation from the Golgi of the beta-COP and presumably the other coatomer subunits.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits. Interacts with SCYL1. Interacts with CAPN8 (By similarity). Interacts with COPG1 (By similarity). Interacts with ARF1 (myristoylated); this interaction is required for binding of COPB1 to Golgi membranes (By similarity). Interacts (via trunk domain) with ARF1 (via switch I region); the interaction is direct (By similarity). Interacts with KCNK2 (via N-terminus); this interaction increases the channel-mediated whole cell currents and promotes plasma membrane expression of KCNK2 (By similarity). Interacts with PRKCE. Interacts with STX17. Interacts with TMEM115 (By similarity). Interacts with TMEM41B (By similarity).
Proteolytically cleaved between Ser-528 and Ser-529 by CAPN8.
The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. Involved in the Golgi disassembly and reassembly processes during cell cycle. Involved in autophagy by playing a role in early endosome function. Plays a role in organellar compartmentalization of secretory compartments including endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), Golgi, trans-Golgi network (TGN) and recycling endosomes, and in biosynthetic transport of CAV1. Plays a functional role in facilitating the transport of kappa-type opioid receptor mRNAs into axons and enhances translation of these proteins in the axonal compartment of dorsal root ganglion (DRG) cells. 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.
E3 ubiquitin-protein ligase that promotes the ubiquitination of different substrates. In turn, participates in different biological processes including interferon production or autophagy. Plays a role in the activation of RNA virus-induced interferon-beta production by promoting the ubiquitination of TRAF3 and TRAF6. Also plays a role in the early recruitment of autophagy adapters to bacteria. Mediates 'Lys-29' and 'Lys-33'-linked ubiquitination of SQSTM1 leading to xenophagic targeting of bacteria and inhibition of their replication.
Demethylates proteins that have been reversibly carboxymethylated. Demethylates PPP2CB (in vitro) and PPP2CA. Binding to PPP2CA displaces the manganese ion and inactivates the enzyme (By similarity).
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.
In the kidney localized primarily in the outer medulla in the thick ascending limb and distal convoluted tubule.
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. 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. 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.
The internal MTS-like signal (iMTS-L) mediates targeting to mitochondria thermogenic fat cells.
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 (By similarity).
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 (By similarity).
Belongs to the complex I NDUFA13 subunit family.
Complex I functions in the transfer of electrons from NADH to the respiratory chain. Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
Homodimer. Component of the BCR(KLHL7) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL7 and RBX1 (By similarity).
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex. The BCR(KLHL7) complex acts by mediating ubiquitination and subsequent degradation of substrate proteins. Probably mediates 'Lys-48'-linked ubiquitination (By similarity).
Accessory subunit that is involved in the functional assembly of the mitochondrial respiratory chain complex I. Complex I has an NADH dehydrogenase activity with ubiquinone as an immediate electron acceptor and mediates the transfer of electrons from NADH to the respiratory chain.
Belongs to the complex I NDUFB10 subunit family.
Belongs to the aggrecan/versican proteoglycan family.
Disappears after the cartilage development.
In kidney is expressed in the papillary area, but not in glomeruli.
May play a role in intercellular signaling and in connecting cells with the extracellular matrix. May take part in the regulation of cell motility, growth and differentiation. Binds hyaluronic acid.
Proteolytically cleaved by ADAMTS5 and ADAMTS15 in the pericellular matrix surrounding myoblasts, facilitating myoblast contact and fusion which is required for skeletal muscle development and regeneration.
Belongs to the ALG6/ALG8 glucosyltransferase family.
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:1961729). It is strictly dependent on the extracellular presence of sodium (PubMed:1961729). 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:9486191). 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 (By similarity).
Highly expressed in liver and low expression in kidney.
Belongs to the connexin family. Delta-type subfamily.
Interacts with PTPN2. Interacts with microtubules. Interacts with VAPB. Interacts (FFAT motif) with MOSPD2 (via MSP domain).
Involved in cellular calcium homeostasis regulation (By similarity). May participate in differentiation and apoptosis of keratinocytes. Overexpression induces apoptosis (By similarity).
The transmembrane region is required for mitochondrial localization.
Activated by calcium/calmodulin. Inhibited by high concentrations of the substrate Ins(1,2,4)P3, and allosterically activated by the product Ins(1,3,4,5)P4.
Catalyzes the phosphorylation of 1D-myo-inositol 1,4,5-trisphosphate (InsP3) into 1D-myo-inositol 1,3,4,5-tetrakisphosphate and participates to the regulation of calcium homeostasis (PubMed:12649294). Can phosphorylate inositol 2,4,5-triphosphate to inositol 2,4,5,6-tetraphosphate.
Highly expressed in tongue epithelium, taste papilla, heart, brain and testis. Weakly expressed in lung, liver and kidney.
Belongs to the CWC16 family. YJU2 subfamily.
Component of the spliceosome. 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.
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. 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. May protect cells from TP53-dependent apoptosis upon dsDNA break damage through association with PRP19-CD5L complex.
Belongs to the protein kinase superfamily. PAN3 family.
Contains a pseudokinase domain. The protein kinase domain is predicted to be catalytically inactive because some of the residues important for catalytic activity are substituted and it lacks the equivalent of the binding site for a peptide substrate. However, it has retained an ATP-binding site and ATP-binding is required for mRNA degradation, stimulating the activity of the PAN2 nuclease in vitro. The nucleotide-binding site is juxtaposed to the RNase active site of PAN2 in the complex and may actually bind nucleosides of a poly(A) RNA rather than ATP, feeding the poly(A)-tail to the active site of the deadenylase and thus increasing the efficiency with which this distributive enzyme degrades oligo(A) RNAs.
Homodimer. Forms a heterotrimer with a catalytic subunit PAN2 to form the poly(A)-nuclease (PAN) deadenylation complex. Interacts (via PAM-2 motif) with poly(A)-binding protein PABPC1 (via PABC domain), conferring substrate specificity of the enzyme complex. Interacts with the GW182 family proteins TNRC6A, TNRC6B and TNRC6C.
Regulatory subunit of the poly(A)-nuclease (PAN) deadenylation complex, one of two cytoplasmic mRNA deadenylases involved in general and miRNA-mediated mRNA turnover. PAN specifically shortens poly(A) tails of RNA and the activity is stimulated by poly(A)-binding protein (PABP). PAN deadenylation is followed by rapid degradation of the shortened mRNA tails by the CCR4-NOT complex. Deadenylated mRNAs are then degraded by two alternative mechanisms, namely exosome-mediated 3'-5' exonucleolytic degradation, or deadenlyation-dependent mRNA decaping and subsequent 5'-3' exonucleolytic degradation by XRN1. PAN3 acts as a positive regulator for PAN activity, recruiting the catalytic subunit PAN2 to mRNA via its interaction with RNA and PABP, and to miRNA targets via its interaction with GW182 family proteins.
The N-terminal zinc finger binds to poly(A) RNA.
The pseudokinase domain, the coiled-coil (CC), and C-terminal knob domain (CK) form a structural unit (PKC) that forms an extensive high-affinity interaction surface for PAN2.
Belongs to the mitochondrial pyruvate carrier (MPC) (TC 2.A.105) family.
Mediates the uptake of pyruvate into mitochondria.
Interacts (via N-terminus) with RAB2B (in GTP-bound form) (By similarity). Interacts with FRG1 (By similarity).
Belongs to the SRC/p160 nuclear receptor coactivator family.
Highly expressed in liver, brain and testis with lower expression in the spleen.
May be involved in the initiation of hepatocyte growth.
Belongs to the nuclear transition protein 1 family.
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.
Associates with the pre-60S ribosomal particle.
Component of the ribosome assembly machinery. Nuclear paralog of the ribosomal protein P0, it binds pre-60S subunits at an early stage of assembly in the nucleolus, and is replaced by P0 in cytoplasmic pre-60S subunits and mature 80S ribosomes.
Regulates the activity of the neutrophil proteases.
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. 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. The IB complex does not contain PRPF19.
May play a role in pre-mRNA splicing as component of the spliceosome (By similarity). 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.
Expressed at high levels in heart, skeletal muscle and ovary. Moderate levels are found in brain, tongue and pancreatic islets. Low levels are found in lung, testis and adrenal gland. Expressed at very low levels in stomach, colon, thyroid and pituitary.
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.
Detected in intestinal epithelium and liver (at protein level).
Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP (By similarity). 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:9096610).
N-glycosylated (PubMed:7730366, PubMed:9096610). N-glycosylation is necessary for normal transport to the cell membrane, but is not the apical targeting signal (PubMed:11069764).
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 (By similarity).
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. Interacts with STAT3 (By similarity).
N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19 (By similarity).
Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues (By similarity).
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 (By similarity).
Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated (By similarity).
Heterodimer of an alpha and a beta subunit or an alpha and a gamma subunit.
Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Binds to calmodulin.
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).
Belongs to the PNRC family. PNRC2 subfamily.
Interacts with UPF1/RENT1; preferentially interacts with hyperphosphorylated form. Interacts with DCP1A. Interacts with many nuclear receptors including ESR1, ESRRA, ESRRG, NR3C1/GR, NR5A1, PGR, TR, RAR and RXR.
Involved in nonsense-mediated mRNA decay (NMD) by acting as a bridge between the mRNA decapping complex and the NMD machinery. May act by targeting the NMD machinery to the P-body and recruiting the decapping machinery to aberrant mRNAs. Required for UPF1/RENT1 localization to the P-body. 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. Also acts as a nuclear receptor coactivator. May play a role in controlling the energy balance between energy storage and energy expenditure.
The interaction between PNRC2 and nuclear receptors is dependent on the SH3 binding motif.
Belongs to the Cu-Zn superoxide dismutase family.
Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
Palmitoylation helps nuclear targeting and decreases catalytic activity.
Succinylation, adjacent to copper catalytic site, probably inhibits activity. Desuccinylation by SIRT5 enhances activity.
Belongs to the PIH1 family. Kintoun subfamily.
Interacts with CFAP300. Interacts with DNAI2 and HSPA1A. Interacts with DNAAF4. Interacts with DNAAF6/PIH1D3.
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.
Interacts with MYORG; this interaction is required for IGF2 secretion. Interacts with integrins ITGAV:ITGB3 and ITGA6:ITGB4; integrin-binding is required for IGF2 signaling.
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.
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.
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. Acts as a ligand for integrin which is required for IGF2 signaling. 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).
Belongs to the autoinducer-2 exporter (AI-2E) (TC 2.A.86) family.
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 (By similarity).
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 production of a soluble form of FAS that inhibits apoptosis. In the case of CASP2/caspase-2, promotes production of a catalytically active form of CASP2/Caspase-2 that induces apoptosis (By similarity).
Requires phosphatidylcholine as an allosteric activator for enzymatic activity.
Expressed in skin and hair germ cells at 19, 20 and 21 dpc.
Expressed in the stratified squamous epithelial layers of the skin, esophagus and tongue.
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.
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. The presence of TRMT10C/MRPP1, HSD17B10/MRPP2 is required to catalyze tRNA molecules in their 5'-ends.
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.
Expressed in heart, kidney, brain, liver, skeletal muscle, lung and spleen. Highest level in testis.
Interacts with E3 ligase SIAH2. Interacts with LIMD1, WTIP and AJUBA.
Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A (PubMed:15925519). Target proteins are preferentially recognized via a LXXLAP motif (By similarity). Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:15925519). Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (By similarity). Also hydroxylates HIF2A (By similarity). Has a preference for the CODD site for both HIF1A and HIF2A (By similarity). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (By similarity). 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 (By similarity). EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle (By similarity). Also regulates susceptibility to normoxic oxidative neuronal death (By similarity). 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 (By similarity). Hydroxylates IKBKB, mediating NF-kappa-B activation in hypoxic conditions (By similarity). Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (By similarity).
Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded protein response (UPR), leading to its degradation.
Interacts with ITGAM (By similarity). Interacts with GORASP2 (By similarity).
Junctional adhesion protein that mediates heterotypic cell-cell interactions with its cognate receptor JAM2 to regulate different cellular processes. 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 (By similarity). 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). Plays a role in angiogenesis. Plays a role in the regulation of cell migration (By similarity). 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.
Expressed by mast cells and their progenitors (at protein level).
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.
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-dependent manner, and by 6-hydroxydopamine (6-OHDA) in PC12 cells.
Highly expressed in brain, gut, lung, and testis.
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.
Interacts with the dopamine receptor DRD2 (By similarity). Interacts with RASL10B (By similarity). Homodimer.
Specifically expressed in neural and endocrine secretory tissues. Expressed in brain, pancreas, hypothalamus, pituitary and adrenal but not in heart, placenta, lung, liver, skeletal muscle or kidney. In brain, it is absent from the cell body layers of the hippocampus and dentate gyrus but abundant in the synaptic neuropil, except for the stratum lucidum and stratum lacunosum moleculare where it is not detected. In the cerebellum, it is mainly detected in the glomeruli of the granule cell layer where it colocalized with synaptophysin. In the olfactory bulb, it is detected mainly in the glomeruli. In the adult adrenal gland, where it is restricted to the medulla (at protein level).
The PH domain is essential for regulated exocytosis and binds phospholipids and plasma membrane. It however does not mediate binding to DCVs.
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. Interacts with PACRG. Interacts with FLCN (By similarity). Interacts with DLEC1 (By similarity).
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 (By similarity).
Cerebellum-specific expression. Expressed in thin parallel fibers of cerebellar granule cells.
In the developing cerebellum, expressed in granule cells in the inner external germinal layer and in migrating granule cells whereas proliferating cells in the outer extessornal germinal layer did not shown expression. Expression levels in the internal granule cell layer peak during the third postnatal week and remain considerably high in the adult cerebellum.
Involved in the regulation of cell migration (PubMed:29053796). May be involved in mediating the organization of the parallel fibers of granule cells during cerebellar development (PubMed:12213440).
Contains ten tandem EGF-like repeats strikingly similar to those found in the cysteine rich 'stalk-like' structure of integrin beta-subunits.
Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By similarity). The phosphorylated form interacts with EPCAM (PubMed:16054130).
Plays a major role in tight junction-specific obliteration of the intercellular space.
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. Interacts with the importin alpha KPNA1 and KPNA2 (By similarity).
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. Inhibits activity of protein phosphatase 2A (PP2A). Does not inhibit protein phosphatase 1. May play a role in cerebellar development and synaptogenesis (By similarity).
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.
Cleaved into a smaller N-terminal chain and a larger chain that contains the fibrinogen C-terminal domain; both cleaved and uncleaved forms are detected in the extracellular space. The cleaved form is not present within the cell.
Forms disulfide-linked dimers and tetramers.
Homooligomer; disulfide-linked via Cys residues in the N-terminal part of the protein. The homooligomer undergoes proteolytic processing to release its carboxyl fibrinogen-like domain, which circulates as a monomer (PubMed:14570927). The homooligomer unprocessed form is able to interact with the extracellular matrix (By similarity).
Mediates inactivation of the lipoprotein lipase LPL, and thereby plays a role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism. May also play a role in regulating glucose homeostasis and insulin sensitivity. Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage (By similarity). Upon heterologous expression, inhibits the adhesion of endothelial cell to the extracellular matrix (ECM), and inhibits the reorganization of the actin cytoskeleton, formation of actin stress fibers and focal adhesions in endothelial cells that have adhered to ANGPTL4-containing ECM (in vitro) (By similarity). Depending on context, may modulate tumor-related angiogenesis (By similarity).
Mediates inactivation of the lipoprotein lipase LPL, and thereby plays an important role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism. Has higher activity in LPL inactivation than the uncleaved protein.
Detected throughout the gray matter of the spinal cord including the motor neurons (at protein level). In the brain, detected in the neurons of the hippocampus and in the Purkinje cells of the cerebellum (at protein level). Also detected in the terospenial cortex, bed nucleus of the stria terminalis (BST) and the ventrolateral thalamus (VL) (at protein level).
Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane. Enzymatic activity is enhanced in the presence of phosphatidylserine (By similarity).
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Interacts with tyrosine phosphorylated form of SHC1 (By similarity). Interacts with EGFR (By similarity). Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR (By similarity). Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells (By similarity). Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin (By similarity). Interacts with c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356' (By similarity). Interacts with p130Cas/BCAR1 (By similarity). Interacts with CENTD3/ARAP3 via its SAM domain (By similarity). Interacts with c-Cbl/CBL and CAP/SORBS1 (By similarity). Interacts with activated EPHA2 receptor (By similarity). Interacts with receptors FCGR2A (By similarity). Interacts with FCGR2B (By similarity). Interacts with tyrosine kinase ABL1 (By similarity). Interacts with tyrosine kinase TEC (By similarity). Interacts with CSF1R (By similarity). Interacts (via N-terminus) with SH3YL1 (via SH3 domain) (By similarity). Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via ITIM) (By similarity). Interacts with NEDD9/HEF1 (By similarity).
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:11238900, PubMed:17535963). Required for correct mitotic spindle orientation and therefore progression of mitosis (By similarity). Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear (PubMed:11238900). While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking (PubMed:12351701, PubMed:10381377). Confers resistance to dietary obesity (By similarity). May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane (By similarity). Part of a signaling pathway that regulates actin cytoskeleton remodeling (By similarity). Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation (By similarity). Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling (By similarity). Regulates cell adhesion and cell spreading (By similarity). Required for HGF-mediated lamellipodium formation, cell scattering and spreading (By similarity). Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation (By similarity). Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth (PubMed:17535963). Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A) (By similarity). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems (By similarity). Involved in EGF signaling pathway (By similarity). Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3 (By similarity). Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity (By similarity). Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1 (By similarity). In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling (By similarity). Plays a role in the localization of AURKA and NEDD9/HEF1 to the basolateral membrane at interphase in polarized cysts, thereby mediates cell cycle homeostasis, cell polarization and cilia assembly (By similarity). Additionally promotion of cilia growth is also facilitated by hydrolysis of (PtdIns(3,4,5)P3) to PtdIns(3,4)P2 (By similarity). Promotes formation of apical membrane-initiation sites during the initial stages of lumen formation via Rho family-induced actin filament organization and CTNNB1 localization to cell-cell contacts (By similarity). May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification (By similarity).
The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain.
The SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or FCGR2A (By similarity). It also mediates the interaction with p130Cas/BCAR1 (By similarity).
Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as insulin, growth factors such as EGF or PDGF, chemokines, integrin ligands and hypertonic and oxidative stress. May be phosphorylated upon IgG receptor FCGR2B-binding. Phosphorylated at Tyr-987 following cell attachment and spreading. Phosphorylated at Tyr-1161 following EGF signaling pathway stimulation (By similarity).
Variant Cys-1142 found in diabetic GK strain may be a cause of diabete in this strain. Genetic variations in Inppl1 may also be a cause of susceptibility to hypertension.
Alpha-1-AGP is synthesized in the liver, the synthesis being controlled by glucocorticoids, interleukin-1 and interleukin-6, it increases 5- to 50-fold upon inflammation.
Contains a beta-barrel that binds various ligands in its interior.
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain (By similarity). Appears to function in modulating the activity of the immune system during the acute-phase reaction.
APOE exists as multiple glycosylated and sialylated glycoforms within cells and in plasma. The extent of glycosylation and sialylation are tissue and context specific.
APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids. APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance. Apolipoproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma. As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL). It also binds a wide range of cellular receptors including the LDL receptor/LDLR and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles. Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells.
Homotetramer. May interact with ABCA1; functionally associated with ABCA1 in the biogenesis of HDLs. May interact with APP/A4 amyloid-beta peptide; the interaction is extremely stable in vitro but its physiological significance is unclear. May interact with MAPT. May interact with MAP2. In the cerebrospinal fluid, interacts with secreted SORL1. Interacts with PMEL; this allows the loading of PMEL luminal fragment on ILVs to induce fibril nucleation.
The mature protein has no cysteine residues; however, in different allelic variants where cysteine residues replace arginine at positions 155 or 168, binding of Apo-E to cell membrane receptors is decreased. The amino end of this protein is therefore thought to interact with the receptor.
Expressed in femur, calvaria, trachea, lung and ovary.
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis. Induces cartilage and bone formation. Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2. 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. Can also signal through non-canonical pathways such as ERK/MAP kinase signaling cascade that regulates osteoblast differentiation. Stimulates also the differentiation of myoblasts into osteoblasts via the EIF2AK3-EIF2A-ATF4 pathway by stimulating EIF2A phosphorylation which leads to increased expression of ATF4 which plays a central role in osteoblast differentiation.
Homodimer; disulfide-linked. Interacts with SOSTDC1 (By similarity). Interacts with GREM2, RGMA, RGMB and RGMC. Interacts with ASPN (By similarity). Interacts with MAFP5 (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2. Interacts with type I receptor BMPR1A. Interacts with type II receptor BMPR2 (By similarity). Interacts with SCUBE3 (By similarity). Interacts with TNFAIP6 (primarily via Link domain); this interaction is inhibited by hyaluronan.
Autophosphorylated. Ligand-binding increases phosphorylation on tyrosine residues and promotes its association with the p85 subunit of phosphatidylinositol 3-kinase.
Monomer and homodimer. Heterodimer with each of the other ERBB receptors (Potential). Interacts with CSPG5, PA2G4, GRB7, MYOC and MUC1. Found in a ternary complex with NRG1 and ITGAV:ITGB3 or ITGA6:ITGB4 (By similarity).
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. May also be activated by CSPG5. Involved in the regulation of myeloid cell differentiation.
Homodimer (By similarity). Heterodimer with MAPRE1 (By similarity). Binds monomeric and polymerized GTP-bound tubulin (By similarity). Interacts with DCTN1 (By similarity). Binds to the C-terminal domain of APC (By similarity). Interacts (via C-terminus) with CLIP1 (By similarity). Interacts with SLAIN2 and SLAIN1 (By similarity). Interacts with APC2 (By similarity). Interacts with SRCIN1 (PubMed:19146815). Interacts with AKAP9 (By similarity). Interacts with PDE4DIP; this interaction, which is PDE4DIP isoform-specific, is required for its recruitment to the Golgi apparatus (By similarity).
Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes microtubule growth. May be involved in spindle function by stabilizing microtubules and anchoring them at centrosomes. 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. Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules (By similarity).
The PHTF domain was initially defined as an atypical homeodomain, suggesting that this protein could act as a transcription regulator (By similarity). 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 (PubMed:12604659).
The protein first appears in meiotic spermatocytes and becomes abundant in spermatids around stage III-IV (at protein level).
Belongs to the dystrophin family. Dystrobrevin subfamily.
Expressed in neurons. In the isocortex, expressed most prominently in the somata (including the nuclei) and the dendrites of the pyramidal cells. Expressed in the hippocampus CA1, CA2, and CA3 neurons, namely in the initial segments of dendrites. Expressed in the Purkinje cells, molecular layer interneurons, and granule cells of cerebellum. Expressed in axon fascicles associated with the spinal trigeminal tract and in the internal capsule in the brainstem.
Interacts with dystrophin short form DP71 and syntrophins SNTG1 and SNTG2 (By similarity). Binds DTNBP1 (By similarity). Forms a specific complex composed of DMD, SNTB2 and SNTA1 in neuron; the interaction with SNTB2 and SNTA1 is DMD independent (PubMed:10545507). Interacts with UTRN and dystrophin short form DP71 in the kidney and liver (PubMed:10545507). Interacts with SNTB1, SNTB2 and SNTA1 in kidney and liver. Interacts with KIF5A (PubMed:14600269). Interacts with HMG20A and HMG20B (By similarity). Interacts with OLFM1 (PubMed:17265465). Interacts with PRKAR2B and PRKAR1A (By similarity).
Phosphorylated by PKA. Phosphorylation at Thr-11 alters the interaction with KIF5A.
Scaffolding protein that assembles DMD and SNTA1 molecules to the basal membrane of kidney cells and liver sinusoids. 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. May be required for proper maturation and function of a subset of inhibitory synapses.
The coiled coil domain may mediate the interaction with dystrophin.
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. Essential for the production of 11-cis retinal for both rod and cone photoreceptors. Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid. 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.
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).
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.
Found in high quantity in the brain of humans and animals infected with degenerative neurological diseases such as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), etc.
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. Interacts with GRB2, APP, ERI3/PRNPIP and SYN1 (By similarity). Mislocalized cytosolically exposed PrP interacts with MGRN1; this interaction alters MGRN1 subcellular location and causes lysosomal enlargement (By similarity). Interacts with APP. Interacts with KIAA1191 (By similarity). Interacts with ADGRG6 (By similarity).
The normal, monomeric form has a mainly alpha-helical structure. The disease-associated, protease-resistant form forms amyloid fibrils containing 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.
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.
Isoform 1 increases from day P4 to P64. Isoform 2 increases after day P8.
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. Isoform 2 may function as a chondroitin sulfate-bearing cell surface receptor.
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 (By similarity).
Heterodimer of an alpha and a beta subunit. Interacts with ARHGAP17 and RCSD1/CAPZIP. Component of the WASH complex, composed of F-actin-capping protein subunit alpha (CAPZA1, CAPZA2 or CAPZA3), F-actin-capping protein subunit beta (CAPZB), WASHC1, WASHC2, WASHC3, WASHC4 and WASHC5. Interacts with ACTG1. Directly interacts with CRACD; this interaction decreases binding to actin (By similarity).
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.
Highest in the pyramidal and dentate granule cell layers of the hippocampus.
Low in adult brain, much higher in younger animals.
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.
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. Regulates the function of the endothelial barrier.
Highest expression in brain. Also expressed in parotid gland, liver, uterus, lung, heart, adrenal gland and ovary. Not detected in spleen, pancreas, intestine, thymus or kidney.
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.
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. C2H2-type zinc fingers 1-3 are required for localization to sites of DNA damage.
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. 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. Modulates the ubiquitination status of replication protein A (RPA) complex proteins in response to replication stress.
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.
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by two subunits (Potential). May interact with TRAF2 (By similarity).
Involved in the activation cascade of caspases responsible for apoptosis execution.
G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1505525, PubMed:1331748). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances (PubMed:22525520). 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:1505525, PubMed:1331748). 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 (By similarity). Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5-hydroxytryptamine levels, and thereby affects neural activity. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine (By similarity). May play a role in the perception of pain (PubMed:22525520).
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. Interacts (via the biotin carboxylation domain) with SIRT4.
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.
This enzyme performs an important anaplerotic function in replenishing citric acid cycle intermediates that exit the mitochondrion for consumption in various pathways.
Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.
Interacts with DIAPH1. Forms a nuclear ternary complex with MRTFA and SRF.
Tumor suppressor which functions to suppress MRTFA-induced SRF transcriptional activity.
Activated by zinc, cobalt and manganese ions (PubMed:15070399). Inhibited by EDTA (PubMed:15070399).
Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate (PubMed:15070399). Also catalyzes the oxidation of other D-2-hydroxyacids, such as D-malate (D-MAL) and D-lactate (D-LAC) (PubMed:15070399). Exhibits high activities towards D-2-HG and D-MAL but a very weak activity towards D-LAC (By similarity).
An autoantigen recognized by serum of pretype I diabetes.
Expressed in brain, heart and anterior pituitary gland. Also expressed in pancreatic islets and adrenal gland.
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.
Belongs to the saccharopine dehydrogenase family.
Exhibits antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria. May act as a ligand for C-C chemokine receptor CCR6. Binds to CCR6 and induces chemotactic activity of CCR6-expressing cells.
Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.
Probably a dodecamer composed of six biotin-containing alpha subunits (MCCC1) and six beta (MCCC2) subunits.
Acts as 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. 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.
Component of the Golgi-associated retrograde protein (GARP) complex, also called VFT (VPS fifty-three) complex, composed of VPS51, VPS52, VPS53 and VPS54. Component of the endosome-associated retrograde protein (EARP) complex, composed of VPS51, VPS52, VPS53 and VPS50/Syndetin (By similarity). The EARP complex interacts with EIPR1 (PubMed:27440922). EIPR1 interacts with GARP complex and mediates its recruitment to the trans-Golgi network. Interacts with RAB6A and STX10. Interacts with BLTP3B (By similarity).
Interacts with calcium ATPase ATP2A1/SERCA1. Interact with ATP2A2; the inhibition decreases ATP2A1 Ca(2+) affinity. Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2.
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).
Acetylation by CREBBP/CBP inhibits the helicase activity. Deacetylation by SIRT7 promotes the helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.
Acetylation inhibits the helicase activity.
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 (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. Interacts with WDR46. Interacts with MCM3AP (By similarity). 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). Binds various RNAs, such as rRNAs, snoRNAs, 7SK and, at lower extent, mRNAs. 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. 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. Functions as cofactor for JUN-activated transcription: required for phosphorylation of JUN at 'Ser-77'. Can unwind double-stranded RNA (helicase) and can fold or introduce a secondary structure to a single-stranded RNA (foldase). 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. Involved in rRNA processing. May bind to specific miRNA hairpins (By similarity). 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 through its WW 2 domain with SYNPO and through its PDZ 5 domain with ACTN4. Interacts with cytoplasmic domain of ADGRB1. Interacts via its WW domains with DRPLA (By similarity). Interacts with ESAM, LRP2 and CXADR. May interact with CTNNB1. Interacts through its PDZ 1 domain with NET1 (By similarity). Interacts with ASIC3 and AMOT. Interacts with FCHSD2 (By similarity). Interacts with IGSF5/JAM4 and through its PDZ 2 and 3 domains with NPHS1 forming a tripartite complex (PubMed:16155592). Interacts with DDN (PubMed:16751601). May interact (via PDZ domain) with RAPGEF2 (By similarity). 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 (By similarity). Interacts with PRRG4 (via cytoplasmic domain) (By similarity).
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.
Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. In adipocytes, plays a crucial role in targeting SLC2A4 vesicle to the plasma membrane in response to insulin, perhaps directing the vesicle to the precise site of fusion (By similarity). It is required for neuron survival and plays an essential role in cortical development (By similarity).
The C-terminus is required for translocation to the plasma membrane.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8. Interacts with ARHQ in a GTP-dependent manner. Interacts with RAB11FIP3 (By similarity).
Catalyzes the reversible interconversion of L-ornithine and 2-oxoglutarate to L-glutamate semialdehyde and L-glutamate.
Expressed in the head and flagellum of epididymal sperm but not in testicular sperm (at protein level).
Interacts with STX1A, STX2 and STX3. 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 (By similarity).
Belongs to the XRCC4-XLF family. XRCC4 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. 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 (By similarity).
Increasing expression in the ovary between fetal day 21 and postnatal day 2. Expression decreases thereafter to lower levels in adult ovaries.
Widely expressed, with highest levels in ovary, kidney, hypothalamus and hippocampus. Within the ovarian follicle, expressed in granulosa cells, but not in oocytes. Present in both preantral and antral follicles, but not in atretic antral follicle.
Within the ovary, required for the organization of somatic cells and oocytes into discrete follicular structures.
Interacts wit the IFT B complex component IFT52.
Plays a role in the export of secreted proteins in the ER.
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KLP2 subfamily.
Expressed in brain at 17 dpc and in cerebellum at 19 dpc.
Plus-end directed kinesin-like motor enzyme involved in mitotic spindle assembly.
Expressed in lung, heart, brain, and kidney, but not significantly in skeletal muscle or testis.
Inactivates MAP kinases. Has a specificity for the ERK family (PubMed:8626780). Implicated in muscle and neuronal differentiation (PubMed:8631996). 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).
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.
Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation.
Homodimer (By similarity). Interacts with SH3RF2 (PubMed:22128169).
Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation.
Enzyme that catalyzes the last step in proline biosynthesis. Proline is synthesized from either glutamate or ornithine; both are converted to pyrroline-5-carboxylate (P5C), and then to proline via pyrroline-5-carboxylate reductases (PYCRs). PYCRL is exclusively linked to the conversion of ornithine to proline.
Belongs to the pectinacetylesterase family. Notum subfamily.
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) (PubMed:9334353). Nectin- and actin-filament-binding protein that connects nectin to the actin cytoskeleton (PubMed:9334353). May play a key role in the organization of epithelial structures of the embryonic ectoderm (By similarity). Essential for the organization of adherens junctions (By similarity).
Homodimer. Interacts with F-actin, nectin and NECTIN3. Essential for the association of nectin and E-cadherin. Isoform 2/s-afadin does not interact with F-actin. Interacts with ZO-1 and occludin, but probably in an indirect manner. Interacts with RIT1, RIT2, NRXN1 and BCR (By similarity). Interacts with ADAM10; the interaction locks ADAM10 at adherens junctions following ADAM10 recruitment to adherens junctions by TSPAN33 (PubMed:30463011).
Isoform 1 increases the viscosity of F-actin in a dose-dependent manner. Isoform 1 causes F-actin to associate into bundles and meshworks.
Isoform 1 is widely expressed, including in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Isoform 2 is mainly expressed in the brain.
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 (By similarity).
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. Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (By similarity).
Phosphorylation regulates its interaction with TBP. Not phosphorylated when bound to DRAP1 (By similarity).
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 (By similarity).
Expressed in brain, heart, kidney, liver and lung (at protein level).
Interacts with AP1G1 and AP2A1 components of the adapter protein complexes AP-1 and AP-2. Interacts with the GAE domain proteins GGA1, GGA2 and GGA3 (By similarity).
The WXXF motifs mediate binding of accessory proteins to the ear-domain of AP-1, GGAs and AP-2 through hydrophobic interactions. Selective binding to the GAE domains of AP-1 or to the alpha-ear domain of AP-2 is tuned by the acidic context surrounding the motif and the properties of the second residue of the motif itself (By similarity).
Binds DNA as a monomer. Interacts with FOXA2. Interacts with NKX2-1. Interacts with HDAC7. Interacts with the histone H3-H4 heterodimer. Associates with nucleosomes containing histone H2A (By similarity). Interacts with AR. Interacts with NR0B2.
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'. Proposed to play a role in translating the epigenetic signatures into cell type-specific enhancer-driven transcriptional programs. Involved in glucose homeostasis; activates the GCG promoter. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas, lungs and prostate; FOXA1 and FOXA2 seem to have at least in part redundant roles. Modulates the transcriptional activity of nuclear hormone receptors. Is required for maximal gene activation mediated by AR in the prostate. Negatively regulates AR transactivation via competition with coactivators such as NCOA2. Is involved in ESR1-mediated transcription. Involved in regulation of apoptosis. Involved in cell cycle regulation. 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.
Belongs to the eukaryotic ribosomal protein eS8 family. Ribosome biogenesis protein NSA2 subfamily.
Component of the pre-66S ribosomal particle.
Involved in the biogenesis of the 60S ribosomal subunit. May play a part in the quality control of pre-60S particles.
Abundant in kidney, liver, cochlea and outer hair cells but not inner hair cells or vestibular type I hair cells. Very low levels in lung, brain, intestine and pancreas.
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.
Belongs to the mitochondrion-specific ribosomal protein mL41 family.
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. Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal (By similarity).
In the developing forebrain, barely detected at postnatal day 1. Expression increases from the first week after birth. High levels are reached during 2 and 3 weeks after birth and slightly decrease at 6 weeks after birth. This expression pattern parallels synaptogenesis.
May play a synaptic role at the postsynaptic lipid rafts possibly through interaction with CAMK2A.
Palmitoylation and myristoylation target the protein to the lipid rafts.
Predominantly expressed in the brain (at protein level) (PubMed:11707601, PubMed:15659234). Within the brain, found in most of forebrain structures, including the cerebral cortex, hippocampal formation, olfactory bulb, anterior olfactory nuclei, piriform cortex, tenia tecta and amygdaloid nuclei. Not detected in glial cells (PubMed:15659234).
Homodimer in the absence of bound vitamin D3 (By similarity). Heterodimer with RXRA after vitamin D3 binding (By similarity). Interacts with MED1 and NCOA6 (PubMed:10866662, PubMed:15065852, PubMed:17227670). Interacts with MED1, NCOA1, NCOA2, NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes (By similarity). Interacts with the corepressor NCOR1 (By similarity). Interacts with SNW1 (By similarity). Interacts with IRX4, the interaction does not affect its transactivation activity (By similarity). 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:17227670). Enters the nucleus upon vitamin D3 binding where it forms heterodimers with the retinoid X receptor/RXR (By similarity). The VDR-RXR heterodimers bind to specific response elements on DNA and activate the transcription of vitamin D3-responsive target genes (By similarity). Plays a central role in calcium homeostasis (PubMed:17227670).
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. Also capable of removing NEDD8 from NEDD8 conjugates but has no effect on Sentrin-1 conjugates. Deubiquitinates BAZ2A/TIP5 leading to its stabilization.
Appears on embryonic day 18 and gradually increases until birth.
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 (By similarity). 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 (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 (By similarity). Acts as a water channel enabling passive water transport 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.
N-glycosylation is not necessary for the cotransporter function.
The cholesterol-binding site is formed by transmembrane helices TM1, TM7 and TM13.
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. May also have pro-apoptotic activity by potentiating both serum-withdrawal and TNF-induced apoptosis (By similarity).
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 (By similarity).
Belongs to the pyrimidine 5'-nucleotidase family.
Specifically hydrolyzes 7-methylguanosine monophosphate (m(7)GMP) to 7-methylguanosine and inorganic phosphate. The specific activity for m(7)GMP may protect cells against undesired salvage of m(7)GMP and its incorporation into nucleic acids. Also has weak activity for CMP. UMP and purine nucleotides are poor substrates (By similarity).
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.
Neuron-specific protein. Expressed in brain (at protein level).
Binds to membranes via its F-BAR domain and mediates membrane tubulation. 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.
Highly expressed in brain (at protein level).
Homodimer. May form heterooligomers with other PACSINs. Interacts with MAPT. Interacts with TRPV4 (By similarity). Interacts (via SH3 domain) with SYNJ1 and WASL. Interacts (via SH3 domain) with DNM1; the interaction is reduced by DNM1 phosphorylation. 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.
Phosphorylated by casein kinase 2 (CK2) and protein kinase C (PKC).
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 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.
Expressed in the hippocampus, kidney, and ovary.
High affinity receptor for melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibits adenylate cyclase activity.
Although highly similar to the deubiquitinase OTULIN, lacks both the conserved active site residue Cys at position 136 which is replaced by an Asp residue and the conserved active site residue His at residue 347 which is replaced by a Gln residue, and does not have deubiquitinase activity.
Does not bind ubiquitin or ubiquitin-like proteins.
The N-terminal region that precedes the OTU domain mediates interaction with cellular membranes.
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, with higher level in testis.
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. 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. 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).
Interacts with AFF4. 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 (By similarity).
Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex.
Binds galactosides (By similarity). Has high affinity for the Forssman pentasaccharide (By similarity). Ligand for HAVCR2/TIM3 (By similarity). Binding to HAVCR2 induces T-helper type 1 lymphocyte (Th1) death (By similarity). 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 (By similarity). 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 (By similarity). Expands regulatory T-cells and induces cytotoxic T-cell apoptosis following virus infection (By similarity). Activates ERK1/2 phosphorylation inducing cytokine (IL-6, IL-8, IL-12) and chemokine (CCL2) production in mast and dendritic cells (By similarity). Inhibits degranulation and induces apoptosis of mast cells (By similarity). Induces maturation and migration of dendritic cells (By similarity). Inhibits natural killer (NK) cell function (By similarity). Can transform NK cell phenotype from peripheral to decidual during pregnancy (By similarity). Astrocyte derived galectin-9 enhances microglial TNF production (PubMed:25158758). 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 (PubMed:8995305). Highly selective to the anion urate (PubMed:8995305).
By viral mimic polyinosinic:polycytidylic acid (poly I:C) and lipopolysaccharides (LPS) in microglia.
Contains two homologous but distinct carbohydrate-binding domains.
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.
The isoform Long is expressed exclusively in the small intestine.
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. Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation-mediated inhibition of ATP1B1. Induces a hyperpolarization-activated chloride current when expressed in Xenopus oocytes.
Regulatory subunit of the sodium/potassium-transporting ATPase which is composed of a catalytic alpha subunit, a non-catalytic beta subunit and an additional regulatory subunit. Interacts with catalytic alpha subunit ATP1A1. Also interacts with non-catalytic beta subunit ATP1B1. Interacts with the alpha1-beta1, alpha2-beta1 and alpha3-beta1 NKA isozymes.
Belongs to the small GTPase superfamily. RasD family.
By thyroid hormone, efaroxan and glibenclamide.
Farnesylated. Farnesylation is required for membrane targeting.
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.
Low levels detected at 16 dpc through P10, and increased between P10 and P15 during the development of brain; the amount did decrease in the adult brain.
Monomer (Potential). Interacts with GNB1, GNB2 and GNB3 (By similarity). Interacts with PIK3CA and UBE2I.
Prominently expressed in the striatum, weakly in the cerebral cortex and the CA fields of the hippocampus. Highly expressed in the hippocampus and cerebellum, only during the postnatal period. Also expressed in pancreatic endocrine cells (islets of Langerhans), adrenal gland and stomach and in a thyroid cell line.
Belongs to the Mediator complex subunit 13 family.
Interacts with HORMAD2. Interacts with IHO1.
Phosphorylated at Ser-375 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.
Homodimer (By similarity). Interacts with SCN10A (PubMed:12591166). Interacts with DIP2A; DIP2A may act as a cell surface receptor for FSTL1. Interacts with BMP4. Interacts with CD14; this interaction promotes TL4-mediated signaling cascade (By similarity).
Secreted glycoprotein that is involved in various physiological processes, such as angiogenesis, regulation of the immune response, cell proliferation and differentiation (By similarity). Plays a role in the development of the central nervous system, skeletal system, lungs, and ureter. Promotes endothelial cell survival, migration and differentiation into network structures in an AKT-dependent manner. Also promotes survival of cardiac myocytes (By similarity). Initiates various signaling cascades by activating different receptors on the cell surface such as DIP2A, TLR4 or BMP receptors (By similarity).
Interacts with EEF1A1, GRIA2, GRIP1 (By similarity). Interacts with CAMLG, TUBG1. Interacts with NPM1 and CDKN2A; TMUB1 can enhance interaction between NPM1 and CDKN2A and is proposed to bridge the proteins; proposed to be mediated by iHOPS (PubMed:18418082, PubMed:22426572, PubMed:22890319). Interacts with ERLIN2 and AMFR; TMUB1 promotes the interaction of ERLIN2 with AMFR (By similarity).
Involved in sterol-regulated ubiquitination and degradation of HMG-CoA reductase HMGCR (By similarity). Involved in positive regulation of AMPA-selective glutamate receptor GRIA2 recycling to the cell surface (PubMed:18665261). Acts as negative regulator of hepatocyte growth during regeneration (PubMed:22426572).
May contribute to the regulation of translation during cell-cycle progression. May contribute to the regulation of cell proliferation (By similarity). May be involved in centrosome assembly. Modulates stabilization and nucleolar localization of tumor suppressor CDKN2A and enhances association between CDKN2A and NPM1 (By similarity).
Processed by regulated intramembrane proteolysis (RIP) in the N-terminus to release iHOPS from membranes.
Belongs to the VAMP-associated protein (VAP) (TC 9.B.17) family.
Homodimer, and heterodimer with VAPA. Interacts with RMDN3, VAMP1 and VAMP2. Interacts (via MSP domain) with ZFYVE27. Interacts with KIF5A in a ZFYVE27-dependent manner. Interacts with STARD3 (via FFAT motif) (By similarity). Interacts with STARD3NL (via FFAT motif) (By similarity). Interacts with CERT1 (By similarity). Interacts with PLEKHA3 and SACM1L to form a ternary complex (By similarity). Interacts with VPS13A (via FFAT motif) (By similarity).
Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity. Involved in cellular calcium homeostasis regulation.
Alternates between an inactive GDP-bound form and an active GTP-bound form (By similarity). Activated by guanine nucleotide-exchange factors (GEFs) and inactivated by GTPase-activating proteins (GAPs) (By similarity).
Interacts (when activated) with GGA1, GGA2 and GGA3; the interaction is required for proper subcellular location of GGA1, GGA2 and GGA3 (By similarity). Interacts with ARHGAP21, ASAP2, HERC1, PRKCABP, PIP5K1B, TMED2, PSCD2, TMED10 and GRIA2 (PubMed:10022920, PubMed:10623590, PubMed:10747863, PubMed:23889934). Interacts with ARFGAP1, which hydrolyzes GTP and thus, regulates its function (PubMed:7890632). Interacts with PI4KB in the Golgi complex. Interacts with NCS1/FREQ in the Golgi and at the plasma membrane. Interacts with PLEKHA3. Interacts with PLEKHA8; the interaction, together with phosphatidylinositol 4-phosphate binding, is required for FAPP2-mediated glucosylceramide transfer activity (By similarity). Interacts (activated) with PICK1 (via PDZ domain); the interaction blocks Arp2/3 complex inhibition (PubMed:23889934). Interacts with IQSEC1 (By similarity). Interacts with C9orf72 (By similarity).
Small GTPase involved in protein trafficking between different compartments (By similarity). Modulates vesicle budding and uncoating within the Golgi complex (By similarity). In its GTP-bound form, triggers the recruitment of coatomer proteins to the Golgi membrane (By similarity). The hydrolysis of ARF1-bound GTP, which is mediated by ARFGAPs proteins, is required for dissociation of coat proteins from Golgi membranes and vesicles (By similarity). 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) (PubMed:23889934).
Interacts with CPLANE1. Interacts with INTU and FUZ; FUZ, INTU and WDPCP probably form the core CPLANE (ciliogenesis and planar polarity effectors) complex.
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).
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. May play a role in angiogenesis (By similarity).
Detected in brain, in cell bodies and dendrites of Purkinje cells in cerebellar neurons (at protein level). Marked expression was found in hippocampus and cerebellum, and in many other tissues.
Monomer (By similarity). Interacts with HRH3.
Binds to OSBPL3, which mediates recruitment of VAPA to plasma membrane sites (By similarity). The ORP3-VAPA complex stimulates RRAS signaling which in turn attenuates integrin beta-1 (ITGB1) activation at the cell surface (By similarity). With OSBPL3, may regulate ER morphology (By similarity). May play a role in vesicle trafficking (PubMed:19289470).
Homodimer, and heterodimer with VAPB. Interacts with VAMP1, VAMP2, STX1A, BET1, SEC22C and with the C-terminal domain of OCLN (By similarity). Interacts with OSBP (By similarity). Interacts (via C-terminus) with RSAD2/viperin (via C-terminus) (By similarity). Interacts with OSBPL1A (PubMed:16004875). Interacts (via MSP domain) with ZFYVE27; may retain ZFYVE27 in the endoplasmic reticulum and regulate its function in cell projections formation (PubMed:19289470). Interacts with OSBPL3 (phosphorylated form). Interacts with KIF5A in a ZFYVE27-dependent manner (By similarity). Interacts with STARD3 (via FFAT motif) (By similarity). Interacts with STARD3NL (via FFAT motif) (By similarity). Interacts with CERT1 (By similarity).Interacts with PLEKHA3 and SACM1L to form a ternary complex (By similarity). Interacts with VPS13A (via FFAT motif) (By similarity).
Forms part of the preprotein translocase of the outer mitochondrial membrane (TOM complex) containing TOMM22, TOMM40, TOMM40L and TOMM70. Interacts with mitochondrial targeting sequences.
Potential channel-forming protein implicated in import of protein precursors into mitochondria.
Widely expressed. Higher levels in heart, brain and liver, very low level in testis.
Forms heterodimers with NONO; this involves formation of a coiled coil domain by helices from both proteins. Found in a RNP complex with CAT2 transcribed nuclear RNA (CTN-RNA). Interacts with NONO and SFPQ. Interaction with NONO is required for its targeting to paraspeckles and perinucleolar caps. 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. 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.
Together with NONO, required for the formation of nuclear paraspeckles. Regulates, cooperatively with NONO and SFPQ, androgen receptor-mediated gene transcription activity in Sertoli cell line. Binds to poly(A), poly(G) and poly(U) RNA homopolymers. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. 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.
Expressed in a number of tissues includinf brain, thymus, spleen, testis and spinal cord.
Regulates G protein-coupled receptor signaling cascades, including signaling downstream of the N-formylpeptide chemoattractant receptors and leukotriene receptors. 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 (By similarity).
Heme transporter that regulates intracellular heme availability through the endosomal or lysosomal compartment.
Developing CNS and PNS at embryonic and postnatal stages.
Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3.
It is first observed after neurulation, in 10.5 dpc rat embryos, and is restricted to subsets of neuroepithelial cells in the spinal cord and the brain, between 10.5 dpc and 13.5 dpc. In the periphery, its expression is restricted to some lineages of neural crest-derived cells, namely in sympathetic and enteric neural precursors. In the PNS its expression is extinguished at or before differentiation.
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 (PubMed:10648228). 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).
Binds ubiquitinated proteins via its RanBP2-type zinc finger.
Heterodimer with UFD1 (PubMed:10811609, PubMed:12644454). The heterodimer binds ubiquitinated proteins (PubMed:12644454). The heterodimer binds to VCP and inhibits Golgi membrane fusion (PubMed:10811609, PubMed:12644454). Interacts with ZFAND2B; probably through VCP (By similarity).
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 (PubMed:10811609, PubMed:11740563, PubMed:11781570, PubMed:12411482, PubMed:12644454, PubMed:14636562). 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 (By similarity).
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 (By similarity). Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 (By similarity). Interacts with KANSL1; the interaction is direct (By similarity). 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 (By similarity). Interacts with the chromodomain of MORF4L1/MRG15 (By similarity). Interacts with ATM (via its Tudor-knot domain) (By similarity). Interacts with MSL1; the interaction is direct (By similarity). Interacts with MSL3 (By similarity). Interacts with NELFD (By similarity).
Histone acetyltransferase which may be involved in transcriptional activation. May influence the function of ATM. As part of the MSL complex it is involved in acetylation of nucleosomal histone H4 producing specifically H4K16ac. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. That activity is less specific than the one of the MSL complex. Can also acetylate TP53/p53 at 'Lys-120'.
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. Interacts with USP10 and SCNN1A. Interacts with TRFC. Interacts with SNX8; 2 molecules of SNX8 seems to associate with one molecule of SNX3. Interacts with PTPRU (By similarity). 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). Plays a role in protein transport between cellular compartments. Together with RAB7A facilitates endosome membrane association of the retromer cargo-selective subcomplex (CSC). May act in part as component of the SNX3-retromer complex which mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. Promotes stability and cell surface expression of epithelial sodium channel (ENAC) subunits SCNN1A and SCNN1G. Not involved in EGFR degradation. Involved in the regulation of phagocytosis in dendritic cells possibly by regulating EEA1 recruitment to the nascent phagosomes. Involved in iron homeostasis through regulation of endocytic recycling of the transferrin receptor Tfrc presuambly by delivering the transferrin:transferrin receptor complex to recycling endosomes; the function may involve the CSC retromer subcomplex. Involved in regulation of neurite outgrowth in primary neurons.
The PX domain mediates specific binding to phosphatidylinositol 3-phosphate (PtdIns(P3)).
Ubiquitinated, leading to its proteasomal degradation. Deubiquitinated by USP10 (By similarity).
Binds to the cytoplasmic domain of amyloid protein (APP). Interacts with HIF1AN (via N-terminus) (By similarity). Interacts with NECAB3; seems to mediate the interaction between NECAB3 and HIF1AN (By similarity).
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.
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 (By similarity).
Detected in brain corpus callosum, medulla oblongata, cerebellum and sciatic nerve. Detected in heart.
Interacts with RALA and GRK2 (By similarity). 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). 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. Signaling triggers an increase of cytoplasmic Ca(2+) levels. Activates RALA; this leads to the activation of phospholipase C (PLC) and the formation of inositol 1,4,5-trisphosphate. Signaling mediates activation of down-stream MAP kinases. Contributes to the regulation of cell shape. Promotes Rho-dependent reorganization of the actin cytoskeleton in neuronal cells and neurite retraction. Promotes the activation of Rho and the formation of actin stress fibers. Promotes formation of lamellipodia at the leading edge of migrating cells via activation of RAC1. Through its function as lysophosphatidic acid receptor, plays a role in chemotaxis and cell migration, including responses to injury and wounding. 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.
Detected at embryonic day 16 (16 dpc) in the striatum. From 16 dpc to 20 dpc to adulthood, the highest expression levels of protein is observed in the striatum, olfactory tubercle, nucleus accumbens, amygdala, and neocortex.
Expressed predominantly in the striatum (PubMed:11056049). Expressed also in olfactory tubercle, nucleus accumbens, amygdala, and neocortex. Spinal cord, pons, and medulla expression remains discrete (PubMed:26918661). Also expressed in peripheral tissues, including adrenal cortex (16 dpc to 21 dpc) and cochlear ganglia (19 dpc to P3) and also at moderate levels in retina (18 dpc to 19 dpc) and spleen (21 dpc to P7) (PubMed:26918661).
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.
A-kinase anchoring protein for GSK3B and PKA that regulates or facilitates their kinase activity towards their targets. The ternary complex enhances Wnt-induced signaling by facilitating the GSK3B- and PKA-induced phosphorylation of beta-catenin leading to beta-catenin degradation and stabilization respectively. Upon cAMP activation, the ternary complex contributes to neuroprotection against oxidative stress-induced apoptosis by facilitating the PKA-induced phosphorylation of DML1 and PKA-induced inactivation of GSK3B. During neurite outgrowth promotes neuron proliferation; while increases beta-catenin-induced transcriptional activity through GSK3B kinase activity inhibition, reduces N-cadherin level to promote cell cycle progression (By similarity). May play a role in cleft palate formation and is required for postnatal life through modulation of the activity of GSK3B during development (By similarity).
Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation of GSK3B leading to GSK3B inactivation; recruits DNM1L through GSK3B for PKA-mediated phosphorylation of DNM1L; promotes beta-catenin degradation through GSK3B-induced phosphorylation of beta-catenin; stabilizes beta-catenin and enhances Wnt-induced signaling through PKA-induced phosphorylation of beta-catenin (PubMed:20007971). Interacts with GSK3B; induces GSK3B-mediated phosphorylation of GSKIP and inhibits GSK3B kinase activity (By similarity).
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.
Farnesyl pyrophosphate and geranyl pyrophosphate inhibit mevalonate kinase activity by binding competitively at the ATP-binding sites.
The authors of PubMed:14730012 identify two forms of Mvk in rat liver, one form localizes to the cytosol and the other form to the peroxisome, whereas according to the authors of PubMed:14730012 the protein is found only in the cytoplasm with no evidence for its peroxisomal localization.
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. As part of PI3KC3-C1, promotes endoplasmic reticulum membrane curvature formation prior to vesicle budding. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2 (By similarity). Involved in the transport of lysosomal enzyme precursors to lysosomes (PubMed:11171063). Required for transport from early to late endosomes (PubMed:11171063).
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. PI3KC3-C1 probably associates with PIK3CB. Interacts with RAB7A in the presence of PIK3R4. Interacts with AMBRA1. Interacts with BECN1P1/BECN2. Interacts with SLAMF1. May interact with DYN2. May be a component of a complex composed of RAB5A (in GDP-bound form), DYN2 and PIK3C3 (By similarity). Interacts with NCKAP1L (By similarity). Interacts with ATG14; this interaction is increased in the absence of TMEM39A (By similarity). Interacts with STEEP1; the interaction is STING1-dependent and required for trafficking of STING1 from the endoplasmic reticulum (By similarity). Interacts with YWHAG (By similarity).
Ubiquitinated via 'Lys-29'- and 'Lys-48'-linked ubiquitination by UBE3C, promoting its degradation. Deubiquitination by ZRANB1/TRABID promotes its stabilization, leading to autophagosome maturation.
At 17 dpc expressed in cells of the ventricular wall in the lateral and third ventricle and to cells in the neuronal parenchyma. At PN1, mainly expressed in the walls of the lateral and third ventricles with an apical polarization.
Expressed in brain, ovaries and testis (PubMed:15018803). Expressed in the tracheal epithelium and in secondary spermatocytes and spermatids present in the seminiferous tubule (PubMed:28194645). Expressed in ependymal cells lining the ventricular walls of the brain (PubMed:28194645).
Expressed in cardiac and striated muscle. Expressed at Z-lines within the muscle fibers and at Z-line and M-line domains at costameres at the sarcolemmal membrane (at protein level). Observed in coagulating gland, bladder, salivary gland, kidney, spleen, thymus, lung and heart. Also observed in ventral prostate, seminal vesicle and liver where expression increases following castration.
Heterotetramer of two type I and two type II keratins (By similarity). Forms a heterodimer with KRT18 (By similarity). Associates with KRT20 (By similarity). Interacts with PNN (By similarity). When associated with KRT19, interacts with DMD (PubMed:15247274). Interacts with TCHP (By similarity). Interacts with APEX1 (By similarity). Interacts with GPER1 (By similarity). Interacts with EPPK1 (By similarity). Interacts with PKP1 and PKP2 (By similarity).
O-glycosylated. O-GlcNAcylation at multiple sites increases solubility, and decreases stability by inducing proteasomal degradation (By similarity).
Together with KRT19, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle.
Detected in developing brain with a peak at 18 dpc.
Mainly expressed in brain, with small amounts in heart, liver, kidney and heart.
May be involved in signal-transduction pathways related to the control of brain development.
Acts as an osmosensitive calcium-permeable cation channel (By similarity). Required for the functional integrity of the kidney glomerular filtration barrier (PubMed:30900988).
Expressed in podocytes of kidney glomeruli.
Belongs to the endoribonuclease YbeY family.
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.
Is widely distributed in the CNS. Predominant expression is seen in the granule cells of the cerebellum.
A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and fatty acids. Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes testosterone to 2alpha- and 16alpha-hydroxytestosterone (PubMed:2434473). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFAs) (PubMed:10491410, PubMed:15766564). Converts arachidonic acid (ARA, C20:4(n-6)) primarily to epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, with both R,S and S,R stereochemistry (PubMed:10491410). Preferentially produces 11R,12S-EET enantiomer. To a lesser extent, catalyzes the hydroxylation of arachidonic acid producing hydroxyeicosatetraenoates (HETEs) (PubMed:10491410). Metabolizes eicosapentaenoic acid (EPA, C20:5(n-3)) to epoxyeicosatetraenoic acid (EETeTr) regioisomers, 8,9-, 11,12-, 14,15-, and 17,18-EETeTr, preferentially producing 17R,18S-EETeTr enantiomer (PubMed:15766564). 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:2434473, PubMed:15766564).
Plays a part in calcium-regulated keratinocyte activation in epidermal repair mechanisms. Has no effect on cell proliferation (By similarity). Possesses ATPase activity. May negatively regulate mitochondrial fusion.
Binds to actin filaments in muscle and non-muscle cells (PubMed:7568216). Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction (By similarity). Smooth muscle contraction is regulated by interaction with caldesmon (By similarity). In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments (By similarity). Binds calcium (By similarity).
Homodimer (PubMed:7568216). Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain (PubMed:7568216).
Gustducin-coupled cycloheximide 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.
Isoform MLC3 is acetylated at position 2.
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.
Belongs to the nuclear hormone receptor family. NR4 subfamily.
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.
Shows a ubiquitous distribution in the cerebral cortex, hippocampus, thalamus, amygdala, and midbrain. Expression increases in prenatally stressed adult offspring in the ventral tegmental area, whereas no changes are observed in the substantia nigra area (at protein level). Not expressed in quiescent liver but is rapidly induced following partial hepatectomy and is specific to hepatic growth as it is not induced in other mitogen-treated cells. Expressed at very low levels in the lung, spleen and stomach and at high levels in the brain.
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). May confer liver-specific regulation of delayed-early genes induced later in the G1 phase of regeneration along with HMR.
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 (By similarity).
Functions as a chaperone necessary for a stable expression of the CYBA and CYBB subunits of the cytochrome b-245 heterodimer (By similarity). Controls the phagocyte respiratory burst and is essential for innate immunity (By similarity).
Interacts with CYBB; CYBC1 may act as a chaperone stabilizing Cytochrome b-245 heterodimer.
Helicase activity toward DNA substrate is inhibited by micromolar concentrations of 5,6-dichloro-1-(beta-D-ribofuranosyl)benzotriazole (DRBT) and 4,5,6,7-tetrabromobenzotriazole (TBBT). Helicase activity toward RNA substrate is inhibited by elevated concentrations of TBBT. Inhibited by some ring-expanded nucleoside analogs.
Homodimer; in free form. Component of the mitochondrial degradosome (mtEXO) complex which is a heteropentamer containing 2 copies of SUPV3L1 and 3 copies of PNPT1. As part of mitochondrial degradosome complex, interacts with GRSF1 in a RNA-dependent manner; the interaction enhances the activity of the complex. Interacts with LAMTOR5/HBXIP, WRN and BLM.
Major helicase player in mitochondrial RNA metabolism. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double-stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Involved in the degradation of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules. ATPase and ATP-dependent multisubstrate helicase, able to unwind double-stranded (ds) DNA and RNA, and RNA/DNA heteroduplexes in the 5'-to-3' direction. Plays a role in the RNA surveillance system in mitochondria; regulates the stability of mature mRNAs, the removal of aberrantly formed mRNAs and the rapid degradation of non coding processing intermediates. Also implicated in recombination and chromatin maintenance pathways. May protect cells from apoptosis. Associates with mitochondrial DNA.
Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces.
Binds the armadillo repeat of CTNNB1 and forms a stable complex. Interacts with TLE1, PIASG, ALYREF/THOC4, EP300, MDFI and MDFIC (By similarity). Interacts with DAZAP2 (By similarity).
Phosphorylated at Thr-153 and/or Ser-164 by NLK. Phosphorylation by NLK at these sites represses LEF1-mediated transcriptional activation of target genes of the canonical Wnt signaling pathway (By similarity).
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 (By similarity). Participates in the Wnt signaling pathway (By similarity). Activates transcription of target genes in the presence of CTNNB1 and EP300 (By similarity). PIASG antagonizes both Wnt-dependent and Wnt-independent activation by LEF1 (By similarity). TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by LEF1 and CTNNB1 (By similarity). Regulates T-cell receptor alpha enhancer function (By similarity). 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).
Involved in the biosynthetic pathway of cholesterol.
Monomer. Interacts with CTTNBP2NL. Interacts with RIPOR1 (via C-terminus); this interaction occurs in a PDCD10-dependent and Rho-independent manner. Interacts with PDCD10; this interaction is required for the association of STK24 with RIPOR1.
Oxidative stress induces phosphorylation. Activated by autophosphorylation at Thr-178 and phosphorylation at this site is essential for its function. Manganese, magnesium and cobalt-dependent autophosphorylation is mainly on threonine residues while zinc-dependent autophosphorylation is on both serine and threonine residues (By similarity).
Proteolytically processed by caspases during apoptosis. Proteolytic cleavage results in kinase activation, nuclear translocation of the truncated form (MST3/N) and the induction of apoptosis (By similarity).
Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. In association with STK26 negatively regulates Golgi reorientation in polarized cell migration upon RHO activation. Regulates also cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12 (By similarity). Acts as a key regulator of axon regeneration in the adult optic nerve and radial nerve.
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:9219091, PubMed:9972236). MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis (PubMed:9219091, PubMed:9972236). Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate (By similarity). 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 (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 (By similarity).
Monomer (PubMed:9219091). Dimer. Forms a multiprotein complex with MMACHC, MMADHC and MTRR.
Belongs to the zona pellucida-binding protein Sp38 family.
Is implicated in sperm-oocyte interaction during fertilization.
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.
Can form homotypic interactions (By similarity). Interacts with IRF4/Pip (By similarity). Interacts with JUN (By similarity). Interacts with TBP (By similarity). May also interact with CREBBP and EP300 (By similarity). Interacts with NONO/p54(nrb) (By similarity).
Sequence specific transcriptional activator which binds to the PU-box, a purine-rich DNA sequence (5'-GAGGAA-3') that can act as a lymphoid-specific enhancer. Promotes development of plasmacytoid dendritic cells (pDCs), also known as type 2 DC precursors (pre-DC2) or natural interferon (IFN)-producing cells. These cells have the capacity to produce large amounts of interferon and block viral replication. Required for B-cell receptor (BCR) signaling, which is necessary for normal B-cell development and antigenic stimulation (By similarity).
The protein contains a weakly acidic N-terminal transactivation domain (TAD) followed by a second TAD rich in proline, serine and threonine. Each of these domains may be required for transcriptional activation of a subset of target genes (By similarity).
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.
Phosphorylation at serine residues by MAPK14 enhances its transcriptional activation activity while phosphorylation at serine residues by CK2 inhibits its transcriptional activation activity.
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 (By similarity).
Interacts with MDM2, TP53, TP73 and USP2. Found in a trimeric complex with USP2, MDM2 and MDM4. Interacts (phosphorylated) with YWHAG; negatively regulates MDM4 activity toward TP53 (By similarity).
Phosphorylated. Phosphorylation at Ser-368 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent (By similarity).
Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein (By similarity).
A 55 kDa isoform is widely expressed while a 90 kDa isoform is detected exclusively in brain and testis (at protein level).
Belongs to the methyltransferase superfamily. Trimethylguanosine synthase family.
Catalyzes the 2 serial methylation steps for the conversion of the 7-monomethylguanosine (m(7)G) caps of snRNAs and snoRNAs to a 2,2,7-trimethylguanosine (m(2,2,7)G) cap structure. The enzyme is specific for guanine, and N7 methylation must precede N2 methylation. Hypermethylation of the m7G cap of U snRNAs leads to their concentration in nuclear foci, their colocalization with coilin and the formation of canonical Cajal bodies (CBs). Plays a role in transcriptional regulation (By similarity).
May form homooligomers. Interacts with CREBBP/CBP, EED/WAIT1, EP300/P300, NCOA6/PRIP, PPARBP/PBP and SMN (By similarity).
Interacts with the cytoplasmic tail of integrins ITGA1, ITGA2, ITGA5, ITGA6, ITGA11 and ITGB1; this interaction is dependent upon its GDP/GTP cycle (By similarity). Interacts with RABGEF1 (via VPS9 domain) (By similarity). Interacts with ANKRD27 (By similarity). Interacts (in GTP-bound form) with VAMP8 in response to starvation; the interaction probably regulates VAMP8 endolysosomal trafficking (By similarity). Interacts (active GTP-bound form) with TMED10; the interaction is indirect and regulates TMED10 abundance and localization at the Golgi (By similarity).
Small GTPase involved in membrane trafficking control (By similarity). 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). During the mitosis of adherent cells, controls the endosomal trafficking of integrins which is required for the successful completion of cytokinesis (By similarity). Involved in neurite growth (PubMed:19745841). 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 (By similarity). Modulates protein levels of the cargo receptors TMED2 and TMED10, and required for appropriate Golgi localization of TMED10 (By similarity).
Cofactor for the transcription factor TCF7. Involved in regulation of lymphoid development by driving multipotent hematopoietic progenitor cells towards a T-cell fate.
Interacts with HSPA8 and LAMP2 isoform A; the interaction may target MLLT11 for degradation via chaperone-mediated autophagy. Interacts with TCF7.
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 (By similarity). 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).
Belongs to the glycosyltransferase 4 family.
Catalyzes the initial step of dolichol-linked oligosaccharide biosynthesis in N-linked protein glycosylation pathway: transfers GlcNAc-1-P from UDP-GlcNAc onto the carrier lipid dolichyl phosphate (P-dolichol), yielding GlcNAc-P-P-dolichol.
DNA- and RNA binding protein, involved in several nuclear processes (By similarity). Binds the conventional octamer sequence in double-stranded DNA (By similarity). Also binds single-stranded DNA and RNA at a site independent of the duplex site (By similarity). Involved in pre-mRNA splicing, probably as a heterodimer with SFPQ (By similarity). Interacts with U5 snRNA, probably by binding to a purine-rich sequence located on the 3' side of U5 snRNA stem 1b (By similarity). Together with PSPC1, required for the formation of nuclear paraspeckles (By similarity). The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs (By similarity). The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1 (By similarity). 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 (By similarity). 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 (By similarity). NONO is involved in transcriptional regulation (By similarity). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity (By similarity). 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 (PubMed:15860628). 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 (By similarity).
Monomer and component of the SFPQ-NONO complex, which is probably a heterotetramer of two 52 kDa (NONO) and two 100 kDa (SFPQ) subunits. NONO is a component of spliceosome and U5.4/6 snRNP complexes (By similarity). 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. Part of complex consisting of SFPQ, NONO and MATR3. Part of a complex consisting of SFPQ, NONO and NR5A1. Part of a complex consisting of SFPQ, NONO and TOP1. Interacts with SPI1 and SPIB. Interacts with RNF43 (By similarity). Interacts with PER1 and PER2 (PubMed:15860628). 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. Interacts (via second RRM domain) with WASL; the interaction is direct. Component of a multiprotein complex with WASL and SFPQ (By similarity). Interacts with ERCC6 (By similarity). Interacts (via DNA-binding domain) with TET1 (By similarity).
Expressed abundantly in the testis. It is also found in the liver, lung and kidney.
Involved in the metabolism of neuropeptides under 20 amino acid residues long (PubMed:2261476). Involved in cytoplasmic peptide degradation. Able to degrade the amyloid-beta precursor protein and generate amyloidogenic fragments (By similarity). Also acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin, an antagonist peptide of the cannabinoid receptor CNR1 (PubMed:12500972, PubMed:18077343).
Component of the R2TP complex composed at least of RUVBL1, RUVBL2, RPAP3 and PIHD1 (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 (By similarity). Interacts with phosphorylated TELO2 and mediates interaction of TELO2 with the R2TP complex (By similarity). Interacts with phosphorylated ECD, EFTUD2/SNRP116, RPB1 and UBR5 and with RPB1 in a phosphorylation-independent manner (By similarity). Interacts with the core C/D box snoRNP particle components NOP58 and FBL and with RUVBL1/TIP49 (By similarity). Interacts with RPAP3 and DNAAF10 (By similarity). Interacts with histone H4 and with SWI/SNF complex member SMARCB1/SNF5 (By similarity). Interacts with the mTORC1 complex member RPTOR (By similarity). Interacts with MSL1 (By similarity).
Involved in the assembly of C/D box small nucleolar ribonucleoprotein (snoRNP) particles (By similarity). Recruits the SWI/SNF complex to the core promoter of rRNA genes and enhances pre-rRNA transcription (By similarity). Mediates interaction of TELO2 with the R2TP complex which is necessary for the stability of MTOR and SMG1 (By similarity). Positively regulates the assembly and activity of the mTORC1 complex (By similarity).
The N-terminal region is required for binding to phosphorylated substrates while the C-terminal region binds to the other R2TP complex components.
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.
ISGylated. Isgylation inhibits its interaction with VTA1 (By similarity).
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. ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4 (By similarity).
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. Interacts with CHMP2A. Interacts with VTA1; the interaction involves soluble CHMP5 (By similarity). Interacts with NOD2 (By similarity).
Component of the mitochondrial ribosome small subunit (28S) which comprises a 12S rRNA and about 30 distinct proteins (By similarity). Interacts with METTL17 (By similarity).
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. It methylates arsenite to form methylarsonate, Me-AsO(3)H(2), which is reduced by methylarsonate reductase to methylarsonite, Me-As(OH)2. Methylarsonite is also a substrate and it is converted into the much less toxic compound dimethylarsinate (cacodylate), Me(2)As(O)-OH.
Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4. Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain. Interacts with MYD88 and TIRAP via their respective TIR domains. Interacts with TICAM2. Interacts with NOX4. Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling. Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6. 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. Interacts with WDFY1 in response to LPS. Interacts with SMPDL3B. 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. Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation. 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 (By similarity). Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (By similarity).
Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate. 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(-) (By similarity). 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 (By similarity).
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.
Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.
The TIR domain mediates interaction with NOX4.
Activated by phosphatidic acid (By similarity). Inhibited by rolipram.
Expressed in epithelial cells. Isoform 33, isoform 4, isoform 5 and isoform 9 are expressed in brain. Isoform 33, isoform 5, isoform 8 and isoform 9 are expressed in heart (at protein level). Isoform 4 and isoform 6 are strongly expressed in cortex and cerebellum. Isoform 7 is strongly expressed in cortex and testis; weakly expressed in kidney, lung, spleen and cerebellum. Isoform 8 is strongly expressed in lung, heart and liver. Isoform 31, isoform 32, isoform 33, isoform 5 and isoform 9 are widely distributed.
Homodimer for the long isoforms. Isoforms with truncated N-termini are monomeric. Binds ARRB2. Isoform 33 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Interacts with PDE4DIP. Isoform 5 interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner. Isoform 33, isoform 4, isoform 7, isoform 8 and isoform 9 but not isoform 32 and isoform 6 interact with SHANK2. Isoform 31 interacts weakly with SHANK2.
Isoform 1 and isoform 9 are rapidly activated by PKA through phosphorylation. Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are also activated.
Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation.
Up-regulated by cAMP and follicle-stimulating hormone.
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 (PubMed:21653697).
Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunit GNAI3 (PubMed:21653697). Preferentially interacts with inactive rather than active GNAI3 (PubMed:21653697). Interaction with GNAI3 is inhibited when NUCB2 binds calcium, probably due to a conformational change which renders the GBA motif inaccessible (PubMed:21653697). 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.
Belongs to the NADPH-dependent diflavin oxidoreductase NDOR1 family.
Interacts with CIAPIN1; as part of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery.
NADPH-dependent reductase which is a central component of the cytosolic iron-sulfur (Fe-S) protein assembly (CIA) machinery. 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. In turn, this reduced cluster provides electrons for assembly of cytosolic iron-sulfur cluster proteins. It can also reduce the [2Fe-2S] cluster of CISD1 and activate this protein implicated in Fe/S cluster repair.
Kappa-casein stabilizes micelle formation, preventing casein precipitation in milk.
Asymmetric dimethylation at Arg-266 constitutes the major methylation site (PubMed:24098712). 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 (PubMed:24098712).
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. Forms hnRNP particles with at least 20 other different hnRNP and heterogeneous nuclear RNA in the nucleus (PubMed:19099192). 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:9578590, PubMed:10567417). Specifically binds single-stranded telomeric DNA sequences, protecting telomeric DNA repeat against endonuclease digestion (PubMed:15659580). 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. Involved in miRNA sorting into exosomes following sumoylation, possibly by binding (m6A)-containing pre-miRNAs. Acts as a regulator of efficiency of mRNA splicing, possibly by binding to m6A-containing pre-mRNAs. 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 (By similarity). Also plays a role in the activation of the innate immune response. Mechanistically, senses the presence of viral DNA in the nucleus, homodimerizes and is demethylated by JMJD6. In turn, translocates to the cytoplasm where it activates the TBK1-IRF3 pathway, leading to interferon alpha/beta production (By similarity).
Homodimer; dimerization is required for nucleocytoplasmic translocation. Identified in the spliceosome C complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with IGF2BP1. Interacts with C9orf72. Interacts with DGCR8. Interacts with TARDBP. Interacts with CKAP5. Interacts with TBK1. Interacts with STING1. Interacts with SRC (By similarity). Interacts with PPIA/CYPA (By similarity).
In the brain, isoform A2 and isoform B1 are abundant in large ganglion-type neurons, such as Purkinje cells, and are less abundant in neighboring glia cells. Isoform A2 is more abundant than isoform B1 in brain. In testis, isoform A2 and isoform B1 are present in spermatogonia and spermatocytes, but not in spermatids or sperm. Isoform A2 is more abundant in the adrenal medulla than in the cortical cells. Isoform B1 is found in both adrenal medulla and cortical cells. Isoform A2 is more abundant than isoform B1 in the adrenal gland. Isoform A2 and isoform B1 are both detected in pancreas and kidney, and at lower levels in heart and lung. Isoform B1 is more abundant than isoform A2 in heart, lung and intestine (at protein level). Isoform A2b and isoform B1b are testis-specific.
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.
Expressed during early postnatal brain development, especially in the caudate putamen and thalamic nuclei. Expression in the cerebral cortex, the hippocampus and the cerebellum is moderate to high at P5 and shows a stable expression throughout development. Isoforms 1, 2, 4 and 6 are predominantly expressed in cerebellum up to the age of approximately 3 weeks. Isoform 1 expression decreases during development of cortex but slightly increases in cerebellum.
Expressed in epithelial cells (at protein level). All isoforms except isoform 7 are expressed predominantly in brain, with highest levels in olfactory bulb, cerebral cortex, cerebellum, central gray matter and hippocampus. Moderate levels of expression are seen in the caudate putamen, thalamic nuclei and brain stem. In cerebellum primarily expressed in Purkinje cells. Isoform 7 is not expressed in brain but expressed in liver, cholangiocytes and thymus. Isoform 7 is present in pancreas, colonic mucosa and thymocytes (at protein level).
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 with ABI1 (via SH3 domain). Interacts (via proline-rich region) with PDE4D isoform 5 (via N-terminal region). Interacts with PDE4D isoform 33, isoform 4, isoform 7, isoform 8 and isoform 9 but not isoform 32 and isoform 6. Interacts weakly with PDE4D isoform 31. Interacts with ABI1.
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, SLC9A3 and CFTR.
May act as a GTPase-activating protein for Rab family protein(s).
Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.
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 T cells. May suppress inflammation-related signaling in asthmatic airway epithelium. May play a role in promoting prenatal immune suppression. Regulates RPS6KB1 signaling, which promotes endothelial cell senescence and inflammation and implicates NOS3/eNOS dysfunction. Can inhibit endothelial autophagy independently of its enzymatic activity implicating mTORC2 signaling. Involved in vascular smooth muscle cell senescence and apoptosis independently of its enzymatic activity.
Belongs to the WD repeat peroxin-7 family.
Belongs to the 6-phosphogluconate dehydrogenase family.
Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH.
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Acts as a GTPase-activating protein (GAP) for tubulin in concert with tubulin-specific chaperone C, but does not enhance tubulin heterodimerization.
Cell autonomous antagonist of the canonical Wnt signaling pathway.
The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.
Does not bind lactose, and may not bind carbohydrates.
Negatively regulates the Hedgehog (SHH) signaling. Binds to the promoter of the SHH signaling mediator, GLI1, and inhibits its expression.
Expressed in ameloblasts as they undergo post-secretory transition. Expression decreases as ameloblasts progress through maturation.
Highest expression in the mandible. Found in the basal lamina of maturation stage ameloblasts of incisors and unerupted molars. Also found in the internal basal lamina of junctional epithelium in molars.
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.
Appears in pancreatic juice after induction of pancreatic inflammation.
Bactericidal C-type lectin. Regulates keratinocyte proliferation and differentiation after skin injury via activation of EXTL3-PI3K-AKT signaling pathway (By similarity).
Lacks the EPN motif and the presence of Gln instead of Glu at amino-acid position 114 may explain its inability to bind peptidoglycan.
Low expression found in healthy pancreas.
Proteolytic processing by trypsin removes an inhibitory N-terminal propeptide and is essential for its antibacterial activity.
Monomer (PubMed:8513495, PubMed:1525821). Heterotrimer composed of RABGGTA, RABGGTB and CHM; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHM (component A) mediates Rab protein binding (PubMed:12620235). Can associate with the Rab GGTase dimer (RGGT or component B) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp). The CHM:RGGT:Rab complex is destabilized by GGpp (By similarity). Interacts with RAB1A, RAB1B, RAB7A and RAB27A and mediates their prenylation (PubMed:11389151, PubMed:12356470, PubMed:15186776, PubMed:8513495). Interacts with RAB5A (By similarity). Interacts with the non-phosphorylated forms of RAB3A, RAB3B, RAB3C, RAB3D, RAB5B, RAB5C RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (By similarity).
Most abundant in the heart, brain, and spleen. Lower levels seen in the lung, liver, muscle and kidney. Extremely low levels seen in the testis.
Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B composed of RABGGTA and RABGGTB, and remains bound to it after the geranylgeranyl transfer reaction. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Besides, a pre-formed complex consisting of CHM and the Rab GGTase dimer (RGGT or component B) can bind to and prenylate Rab proteins; this alternative pathway is proposed to be the predominant pathway for Rab protein geranylgeranylation.
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 (By similarity).
Homodimer. 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 BLOC1S4, BLOC1S5, DTNBP1/BLOC1S7, F-actin, SNAP25 isoform 1 and isoform 2, SNAP47 and STX12 (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.
Arachidonate 12-lipoxygenase activity is decreased when the pH decreases from 7.4 to 6.0.
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:23382512). Shows increasing catalytic activity within the series arachidonic acid < 5,8,11-eicosatrienoic acid < linoleic acid < 8,11,14-eicosatrienoic acid (By similarity).
Expressed in the cerebral cortex, cerebellum and whole brain.
Involved in the biosynthesis of L2/HNK-1 carbohydrate epitope on both glycolipids and glycoproteins. Substrates include asialo-orosomucoid (ASOR), paragloboside (lacto-N-neotetraosylceramide), Gal-beta-1,4-GlcNAc-beta-1,3-Gal-beta-1,4-Glc-pyridylamine and Gal-beta-1,3-GlcNAc-beta-1,3-Gal-beta-1,4-Glc-pyridylamine.
Regulates (in vitro) the inhibition of rhodopsin phosphorylation in a calcium-dependent manner.
Chaperone protein which promotes assembly of the 20S proteasome as part of a heterodimer with PSMG2. The PSMG1-PSMG2 heterodimer binds to the PSMA5 and PSMA7 proteasome subunits, promotes assembly of the proteasome alpha subunits into the heteroheptameric alpha ring and prevents alpha ring dimerization.
Forms a heterodimer with PSMG2. The PSMG1-PSMG2 heterodimer interacts directly with the PSMA5 and PSMA7 proteasome alpha subunits.
Appears to be involved in myelination. Could also participate in ion transport events as addition of plasmolipin to lipid bilayers induces the formation of ion channels, which are voltage-dependent and K(+)-selective.
Expression restricted to the sciatic nerve, brain and kidney. In the sciatic nerve, found in Schwann cells; in the brain, in developing oligodendrocytes, especially of the corpus callosum, of cortical white matter, in the optic nerve and in the stratum radiatum and stratum oriens of the hippocampus. In kidney, segregated to the apical surface of renal tubular epithelia.
Hexamer arranged as a trimer of two plasmolipin subunits.
In the sciatic nerve, first detected at postnatal day P4, increases to a maximum at day P14 and then declines to moderate levels in adulthood. In the brain, onset of expression is at day P1, levels increase to reach a maximum at P20 and decline slightly to adulthood.
The RNA gate region regulates mRNA cap recognition to prevent promiscuous mRNA-binding before assembly of eif3d into the full eukaryotic translation initiation factor 3 (eIF-3) complex.
mRNA cap-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, a complex required for several steps in the initiation of protein synthesis of a specialized repertoire of mRNAs. 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. In the eIF-3 complex, EIF3D specifically recognizes and binds the 7-methylguanosine cap of a subset of mRNAs.
Expressed in the mesenchymal cells surrounding the Muellerian duct at embryonic days 14, 15, and 16 and in tubular and follicular structures of the fetal gonads.
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 anti-Muellerian hormone.
Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space.
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space.
Interacts with KDM5B (By similarity). Interacts with GRG6/TLE6 (By similarity). Interacts with TLE1; the interaction is inhibited by interaction with TLE6/GRG6 (By similarity).
Is expressed in the cortex, olfactory bulb, hippocampus, and caudate putamen.
More abundant in fetal brain compared with the adult brain.
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.
May play a role in innate immunity in mouth, nose and lungs. Binds bacterial lipopolysaccharide (LPS) and modulates the cellular responses to LPS (By similarity).
Belongs to the nucleoporin Nup84/Nup107 family.
Functions as a component of the nuclear pore complex (NPC).
Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation, acting at both pre- and postsynaptic level.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Participates in the formation of novel hepoxilin regioisomers.
Yb subclass selectively binds steroid hormones.
Homooligomer. Interacts with GORAB. Interacts with COPA, COPB1 and COPB2. Interacts with AP2B1 (By similarity).
Regulates COPI-mediated retrograde protein traffic at the interface between the Golgi apparatus and the endoplasmic reticulum. Involved in the maintenance of the Golgi apparatus morphology. Has no detectable kinase activity in vitro.
Among the many cysteines in the lumenal domain, most are probably involved in disulfide bonds.
Belongs to the cyclic nucleotide phosphodiesterase family. PDE3 subfamily.
Binds 2 divalent metal cations per subunit.
Cyclic nucleotide phosphodiesterase with specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has also activity toward cUMP. 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.
Homodimer. 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.
Component of the large ribosomal subunit. May bind IPO9 with low affinity (By similarity). Interacts with RBM3 (PubMed:15684048).
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. 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. Binds vitamin E. May transport vitamin E in body fluids under conditions where the lipoprotein system is not sufficient. May be involved in the transport of vitamin E across the blood-brain barrier.
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). Palmitoleic acid is most likely not the physiological ligand. Instead, this pocket may accomodate the covalently bound lipid moiety of Wnt family members.
Acts on GalNAc. Also acts as a galactokinase when galactose is present at high concentrations (By similarity).
Belongs to the GHMP kinase family. GalK subfamily.
Detected in brain and kidney (at protein level).
Homodimer (By similarity). Interacts with GRID2IP (By similarity). Interacts with EMB; interaction mediates SLC16A7 targeting to the plasma membrane (PubMed:15917240, PubMed:20695846). 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:10417314, PubMed:20695846). Dimerization is functionally required and both subunits work cooperatively in transporting substrate (By similarity).
Transport activity exhibits steep dependence on substrate concentration. Substrate concentration sensitivity of SLC16A7 arises from the strong inter-subunit cooperativity of the SLC16A7 dimer during transport. Inhibited by AR-C155858.
Binds cytoplasmic tail of integrin alpha-1. Interacts with MED15/ARC105; this interaction leads to MED15 ubiquitination and proteasomal degradation. Interacts with the HN peptide. Interacts with PHOX2B. Interacts with PAX6.
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.
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. They are also involved in MED15-binding.
Induces a potassium channel when expressed in Xenopus oocytes.
Selectively present in the distal parts of the nephron (medullary and papillary collecting ducts and end portions of cortical collecting tubule) and in the epithelial cells of the distal colon. No expression is found in renal proximal tubule, loop of henle and distal tubule, proximal colon, small intestine, lung, choroid plexus, salivary glands, or brain.
Expression is induced by partial hepatectomy.
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 (By similarity).
Belongs to the ubiquitin-activating E1 family. ULA1 subfamily.
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.
May have a protective function during conditions of oxidative stress. May be involved in intracellular oxygen storage or transfer. Plays a role in the development of liver fibrosis. Has a peroxidase activity.
Expressed in lymphoid and non-lymphoid organs.
Functions as an inhibitory receptor that plays a constitutive negative regulatory role on cytolytic function of natural killer (NK) cells, B-cells and T-cells. Activation by Tyr phosphorylation results in recruitment and activation of the phosphatases PTPN6 and PTPN11. It also reduces the increase of intracellular calcium evoked by B-cell receptor ligation. May also play its inhibitory role independently of SH2-containing phosphatases. Modulates cytokine production in CD4+ T-cells, down-regulating IL2 and IFNG production while inducing secretion of transforming growth factor beta. Down-regulates also IgG and IgE production in B-cells as well as IL8, IL10 and TNF secretion. Inhibits proliferation and induces apoptosis in myeloid leukemia cell lines as well as prevents nuclear translocation of NF-kappa-B p65 subunit/RELA and phosphorylation of I-kappa-B alpha/CHUK in these cells. Inhibits the differentiation of peripheral blood precursors towards dendritic cells (By similarity).
ITIM (immunoreceptor tyrosine-based inhibitor motif) motif is a cytoplasmic motif present in 2 copies in the intracellular part of LAIR1. When phosphorylated, ITIM motif can bind the SH2 domain of several SH2-containing phosphatases, leading to down-regulation of cell activation.
Interacts with SH2 domains of tyrosine-protein phosphatases PTPN6 and PTPN11. The interaction with PTPN6 is constitutive. Interacts with the SH2 domain of CSK. Binds with high affinity to extracellular matrix collagens, the interaction is functionally important (By similarity).
Phosphorylation at Tyr-227 and Tyr-257 activates it. May be phosphorylated by LCK (By similarity).
Belongs to the Antp homeobox family. Proboscipedia subfamily.
Belongs to the bacterial ribosomal protein bL32 family.
Belongs to the NAD(P)H dehydrogenase (quinone) family.
The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinones involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.
Uses dihydronicotinamide riboside (NRH) rather than NAD(P)H as an electron donor.
Acts as an acyl-protein thioesterase that hydrolyzes fatty acids from acylated residues in proteins. Regulates the mitochondrial S-depalmitoylation of the nucleophilic active site residue of peroxiredoxin-5/PRDX5, a key antioxidant protein, therefore modulating mitochondrial antioxidant ability. Also catalyzes the deglucuronidation of mycophenolic acid acyl-glucuronide, an active metabolite of the immunosuppressant drug mycophenolate.
Homodimer. Binds GGA1, GGA2 and GGA3 (By similarity).
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 (By similarity).
Nitration of Tyr-451 is irreversible and interferes with normal dynein intracellular distribution.
Synthesizes selenophosphate from selenide and ATP.
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. Interacts with FBXW7; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN.
Phosphorylated by GSK3-beta which may promote its degradation. Phosphorylated by AURKA.
Positively regulates the transcription of MYCNOS in neuroblastoma cells.
Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to a cysteine at the fourth position from the C-terminus of proteins with the C-terminal sequence Cys-aliphatic-aliphatic-X. Known substrates include RAC1, RAC2, RAP1A and RAP1B.
Heterodimer of FNTA and PGGT1B. PGGT1B mediates interaction with substrate peptides.
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 (By similarity).
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 BLOC1S4, BLOC1S6, 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.
Expressed in liver, brown adipose tissue and heart (at protein level).
Homotetramer. Interacts with BNIP3 (By similarity).
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:16476568). Thereby, could be responsible for the production of acetate in a side reaction to beta-oxidation (Probable). Abolishes BNIP3-mediated apoptosis and mitochondrial damage (By similarity).
The 3-oxoacetyl-CoA thiolase activity is inhibited by acetyl-CoA while the acetyl-CoA hydrolase activity is inhibited by acetoacetyl-CoA.
Up-regulated in liver, brown adipose tissue, heart, intestine and kidney by DEHP/bis(2-ethylhexyl)phthalate (at protein level).
RAP domain is required for FASTKD3 function in mRNA stability and translation.
Required for normal mitochondrial respiration. Increases steady-state levels and half-lives of a subset of mature mitochondrial mRNAs MT-ND2, MT-ND3, MT-CYTB, MT-CO2, and MT-ATP8/6. Promotes MT-CO1 mRNA translation and increases mitochondrial complex IV assembly and activity.
DNA helicase that plays an important role in DNA replication, transcription and repair. Binds to the RNA polymerase II subunit POLR2A during transcription elongation and suppresses transcription-associated genomic instability. Associates also with POLR1A and enforces the stability of ribosomal DNA arrays. Plays an important role in mitotic chromosome separation after cross-over events and cell cycle progress. Mechanistically, removes RAD51 filaments protecting stalled replication forks at common fragile sites and stimulates MUS81-EME1 endonuclease leading to mitotic DNA synthesis. Required for efficient DNA repair, including repair of inter-strand cross-links. Stimulates DNA decatenation mediated by TOP2A. Prevents sister chromatid exchange and homologous recombination.
Monomer. Interacts with TOP2A, TOP3A and TOP3B. Interacts with RNA polymerase II subunit POLR2A. Identified in a complex with the RNA polymerase II core bound to DNA. Interacts with RAD51. Interacts with WRN; this interaction stimulates WRN helicase activity on DNA fork duplexes. Interacts with MUS1; this interaction promotes MUS81-dependent mitotic DNA synthesis.
Phosphorylated by CDK1 at Ser-728; this phosphorylation is required for RECQL5-mediated disruption of RAD51 filaments on stalled replication forks.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv11.2/KCNH6 sub-subfamily.
Highly expressed in celiac and superior mesenteric ganglia, but not detected in brain or in heart. Detected at low levels in retina. Also found in pituitary. Also found in the olfactory bulb (granular and mitral cell layers) (PubMed:11425889).
Pore-forming (alpha) subunit of voltage-gated potassium channel. Elicits a slowly activating, 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 KCNH2/ERG1 and KCNH7/ERG3.
The function of this enzyme is unclear as allantoicase activity is not known to exist in mammals.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRB3 sub-subfamily.
Heteropentamer, formed by a combination of alpha, beta, gamma, delta and rho chains (PubMed:2548852, PubMed:2540033, PubMed:9092594). Can form functional homopentamers (in vitro) (By similarity). Interacts with UBQLN1 (PubMed:11528422). May interact with KIF21B (PubMed:25172774). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (PubMed:28279354). Interacts with LHFPL4 (By similarity). Interacts with GIT1; this interaction is required for synaptic GABRB3 surface stability and inhibitory synapse strength (PubMed:25284783).
Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:2548852, PubMed:2540033). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA- gated ion channel (By similarity). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer (By similarity). The alpha1/beta3/gamma2 receptor exhibits 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). Plays an important role in somatosensation and in the production of antinociception (By similarity).
By bitter compounds denatonium and quinine.
Expressed in scattered solitary ovoid or bipolar cells among the oral epithelium from day 1-7, but with higher frequency in the soft palate as compared with the nasoincisor, circumvallate, and foliate papillae at day 1. During the second week, the solitary cells could no longer be recognized while cells expressing GNAT3 within the taste buds gradually increased. The onset of taste transduction accomplished by the palatal taste buds developed earlier than that achieved by taste buds in the circumvallate and foliate papillae.
Expressed in taste buds (sensory organs of clustered epithelial cells) of the circumvallate, foliate and fungiform papillae of the tongue, as well as in nasoincisor, palatal and epiglottal taste buds at protein level. Expressed in enteroendocrine of the gut, in the lumenal pole of a subset of brush cells lining the stomach and the intestine at protein level. Detected in solitary cells throughout the respiratory track. Expressed 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 for the prevention and treatment of malabsorption syndromes and diet-related disorders including diabetes and obesity.
Potential N-myristoylation may anchor alpha-subunit to the inner surface of plasma membrane.
Transgenic expression of GNAT3 restores responsiveness of GNAT3 deficient mice to both bitter and sweet compounds, whereas expression of mutated Gly-352 transgene do not. Furthermore, in wild-type mice, this mutated transgene acts as dominant-negative by inhibition of endogenous GNAT3 interactions with taste receptors.
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 (By similarity).
By thyroid hormones in hypothyroid animals.
Highly expressed in neonatal and adult ventricle and in brain. Highly expressed in the pyramidal layer in hippocampus, in anterior dorsal nucleus in thalamus, in the mammillary nucleus in hypothalamus, in red nucleus, in trigeminal mesencephalic, spinal and principal nuclei, in cochlear and trapezoid nuclei and in the dorsal tegemental nucleus.
Homotetramer. Heterotetramer with HCN1. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2 (By similarity).
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.
Phosphorylation at Ser-641 by PRKG2 shifts the voltage-dependence to more negative voltages, hence counteracting the stimulatory effect of cGMP on gating.
Belongs to the nucleoporin interacting component (NIC) family.
Part of the nuclear pore complex (NPC). Component of the p62 complex, a complex composed of NUP62 and NUP54. Forms a complex with NUP35, NUP155, NUP205 and lamin B; the interaction with NUP35 is direct. Does not interact with TPR. Interacts with SMAD4 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling.
Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. May anchor nucleoporins, but not NUP153 and TPR, to the NPC. During renal development, regulates podocyte migration and proliferation through SMAD4 signaling.
Expressed in the brain, heart, spleen, lung, liver, kidney and testis.
Mediates endoplasmic reticulum to Golgi transport (PubMed:10930451, PubMed:14742712, PubMed:9506515). 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 (PubMed:18167358).
Part of a ternary complex containing STX5A, NSFL1C and VCP (PubMed:9506515). Part of a unique SNARE complex composed of the Golgi SNAREs GOSR1, GOSR2 and YKT6. This complex also includes VTI1A (By similarity). Interacts with COG4 (By similarity). Interacts with GM130/GOLGA2 (PubMed:18167358). Interacts (via IxM motif) with SEC24C and SEC24D; mediates STX5 packaging into COPII-coated vesicles (By similarity). Interacts with VLDLR; this interaction mediates VLDLR translocation from the endoplasmic reticulum to the plasma membrane (By similarity).
Produced by alternative initiation at Met-55 of isoform 1.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK4 subfamily.
Expressed at embryonic day 15 in brain and spinal cord. At embryonic day 19 expression accumulates in the hippocampal formation. Prominent expression in the subicular cortex at postnatal days P1, P8 and P15 but then markedly reduced in the adult.
Forms a heteromeric channel with GRIK1 or GRIK3.
Strong expression in hippocampal CA3 pyramidal cells. Low expression in hippocampal dentate granule cells, in layers II, V and VI of the cortex, and in cerebellar Purkinje cells. No expression in the striatum, reticular thalamus, hypothalamus or amygdaloid complex.
Nervous system. Strongly expressed in brain, where it is predominant in neurons from cerebral cortex and thalamus (at protein level).
Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse. Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior.
Forms a water-specific channel (PubMed:7530250). Plays an important role in fluid secretion in salivary glands. Required for TRPV4 activation by hypotonicity. Together with TRPV4, controls regulatory volume decrease in salivary epithelial cells. Seems to play a redundant role in water transport in the eye, lung and in sweat glands (By similarity).
Homotetramer. Interacts with TRPV4; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity.
Salivary glands, lacrimal glands, corneal epithelium in eye, trachea and lung.
Interacts with SOCS7 (By similarity). Interacts (via IRS-type PTB domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY motif) (By similarity). Interacts with UBTF, FER and PIK3CA (By similarity). Interacts (via phosphorylated YXXM motifs) with PIK3R1 (PubMed:1380456). Interacts with ROCK1 (PubMed:11739394). Interacts (via PH domain) with PHIP (PubMed:11018022). Interacts with GRB2 (PubMed:8491186). Interacts with ALK (By similarity). Interacts with EIF2AK2/PKR (By similarity). Interacts with GKAP1 (PubMed:25586176). Interacts with DGKZ in the absence of insulin; insulin stimulation decreases this interaction (PubMed:27739494). 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 (By similarity).
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.
Serine phosphorylation of IRS1 is a mechanism for insulin resistance. Ser-307 phosphorylation inhibits insulin action through disruption of IRS1 interaction with the insulin receptor, and Ser-789 phosphorylation is increased in the liver of insulin-resistant rats (PubMed:11606564, PubMed:12006586, PubMed:7504175). Phosphorylation of Tyr-895 is required for GRB2-binding. Phosphorylated by ALK. Phosphorylated at Ser-265, Ser-302, Ser-632 and Ser-1100 by RPS6KB1; phosphorylation induces accelerated degradation of IRS1 (By similarity). Phosphorylated on tyrosine residues in response to insulin (By similarity). In skeletal muscles, dephosphorylated on Tyr-608 by TNS2 under anabolic conditions; dephosphorylation results in the proteasomal degradation of IRS1 (By similarity).
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).
Plays a role in the biomineralization of teeth. 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.
Several forms are produced by C-terminal processing.
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 (By similarity).
Downstream effector molecule involved in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Promotes formation of actin filaments. Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex (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 (By similarity).
Heterohexamer (Probable). Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8C, LRRC8D and/or LRRC8B) to form a heterohexamer (PubMed:28833202). Detected in a channel complex that contains LRRC8A, LRRC8C and LRRC8E (By similarity). 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:28833202). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (By similarity). Mediates efflux of amino acids, such as aspartate, in response to osmotic stress (By similarity). The VRAC channel also mediates transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (By similarity). 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:28833202). 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 (By similarity).
Catalyzes the 2-hydroxylation of racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA (PubMed:10588950, PubMed:10744784). Shows activity also towards 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) (By similarity). Does not hydroxylate long and very long straight chain acyl-CoAs or 2-methyl-and 4-methyl-branched acyl-CoAs (By similarity).
Interacts specifically with FKBP52 and PHYHIP.
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.
Heterohexamer. Oligomerizes with other LRRC8 proteins (LRRC8A, LRRC8B, LRRC8C and/or LRRC8E) to form a heterohexamer. In vivo, the subunit composition may depend primarily on expression levels, and heterooligomeric channels containing various proportions of the different LRRC8 proteins may coexist.
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:28833202). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (By similarity). Plays a redundant role in the efflux of amino acids, such as aspartate, in response to osmotic stress (By similarity). 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:28833202). Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion (By similarity). VRAC channels containing LRRC8D inhibit transport of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol (By similarity).
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:32165585). 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:32165585).
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:32165585). 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:32165585). 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:32165585). Interacts with the V0 complex V-ATPase subunit a4 ATP6V0A4 (By similarity). Interacts with LASS2 (By similarity). Interacts with RNF182; this interaction leads to ubiquitination and degradation via the proteasome pathway (By similarity).
Homohexamer. Interacts with TOR1AIP1 (By similarity).
Aminocarboxypropyltransferase that catalyzes the aminocarboxypropyl transfer on pseudouridine at position 1248 (Psi1248) in 18S rRNA. It constitutes the last step in biosynthesis of the hypermodified N1-methyl-N3-(3-amino-3-carboxypropyl) pseudouridine (m1acp3-Psi) conserved in eukaryotic 18S rRNA.
Belongs to the TDD superfamily. TSR3 family.
Contains a PDZ-binding motif at positions 767-770.
Expressed in brain, detected at high levels in hippocampal CA1 (at protein level).
Expression increases in prefrontal cortex from 6 months to, at least, 39 months.
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:25498153). In neurons, is involved in dendritic spine formation and synaptic plasticity in a specific RAC1-GAP activity (PubMed:25498153). 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 (PubMed:25498153). In association with SHANK3, promotes GRIA1 exocytosis from recycling endosomes and spine morphological changes associated to long-term potentiation (By similarity).
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 (By similarity).
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 (PubMed:25498153).
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.
Heterohexamer; possibly composed of 3 copies of TIMM8B and 3 copies of TIMM13, named soluble 70 kDa complex. Associates with the TIM22 complex, whose core is composed of TIMM22 (By similarity).
Probable mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space (By similarity).
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM8B from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. KIF27 subfamily.
Plays an essential role in motile ciliogenesis.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (PubMed:26582389). Interacts with BIRC6/bruce (By similarity). Interacts with MYRIP. Interacts with SH3BP1; required for the localization of both SH3BP1 and the exocyst to the leading edge of migrating cells (By similarity). Interacts with SLC6A9 (PubMed:16181645).
The functional 150 kDa pyruvate import complex is a heteromer of MPC1 and MPC2.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type C (BoNT/C), which hydrolyzes the 253-Lys-|-Ala-254 bond (PubMed:7737992). Cleavage inhibits neurotransmitter release (PubMed:7901002).
Expressed predominantly in cerebral cortex, hippocampus, cerebellum, adrenal medulla and retina with weak expression detected in non-neuronal tissues.
Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A; this complex constitutes the basic catalytic machinery of the complex neurotransmitter release apparatus (PubMed:14665625, PubMed:16888141, PubMed:19196426, PubMed:9759724, PubMed:11533035, PubMed:11832227, PubMed:12496247, PubMed:19571812, PubMed:28813412, PubMed:18337752, PubMed:21785414, PubMed:26280336). The SNARE complex interacts with CPLX1 (PubMed:21785414, PubMed:28813412). Interacts with STXBP1 (PubMed:10746715, PubMed:12730201, PubMed:18337752). Interacts (via C-terminus) with KCNB1 (via C-terminus); the interaction increases in a calcium-dependent manner and induces a pore-independent enhancement of exocytosis in neuroendocrine cells, chromaffin cells, pancreatic beta cells and from the soma of dorsal root ganglia (DRG) neurons (PubMed:17301173, PubMed:18167541, PubMed:20484665, PubMed:22411134). Interacts with SYTL4 (By similarity). Interacts with STXBP6 (PubMed:12145319). Interacts with PLCL1 (via C2 domain) (PubMed:23341457). Interacts with OTOF (By similarity). Interacts with LGI3 (By similarity). Interacts with SLC6A4 (PubMed:11709063). Interacts with SYT6 and SYT8; the interaction is Ca(2+)-dependent (By similarity). Interacts with VAMP8 (PubMed:10336434). Interacts with SNAP23 (PubMed:9507000). Interacts with VAPA and SYBU (By similarity). Interacts with PRRT2 (By similarity). Interacts with SEPT8 (PubMed:19196426). Interacts with STXBP5L (By similarity). Interacts with synaptotagmin-1/SYT1 (PubMed:26280336, PubMed:28813412). Interacts with SEPTIN5; in the cerebellar cortex (By similarity). Interacts with SEPTIN4; in the striatum (By similarity).
Phosphorylated by CK2 (By similarity). Phosphorylation at Ser-188 by DAPK1 significantly decreases its interaction with STXBP1 (By similarity).
Phosphorylated by CK2. Phosphorylation at Ser-188 by DAPK1 significantly decreases its interaction with STXBP1.
Plays an essential role in hormone and neurotransmitter calcium-dependent exocytosis and endocytosis (PubMed:7901002, PubMed:17301173, PubMed:18167541, PubMed:20484665, PubMed:22411134, PubMed:28813412). Part of the SNARE (Soluble NSF Attachment Receptor) complex composed of SNAP25, STX1A and VAMP2 which mediates the fusion of synaptic vesicles with the presynaptic plasma membrane (PubMed:14665625, PubMed:16888141, PubMed:19571812). STX1A and SNAP25 are localized on the plasma membrane while VAMP2 resides in synaptic vesicles. The pairing of the three SNAREs from the N-terminal SNARE motifs to the C-terminal anchors leads to the formation of the SNARE complex, which brings membranes into close proximity and results in final fusion (PubMed:14665625, PubMed:16888141, PubMed:19571812). Participates in the calcium-dependent regulation of acrosomal exocytosis in sperm (By similarity). Also plays an important role in the exocytosis of hormones such as insulin or glucagon-like peptide 1 (GLP-1) (By similarity).
Sumoylated, sumoylation is required for regulation of synaptic vesicle endocytosis.
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.
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.
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 (By similarity).
Tetramer composed of two catalytic chains (alpha and beta), and two inhibitory chains (gamma).
The C-terminal region is important in conferring inhibition.
Expressed in pancreas. In the CNS, highly expressed in the SCN, internal granular layer of granular cells of the olfactory bulb, tuberculum olfactorium, piriform cortex, gyrus dentatus of the hippocampus, cerebellum, pars tuberalis/median eminence, and pituitary, and moderately in the tenia tecta, caudate putamen, accumbens nucleus, spinal cord, superior and inferior colliculus and pineal gland.
Homodimer (By similarity). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with TIMELESS, PER2, PER3, CRY1 and CRY2 (By similarity). Interacts with BMAL1 and CLOCK (By similarity). Interacts with GPRASP1 (PubMed:11597585). Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation (By similarity). Interacts with NONO and WDR5 (PubMed:15860628). Interacts with SFPQ (By similarity). Interacts with USP2 (By similarity). Interacts with HNF4A (By similarity).
In pancreas, expression exhibits a circadian rhythm in the presence of light/dark cycles.
Phosphorylated on serine residues by CSNK1D, CSNK1E and probably also by CSNK1G2. Phosphorylation by CSNK1D or CSNK1E promotes nuclear location of PER proteins as well as ubiquitination and subsequent degradation. May be dephosphorylated by PP1.
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Regulates circadian target genes expression at post-transcriptional levels, but may not be required for the repression at transcriptional level. Controls PER2 protein decay. Represses CRY2 preventing its repression on CLOCK/BMAL1 target genes such as FXYD5 and SCNN1A in kidney and PPARA in liver. Besides its involvement in the maintenance of the circadian clock, has an important function in the regulation of several processes. Participates in the repression of glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) by BMAL1:CLOCK. Plays a role in the modulation of the neuroinflammatory state via the regulation of inflammatory mediators release, such as CCL2 and IL6. In spinal astrocytes, negatively regulates the MAPK14/p38 and MAPK8/JNK MAPK cascades as well as the subsequent activation of NFkappaB. Coordinately regulates the expression of multiple genes that are involved in the regulation of renal sodium reabsorption. Can act as gene expression activator in a gene and tissue specific manner, in kidney enhances WNK1 and SLC12A3 expression in collaboration with CLOCK. Modulates hair follicle cycling. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1.
Ubiquitinated; requires phosphorylation by CSNK1E and interaction with BTRC and FBXW11. Deubiquitinated by USP2.
Identified in the spliceosome C complex. Interacts with CCNDBP1.
Involved in pre-mRNA splicing as component of the spliceosome.
Expressed in vascular smooth muscle cells.
NOX1, NOXA1, NOXO1, RAC1 and CYBA forms a functional multimeric complex supporting ROS production. Interacts with NOXA1 and NOXO1 (By similarity).
Pyridine nucleotide-dependent oxidoreductase that generates superoxide and might conduct H(+) ions as part of its electron transport mechanism.
The oxidase activity is potentiated by NOXA1 and NOXO1.
High in liver, also detected in heart, lung, kidney, spleen and intestine.
Mitochondrial carbonic anhydrase that catalyzes the reversible conversion of carbon dioxide to bicarbonate/HCO3 (PubMed:7937950). 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 (By similarity).
Belongs to the G-protein coupled receptor 1 family. Endothelin receptor subfamily. EDNRA sub-subfamily.
Predominantly expressed in vascular smooth muscle cells of a variety of issues, bronchial smooth muscle cells, myocardium, and the pituitary gland.
Receptor for endothelin-1. Mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of binding affinities for ET-A is: ET1 > ET2 >> ET3.
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 (By similarity).
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. Has transcription repressor activity in vitro (By similarity).
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. 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. Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1.
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.
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).
Phosphorylation at Ser-8 by AMPK inactivates the enzyme activity. 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. Phosphorylated at Ser-641 by PASK, leading to inactivation; phosphorylation by PASK is inhibited by glycogen. Phosphorylated at Ser-641 by DYRK2, leading to inactivation. Dephosphorylation at Ser-641 and Ser-645 by PP1 activates the enzyme (By similarity).
Interacts with BRD3. Interacts with AR and CCAR1.
Transcriptional activator which regulates endothelin-1 gene expression in endothelial cells. Binds to the consensus sequence 5'-AGATAG-3' (By similarity). Plays an important role in the regulation of phagocytosis in alveolar macrophages, particularly during P.carinii infection.
Amino acid transport activity is increased by sodium. Transport of L-glutamine, leucine and tyrosine is increased by arginine binding.
Associated component of the Ragulator complex (composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5). 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. Interacts with TM4SF5. Interacts with NPC1; this interaction inhibits cholesterol-mediated mTORC1 activation via its sterol transport activity.
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. 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. Following activation by amino acids, the Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. SLC38A9 mediates transport of amino acids with low capacity and specificity with a slight preference for polar amino acids. Acts as an arginine sensor. 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. The transport is most active at acidic pH. Can disassemble the lysosomal folliculin complex (LFC), and thereby triggers GAP activity of FLCN:FNIP2 toward RRAGC. Acts as an cholesterol sensor that conveys increases in lysosomal cholesterol, leading to lysosomal recruitment and activation of mTORC1 via the Rag GTPases. 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.
The cytosolic N-terminus part of the protein mediates interaction with the Ragulator complex. The cytosolic N-terminus part of the protein destabilizes the LFC and thereby triggers GAP activity of FLCN:FNIP2 toward RRAGC. 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 (By similarity). 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).
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 target proteins (By similarity).
Interacts with the ATP-binding domain of HSPA1A. Detected in a ternary complex containing STUB1, HSPA1A and HSPBP1 (By similarity). Interacts with PGLYRP1; this interaction blocks the cytotoxic activity of the PGLYRP1-HSPA1A complex (By similarity).
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. 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). 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. 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 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 (By similarity). 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 (By similarity). 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 (By similarity).
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 phosphorylated HERC2 (via C-terminus). Interacts with PIWIL1; leading to sequester RNF8 in the cytoplasm. Interacts with WRAP53/TCAB1.
The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and phosphorylated HERC2 (By similarity). This domain is also required for proper recruitment to DNA damage sites after UV irradiation, ionizing radiation, or treatment with an alkylating agent (By similarity).
Found in a complex with p53/TP53 and CABLES1.
Participates in the apoptotic response to DNA damage. Isoforms containing the transactivation domain are pro-apoptotic, isoforms lacking the domain are anti-apoptotic and block the function of p53 and transactivating p73 isoforms. May be a tumor suppressor protein.
Expressed in the central nervous system except in the cerebellum. Enriched within the striatum relative to other brain areas.
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-49 by PKA deactivates PTPN5. Phosphorylation at Thr-59 and Ser-72 by MAPKs stabilizes the phosphatase, dephosphorylation of these sites results in ubiquitin-mediated degradation of the active phosphatase (By similarity).
Component of the VBC (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 VBC 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 (By similarity). Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with LIMD1 (via LIM zinc-binding 2). Interacts with AJUBA (via LIM domains) and WTIP (via LIM domains) (By similarity). Interacts with EPAS1. Interacts with CARD9 (PubMed:17936701). 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 (By similarity). Interacts with ALAS1 (hydroxylated form) (By similarity).
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 (By similarity).
Activation requires multiple phosphorylation events on serine/threonine residues. Activation appears to be first mediated by phosphorylation of multiple sites in the autoinhibitory domain, which facilitates phosphorylation at Thr-412, disrupting the autoinhibitory mechanism and allowing phosphorylation of Thr-252 by PDPK1. The active conformation of the kinase is believed to be stabilized by a mechanism involving three conserved phosphorylation sites located in the kinase domain activation loop (Thr-252) and in the AGC-kinase C-terminal domain (Ser-394 in the middle of the tail/linker region and Thr-412 within a hydrophobic motif at its end). Activated by mTORC1; isoform Alpha I and isoform Alpha II are sensitive to rapamycin, which inhibits activating phosphorylation at Thr-412. Activated by PDPK1 (By similarity).
Dephosphorylation by PPP1CC at Thr-412 in mitochondrion (By similarity). Phosphorylation at Thr-412 is regulated by mTORC1. The phosphorylation at this site is maintained by an agonist-dependent autophosphorylation mechanism. Activated by phosphorylation at Thr-252 by PDPK1.
Interacts with PPP1R9A/neurabin-1 (PubMed:9653190). Interacts with RPTOR (PubMed:11967149, PubMed:12604610). Interacts with IRS1 (By similarity). Interacts with EIF3B and EIF3C (By similarity). Interacts with POLDIP3 (By similarity). Interacts with TRAF4 (By similarity). Interacts (via N-terminus) with IER5 (By similarity).
Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial RMP leading to dissociation of a RMP:PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR (By similarity) (PubMed:8524831). Following activation by mTORC1, phosphorylates EPRS and thereby plays a key role in fatty acid uptake by adipocytes and also most probably in interferon-gamma-induced translation inhibition (PubMed:28178239).
The TOS (TOR signaling) motif is essential for activation by mTORC1.
The autoinhibitory domain is believed to block phosphorylation within the AGC-kinase C-terminal domain and the activation loop.
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 (By similarity).
Essential for cell viability. TAF9 and TAF9L 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 (By similarity).
Belongs to the eukaryotic ribosomal protein eL20 family.
Component of the large ribosomal subunit. Binds IPO9 with high affinity.
Homodimer (By similarity). Interacts (via N-terminus) with MYO5A, the interaction is required for its role in dendrite formation (PubMed:19812310). Interacts with RAC1 (PubMed:19812310). Interacts with RAB8A; interaction is dependent on the phosphorylation of RAB8A on 'Thr-72' (By similarity). Interacts with RAB10 and RAB12; interaction is dependent on the phosphorylation of 'Thr-73' on RAB10 and 'Ser-105' on RAB12 (By similarity).
Involved in cell shape and neuronal morphogenesis, positively regulating the establishment and maintenance of dendritic spines (PubMed:19812310). Plays a role in cellular protein transport, including protein transport away from primary cilia (By similarity). May function via activation of RAC1 and PAK1 (PubMed:19812310).
Expressed in heart, brain, kidney, stomach, small intestine and lung. Not expressed in spleen, thymus, skeletal muscle, testis and skin.
Inositol 5-phosphatase, which converts inositol 1,4,5-trisphosphate to inositol 1,4-bisphosphate. Also converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate and inositol 1,3,4,5-tetrakisphosphate to inositol 1,3,4-trisphosphate in vitro. May be involved in modulation of the function of inositol and phosphatidylinositol polyphosphate-binding proteins that are present at membranes ruffles.
The 5 Arg-Ser-Xaa-Ser-Xaa-Xaa (RSXSXX) motifs may constitute binding sites for the 14-3-3 protein.
As a subunit of eukaryotic initiation factor 2 (eIF-2), involved in the early steps of protein synthesis. In the presence of GTP, eIF-2 forms a ternary complex with initiator tRNA Met-tRNAi and then recruits the 40S ribosomal complex and initiation factors eIF-1, eIF-1A and eIF-3 to form the 43S pre-initiation complex (43S PIC), a step that determines the rate of protein translation. The 43S PIC binds to mRNA and scans downstream to the initiation codon, where it forms a 48S initiation complex by codon-anticodon base pairing. This leads to the displacement of eIF-1 to allow GTPase-activating protein (GAP) eIF-5-mediated hydrolysis of eIF2-bound GTP. Hydrolysis of GTP and release of Pi, which makes GTP hydrolysis irreversible, causes the release of the eIF-2-GDP binary complex from the 40S subunit, an event that is essential for the subsequent joining of the 60S ribosomal subunit to form an elongation-competent 80S ribosome. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must be exchanged with GTP by way of a reaction catalyzed by GDP-GTP exchange factor (GEF) eIF-2B (By similarity). Along with its paralog on chromosome X, may contribute to spermatogenesis up to the round spermatid stage (By similarity).
Histone methyltransferase that sequentially mono-, di-, and tri-methylates both 'Lys-4' (H3K4) and 'Lys-36' (H3K36) of histone H3 to produce respectively trimethylated 'Lys-4' (H3K4me3) and trimethylated 'Lys-36' (H3K36me3) histone H3 and plays a key role in meiotic prophase by determining hotspot localization thereby promoting meiotic recombination. Can also methylate all four core histones with H3 being the best substrate and the most highly modified. 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. 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. Thereby promotes double-stranded breaks (DSB) formation, at this subset of PRDM9-binding sites, that initiates meiotic recombination for the proper meiotic progression. 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. In this way, controls the DSB repair pathway, pairing of homologous chromosomes and sex body formation. 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. In addition performs automethylation. Acetylation and phosphorylation of histone H3 attenuate or prevent histone H3 methylation.
Homodimer. 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.
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-372 and Lys-378. Lysines can be simultaneously methylated, such as Lys-372(me3)/Lys-376(me1), Lys-372(me1)/Lys-378(me1) and Lys-372(me1)/Lys-376(me1)/Lys-378(me1). Automethylation is an intramolecular (cis) process.
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.
Following injection with puromycin which induces nephrosis, down-regulated by 40% 3 days post-injection and by 80% at day 10. Also down-regulated by HgCl2 with rapid decrease at day 3.
Interacts with NPHS2 and with CD2AP (via C-terminal domain). 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 (By similarity). Interacts with MAGI1 (via PDZ 2 and 3 domains) forming a tripartite complex with IGSF5/JAM4. Interacts with DDN; the interaction is direct. Forms a complex with ACTN4, CASK, IQGAP1, MAGI2, SPTAN1 and SPTBN1. Interacts with phosphatidylinositol 3-kinase regulatory subunit PIK3R1; the interaction is reduced by high glucose levels (By similarity).
Phosphorylated at Tyr-1204 by FYN, leading to the recruitment and activation of phospholipase C-gamma-1/PLCG1 (PubMed:19179337). Tyrosine phosphorylation is reduced by high glucose levels (By similarity). Dephosphorylated by tensin TNS2 which leads to reduced binding of NPHN1 to PIK3R1 (By similarity).
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.
Strongly expressed in the podocytes of kidney glomeruli (at protein level) and at lower levels in the spleen.
Binds promoter DNA and regulates initiation of transcription. Required for normal mitochondrial transcription and translation, and for normal assembly of mitochondrial respiratory complexes. Required for normal mitochondrial function. 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 (By similarity).
In keratinocytes, by wounding or contact with collagen.
Belongs to the eukaryotic ribosomal protein eS4 family.
Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis.
Isoform B is expressed in kidney, liver, lung, ovary, spleen and uterus. Increased level in uterus during gestation (PubMed:8772180). Isoform A and isoform C are predominantly expressed in cerebral microvessels and choroid plexus, with lower levels in cortex, cerebellum and hypothalamus but also liver and lung (PubMed:11861497). Isoform F is expressed at high levels in brain, liver and spleen and less in stomach, kidney, thymus, heart, lung and hypothalamus (PubMed:11861497, PubMed:8772180).
May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis (PubMed:10698121). Does not induce phosphorylation of and activate STAT3 (By similarity).
On ligand binding, phosphorylated on two conserved C-terminal tyrosine residues (isoform B only) by JAK2. Tyr-985 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-1138 is required for STAT3 binding/activation. Phosphorylation of Tyr-1077 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). Interaction with SOCS3 inhibits JAK/STAT signaling and MAPK cascade (By similarity).
Receptor for hormone LEP/leptin (Probable). 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 (PubMed:8690163). 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 (By similarity). 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-cells. Leptin increases Th1 and suppresses Th2 cytokine production (By similarity).
The fatty (Fa) mutation produces profound obesity of early onset caused by hyperphagia, defective non-shivering thermogenesis, and preferential deposition of energy into adipose tissue.
Most prominently found in the gastrointestinal tract, skin, lung, and brain but not in liver.
Male-specific expression in proximal caput of the epididymis.
Secreted proximal epididymal protein required for post-testicular sperm maturation and male fertility. May be involved in sperm adhesion to the egg zona pellucida. Does not have ribonuclease activity (By similarity).
The N-terminus is blocked. Glycosylated (By similarity).
Expressed in the brain (at protein level) (PubMed:23011729). Expressed in the brain, liver, kidney, spleen, heart, lung and sciatic nerve (PubMed:7514426).
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 (By similarity). Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation (PubMed:23576431). Through binding with PLEKHM2 and ARL8B, directs lysosome movement toward microtubule plus ends. 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 (By similarity).
Oligomer composed of two heavy chains and two light chains. Interacts with GRIP1 and PPP1R42 (By similarity). Interacts with SYBU. Interacts with JAKMIP1. Interacts with PLEKHM2. Interacts with ECPAS (By similarity). 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).
Homomer. Forms heteromers with ACKR4 (By similarity).
Receptor for the C-X-C chemokine CXCL9, CXCL10 and CXCL11 and mediates the proliferation, survival and angiogenic activity of mesangial cells through a heterotrimeric G-protein signaling pathway. Binds to CCL21. Probably promotes cell chemotaxis response (By similarity).
Sulfation on Tyr-27 and Tyr-29 is essential for CXCL10 binding.
Acetylates the free alpha-amino group of cysteine S-conjugates to form mercapturic acids. 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. May also regulate amyloid beta-peptide secretion through acetylation of BACE1 and the regulation of its expression in neurons (By similarity).
Interacts with PROM1. Interacts with BACE1 (By similarity).
Galectin that binds lactose and a related range of sugars.
Highly expressed in full-length form in small and large intestine and stomach but was not detected in other tissues including lung, liver, kidney and spleen.
Forms homomultimers (PubMed:23723986). Multimerization appears to be important for presynaptic targeting (PubMed:23723986). Interacts with BSN (By similarity).
Highest levels in brain with lower levels in testis. Weakly expressed in heart, spleen and liver. In the hippocampal CA3 region, localizes to mossy fiber terminals but is absent from inhibitory nerve terminals. Localizes to inhibitory terminals throughout the cerebellar cortex (at protein level) (PubMed:17869247). Expressed in the calyx of Held (PubMed:26212709).
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.
Constitutively expressed in the adult hippocampus.
In the developing hippocampus, expression is high at P8, then decreased along with hippocampal development.
Isoform 1 and isoform 2 encode coiled-coil structures that mediate homo- and heteromultimerization. Interacts with NFATC2; interaction is reduced by AKT activation. Interacts with NFATC1 and NFATC4 (By similarity). Interacts with DAGLA (via PPXXF motif); this interaction is required for the cell membrane localization of DAGLA (Probable).
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. Required for normal hearing (By similarity). Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA (By similarity).
Inhibited by the toxins okadaic acid, tautomycin and microcystin Leu-Arg. The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress (By similarity).
PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. The targeting or regulatory subunits determine the substrate specificity of PP1. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with PPP1R7 and PPP1R12C. Interacts with PPP1R16B. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with PPP1R12A and NUAK1; the interaction is direct. Interacts with TRIM28; the interaction is weak. Interacts with FOXP3. Interacts with RRP1B. Interacts with SERPINE1. Interacts with LZTR1 (By similarity).
Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase (PP1) is essential for cell division, it participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E (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.
The PX domain mediates interaction with membranes enriched in phosphatidylinositol 3-phosphate.
Belongs to the ELO family. ELOVL7 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 with higher activity toward C18 acyl-CoAs, especially C18:3(n-3) acyl-CoAs and C18:3(n-6)-CoAs. Also active toward C20:4-, C18:0-, C18:1-, C18:2- and C16:0-CoAs, and weakly toward C20:0-CoA. Little or no activity toward C22:0-, C24:0-, or C26:0-CoAs. May participate in the production of saturated and polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
Efficient DNA binding requires dimerization with another bHLH protein. Heterodimer; forms a heterodimer with ARNT, ARNT2 or BMAL1.
Expression is regulated by neuronal activity (PubMed:18815592). Induced in excitatory neurons specifically upon calcium influx (PubMed:18815592). Induced in the lateral nucleus of the amygdala in a learning-dependent manner (at protein level) (PubMed:21887312).
Specifically expressed in neurons (PubMed:18815592). Expressed in the lateral nucleus of the amygdala (at protein level) (PubMed:21887312).
Transcription factor expressed in neurons of the brain that regulates the excitatory-inhibitory balance within neural circuits and is required for contextual memory in the hippocampus (By similarity). Plays a key role in the structural and functional plasticity of neurons (By similarity). Acts as an early-response transcription factor in both excitatory and inhibitory neurons, where it induces distinct but overlapping sets of late-response genes in these two types of neurons, allowing the synapses that form on inhibitory and excitatory neurons to be modified by neuronal activity in a manner specific to their function within a circuit, thereby facilitating appropriate circuit responses to sensory experience (By similarity). In excitatory neurons, activates transcription of BDNF, which in turn controls the number of GABA-releasing synapses that form on excitatory neurons, thereby promoting an increased number of inhibitory synapses on excitatory neurons (By similarity). In inhibitory neurons, regulates a distinct set of target genes that serve to increase excitatory input onto somatostatin neurons, probably resulting in enhanced feedback inhibition within cortical circuits (By similarity). The excitatory and inhibitory balance in neurons affects a number of processes, such as short-term and long-term memory, acquisition of experience, fear memory, response to stress and social behavior (PubMed:21887312). Acts as a regulator of dendritic spine development in olfactory bulb granule cells in a sensory-experience-dependent manner by regulating expression of MDM2 (By similarity). Efficient DNA binding requires dimerization with another bHLH protein, such as ARNT, ARNT2 or BMAL1 (By similarity). Can activate the CME (CNS midline enhancer) element (By similarity).
Ubiquitinated, leading to degradation by the proteosome.
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.
Monomer (Probable). Interacts (via the UPAR/Ly6 domains) with SRPX2. Interacts with MRC2 (By similarity). Interacts with SORL1 (via N-terminal ectodomain); this interaction decreases PLAUR internalization (By similarity). The ternary complex composed of PLAUR-PLAU-SERPINE1 also interacts with SORL1 (By similarity).
Up-regulated in transformed thyroid cell lines.
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, dehydroepiandrosterone (DHEA) to 4-androstenedione, and androstenediol to testosterone (PubMed:1537836, PubMed:1985917). 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:1537836). Expected to use NAD(+) as preferred electron donor for the 3beta-hydroxy-steroid dehydrogenase activity and NADPH for the 3-ketosteroid reductase activity (Probable).
Adrenal glands, kidney, testes and ovaries.
Belongs to the cyclophilin-type PPIase family. PPIL4 subfamily.
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).
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. In turn, participates in the regulation of many biological processes including cell cycle, apoptosis, osteoclastogenesis as well as innate or adaptive immunity. Acts as negative regulator of NF-kappa-B-dependent transcription by promoting the ubiquitination and stabilization of the NF-kappa-B inhibitor TNFAIP3. May promote the ubiquitination of TRAF6 as well. Acts also as a negative regulator of T-cell activation. Inhibits cellular dsRNA responses and interferon production by targeting MAVS component for proteasomal degradation. Ubiquitinates the CDK inhibitor CDKN1A leading to its degradationand probably also CDKN1B and CDKN1C. This activity stimulates cell cycle G1-to-S phase transition and suppresses cellular senescence. May play a role in spermatogenesis.
Interacts with XAF1, the interaction increases XAF1 stability and proapoptotic effects, and may regulate IFN signaling.
Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well.
Urogenital ridge, testis, ovary, brain and lung. In lung, found exclusively in pulmonary vessels of all sizes. Also expressed in aorta, vena cava and certain blood vessels of kidney, spleen, heart and intestine. For most blood vessels, a higher level of expression is found in endothelium than in adjacent smooth muscle.
Catalyzes the transfer of endogenously produced octanoic acid from octanoyl-acyl-carrier-protein onto the lipoyl domains of lipoate-dependent enzymes. Lipoyl-ACP can also act as a substrate although octanoyl-ACP is likely to be the physiological substrate.
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 binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding.
Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked oligosaccharides. Glycosaminoglycans (GAGs), present in the agrin 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 doamin 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.
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. This neuron-specific (z+) isoform is a 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 transmembrane agrin (TM-agrin) isoform, 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.
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, isoform 5 and isoform 6: 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.
Monomer. 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 (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. Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN.
More abundant early in development. At 13 dpc, highly expressed in the developing nervous system. Isoform y(+4)z(0), containing the 'y' insert but no 'z' insert, is the most prevelant at this stage with pronounced expression in developing spinal and sympathetic ganglia. Isoforms with no 'y' insert (y0) localized to peripheral tissue. At 15 dpc, y(+4) isoform continues to be highly expressed in neural tissue predominantly in the spinal column and developing brain. The y(0) isoform is weakly expressed in capillaries and meninges and the y(0)(z0) in non-neural tissues, predominantly in epithelial cells lining the developing lung bronchioles and kidney tubules. Isoforms Z(+8) and z(+19) are highly expressed in ventral motor columns and facial nerve with weaker expression throughout spinal cord tissue. At later stages of development, isoform y(4)z(0) is the most prominent form in developing cortex, corpus striatum, hippocampus and cerebellum. Isoform y(0)z(0) expression is still detected in brain capillaries at stage P1. The z(+19) isoform is most highly expressed from 15 dpc to 18 dpc and declines slightly to P1. Isoforms y(1)4z(0) and y(+4)z(+8) are still expressed in adulthood, the former scattered throughout the spinal cord gray matter and, the latter, in motor neurons of the ventral spinal cord.
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.
Associated component of the telomerase holoenzyme complex (By similarity). Component of the vault ribonucleoprotein particle, at least composed of MVP, PARP4 and one or more vault RNAs (vRNAs). 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 (By similarity). Also a component of the ribonucleoprotein vaults particle, a multi-subunit structure involved in nucleo-cytoplasmic transport. Responsible for the localizing and stabilizing vault RNA (vRNA) association in the vault ribonucleoprotein particle. Binds to TERC (By similarity).
Belongs to the prefoldin subunit alpha family.
May interact with HTR2A. Interacts (via PDZ domain) with CADM1 (via C-terminus). Interacts with HTR4 (By similarity).
Proposed core component of the chromatin remodeling Ino80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding.
Component of the TTT complex composed of TELO2, TTI1 and TTI2. Interacts with TELO2 and TTI1. 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.
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 (By similarity).
Acyltransferase and acetyltransferase activities are activated by phosphorylation and autoacetylation. Autoacetylation activates the histone acetyltransferase activity.
Autoacetylated. Autoacetylation is required for histone acetyltransferase activity. 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. Deacetylated by HDAC3 and SIRT1. Deacetylation by HDAC3 promotes its ubiquitination and cytoplasmic localization.
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. Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription. 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. 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. 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 (By similarity). 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. 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. 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. Directly acetylates and activates ATM. Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex. Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2. Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity. Involved in skeletal myoblast differentiation by mediating acetylation of SOX4. Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity (By similarity). 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. 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. Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1. 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. Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol. 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. Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins. Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis. Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes. Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment. Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis (By similarity).
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 (By similarity). KAT5/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4 (By similarity). The NuA4 complex interacts with MYC (By similarity). Interacts with ATM (By similarity). Interacts with JADE1 (By similarity). Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7 (By similarity). Interacts with the cytoplasmic tail of APP and APBB1/FE65 (PubMed:11441186, PubMed:19282473). Interacts with TRIM24 and TRIM68 (By similarity). Forms a complex with SENP6 and UBE2I in response to UV irradiation (By similarity). Identified in a complex with HINT1 (By similarity). Interacts with ATF2 and CUL3 (By similarity). Interacts with NR1D2 (via N-terminus) (By similarity). Component of a SWR1-like complex (By similarity). Interacts with FOXP3 (By similarity). Interacts with ZBTB49 (By similarity). Interacts with SRF (By similarity). Interacts with ATF3; promoting autoacetylation and deubiquitination by USP7 (By similarity). Interacts with EP300/p300; interaction promotes KAT5 autoacetylation (By similarity). Interacts with PRKDC; interaction is impaired following KAT5 sumoylation (By similarity).
Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase. The phosphorylated form has a higher activity. Phosphorylation at Ser-90 by CDK1 or CDK9 is a prerequisite for phosphorylation at Ser-86 by GSK3. Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase and acyltransferase activities. Phosphorylation at Ser-90 by CDK9 promotes KAT5 recruitment to chromatin. Phosphorylation by VRK1 following DNA damage promotes KAT5 association with chromatin and histone acetyltransferase activity.
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. Sumoylation with SUMO2 by PIAS4 at Lys-430 promotes repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). Sumoylation by PIAS4 impairs interaction with PRKDC, inhibiting non-homologous end joining (NHEJ)-mediated repair of DSBs, thereby facilitating HR. Desumoylated by SENP3.
Ubiquitinated by MDM2, leading to its proteasome-dependent degradation. Ubiquitination is prevented by autoacetylation at Lys-327. Ubiquitinated following deacetylation by HDAC3, leading to cytoplasmic localization. Deubiquitinated by USP7 following interaction with ATF3, promoting its stabilization.
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 (By similarity).
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. 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 (By similarity). Interacts with SEPTIN2, SEPTIN7, SEPTIN8, SEPTIN9 and SEPTIN11 (PubMed:15485874).
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 throughout adult and fetal brain. Detected in cerebellum, cortex and hippocampus (at protein level).
Homodimer. 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 (By similarity). Interacts with clathrin.
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 (By similarity).
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 (By similarity). Inhibits NKA activity in its unphosphorylated state and stimulates activity when phosphorylated (PubMed:17283221). Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation-mediated inhibition of ATP1B1 (By similarity). Contributes to female sexual development by maintaining the excitability of neurons which secrete gonadotropin-releasing hormone (By similarity).
Homotetramer (By similarity). Monomer (By similarity). Regulatory subunit of the sodium/potassium-transporting ATPase (NKA) which is composed of a catalytic alpha subunit, a 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 (PubMed:17283221, PubMed:19339511, PubMed:23532852). Also interacts with the catalytic alpha-2 and alpha-3 subunits ATP1A2 and ATP1A3 (PubMed:23532852). Very little interaction with ATP1A1, ATP1A2 or ATP1A3 when phosphorylated at Ser-83 (PubMed:23532852). Interacts with the non-catalytic beta-1 subunit ATP1B1 (PubMed:23532852). Oxidative stress decreases interaction with ATP1A1 but increases interaction with ATP1B1 (By similarity).
In adult brain, highest levels are found in the cerebellum and in the lateral, third and fourth ventricles of the choroid plexus (at protein level) (PubMed:12657675). Also detected in cells of a portion of the ependymal lining of the lateral ventricle on its rostral surface posterior to the caudate putamen (at protein level) (PubMed:12657675). Expressed in a subset of neurons which secrete gonadotropin-releasing hormone (PubMed:19187398).
In the medial basal hypothalamus, levels are low at birth and increase during neonatal and infantile development to reach a maximum during the mid-to-late juvenile period at postnatal days 24-30.
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 (PubMed:17283221). 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 (PubMed:23532852). May be phosphorylated by DMPK (By similarity).
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.
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.
Belongs to the universal ribosomal protein uS2 family.
Cleaved by stromelysin-3 (ST3) at the cell surface. Cleavage by stromelysin-3 may be a mechanism to alter cell-extracellular matrix interactions.
Expressed in most neurons and in a subset of glial cells. The overall distribution of LR correlates with that reported for laminin-1 but also with brain regions classically associated with prion-related neurodegeneration.
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. 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. 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.
Increased by methamphetamine (PubMed:28694771, PubMed:27031958). Up-regulated by cyclosporin A (PubMed:27451286). Induced by energy nd amino acid deprivation (PubMed:20181828).
Monomer. Directly interacts with MSL1 and binds MORF4L1, two components of histone acetyltransferase complex; the interaction with MORF4L1 may be mediated by MSL1. Interacts with EP300; this interaction enhances the effect of EP300 on PAX2 transcription factor activity. Interacts with PAXIP1; this interaction prevents PAXIP1 inhibition of PAX2 transcription factor activity. Interacts with COPS5; this interaction allows COPS5-dependent CDKN1B nuclear to cytoplasm translocation. Interacts with RNF2. Interacts with FOXO3; this interaction represses FOXO3 transactivation. Interacts with PTMA; regulates apoptotic process (By similarity). Interacts with MYOD1, EP300 and DDX5; this interaction coordinates the association of anti-proliferative and pro-myogenic proteins at the myogenin promoter (By similarity). Interacts with TP53; interaction is stress-dependent. Forms a complex with EP300 and TP53; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (By similarity).
Phosphorylated. Phosphorylation promotes DNA-binding activity.
Strongly activated in pancreatic acinar cells during the acute phase of pancreatitis, in developing pancreas and during pancreatic regeneration.
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:27031958, PubMed:28694771, PubMed:20181828). 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 (By similarity). Protects pancreatic cancer cells from stress-induced cell death by binding the RELB promoter and activating its transcription, leading to IER3 transactivation (By similarity). Negatively regulates apoptosis through interaction with PTMA (By similarity). 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 (PubMed:28694771, PubMed:27031958). 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) (By similarity). Coactivator of PAX2 transcription factor activity, both by recruiting the EP300 cofactor to increase PAX2 transcription factor activity and by binding PAXIP1 to suppress PAXIP1-induced inhibition on PAX2 (By similarity). Positively regulates cell cycle progression through interaction with COPS5 inducing cytoplasmic translocation of CDKN1B leading to the CDKN1B degradation (By similarity). 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 (By similarity). 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).
Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.
This is an intracellular thiol proteinase inhibitor.
Belongs to the Nudix hydrolase family. DIPP subfamily.
Binds 3 Mg(2+) or Mn(2+) ions per subunit.
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), PP-InsP4 and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction (By similarity). Can also catalyze the hydrolysis of diadenosine 5',5'''-P1,P6-hexaphosphate (Ap6A) but not diadenosine 5',5'''-P1,P5-pentaphosphate (Ap5A) and the major reaction products are ADP and p4a from Ap6A (By similarity). Also able to hydrolyze 5-phosphoribose 1-diphosphate (By similarity). Does not play a role in U8 snoRNA decapping activity (By similarity). Binds U8 snoRNA (By similarity).
Overexpressed in frontal cortex upon chronic lithium treatment.
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) (By similarity).
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 (By similarity).
The PWWP domain mediates the interaction with nucleosomes.
Heterodimer of an alpha and a beta subunit. Alpha-D associates with beta-2 (By similarity).
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 (By similarity).
Detected in brain, especially in cerebellum. Detected in pituitary gland, and at lower levels in the olfactory bulb.
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.
Interacts (via N-terminal extracellular domain) with CRH and UCN. Interacts with DLG1; this inhibits endocytosis of CRHR1 after agonist binding (By similarity). Heterodimer; heterodimerizes with GPER1.
Phosphorylation at Ser-301 by PKA prevents maximal coupling to Gq-protein, and thereby negatively regulates downstream signaling.
Exhibits histone deacetylase (HDAC) enhancer properties. May play a role in cell cycle progression and wound repair of bronchial epithelial cells.
Homodimer (By similarity). Interacts with BRS3 (By similarity). Interacts (via N-terminus) with SIN3B (By similarity).
Hematopoietic cytokine that plays an essential role in the development, expansion, and survival of naive and memory T-cells and B-cells thereby regulating the number of mature lymphocytes and maintaining lymphoid homeostasis.
Interacts with APC2 (By similarity). Interacts with KIF2A (By similarity). Interacts with ANKRD53; recruits ANKRD53 to the spindle during mitosis (By similarity).
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 (By similarity).
Belongs to the damage-control phosphatase family. Sugar phosphate phosphatase III subfamily.
Human C6orf211 has been reportedly associated with a protein carboxyl methyltransferase activity, but whether this protein indeed has such an activity remains to be determined (By similarity). It has been later shown to belong to a family of metal-dependent phosphatases implicated in metabolite damage-control (By similarity).
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 (By similarity). Possibly methylates PCNA, suggesting it is involved in the DNA damage response (By similarity).
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.
Interacts with the C-terminal region of SCN9A.
Involved in nervous system development and function. Promote neuronal excitability by elevating the voltage dependence of neuronal sodium channel SCN8A fast inactivation.
Belongs to the eukaryotic ribosomal protein eS28 family.
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. 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 and NFKB1. Interacts with MYOD1. Interacts with HDAC1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (By similarity).
Protects T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3A transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11. 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. 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.
Homooligomer and heterooligomer with other family members. Binds TCF7 and the NF-kappa-B subunit RELA. Interacts with PHF12. Interacts (via Q domain) with SIX3. Interacts with SIX6 (By similarity).
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 (By similarity).
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.
Detected in dorsal root ganglia (at protein level). Detected in dorsal root ganglia.
Down-regulated after peripheral nerve injury.
Glutamine--tRNA ligase. Plays a critical role in brain development.
Monomer. 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. Interacts with RARS1. Part of a complex composed of RARS1, QARS1 and AIMP1.
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 (By similarity). 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 (By similarity).
The vitamin K-dependent, enzymatic carboxylation of some glutamate residues allows the modified protein to bind calcium.
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 ENY2 and USP22.
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. 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. Regulates H2B monoubiquitination (H2Bub1) levels. Affects subcellular distribution of ENY2, USP22 and ATXN7L3B.
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.
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. 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. 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 (By similarity). 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 (By similarity). Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner. 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. 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. Serves as a corepressor of RARA, mediating its deacetylation and repression, leading to inhibition of RARE DNA element binding. In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response. 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 (By similarity). Catalyzes decrotonylation of MAPRE1/EB1 (By similarity).
Interacts with BTBD14B (PubMed:16033423). Interacts with HDAC7 and HDAC9. Interacts with HDAC10, DAXX and DACH1. Found in a complex with NCOR1 and NCOR2. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2. Interacts with BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY. Interacts with GLIS2. Interacts (via the DNA-binding domain) with NR2C1; the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation. Component of the Notch corepressor complex. Interacts with CBFA2T3 and NKAP. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with and deacetylates MAPK14. Interacts with ZMYND15. Interacts with SMRT/NCOR2 and BCL6 on DNA enhancer elements. Interacts with INSM1. Interacts with XBP1; the interaction occurs in endothelial cell (EC) under disturbed flow. Interacts (via C-terminus) with CCAR2 (via N-terminus). Interacts with and deacetylates MEF2D (By similarity). Interacts with BEND3 (By similarity). Interacts with NKAPL (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (By similarity). 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 (By similarity). Interacts with SETD5 (By similarity).
Interacts with renin (By similarity). Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump (PubMed:32165585). Interacts (via N-terminus) with ATP6AP1 (via N-terminus) (PubMed:32165585). Interacts with ATP6V0D1; ATP6V0D1 is a V-ATPase complex subunit and the interaction promotes V-ATPase complex assembly (PubMed:32165585). Interacts with TMEM9; TMEM9 is a V-ATPase assembly regulator and the interaction induces the interaction with ATP6V0D1 (By similarity). Interacts with VMA21 (via N-terminus); VMA21 is a V-ATPase accessory component (By similarity).
Multifunctional protein which functions as a renin, prorenin cellular receptor and is involved in the assembly of the lysosomal proton-transporting V-type ATPase (V-ATPase) and the acidification of the endo-lysosomal system (By similarity). May mediate renin-dependent cellular responses by activating ERK1 and ERK2 (By similarity). By increasing the catalytic efficiency of renin in AGT/angiotensinogen conversion to angiotensin I, may also play a role in the renin-angiotensin system (RAS) (By similarity). Through its function in V-type ATPase (v-ATPase) assembly and acidification of the lysosome it regulates protein degradation and may control different signaling pathways important for proper brain development, synapse morphology and synaptic transmission (By similarity).
Proteolytically cleaved by a furin-like convertase in the trans-Golgi network to generate N- and C-terminal fragments.
Belongs to the eIF-2B alpha/beta/delta subunits family. MtnA subfamily.
Catalyzes the interconversion of methylthioribose-1-phosphate (MTR-1-P) into methylthioribulose-1-phosphate (MTRu-1-P).
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.
Expressed in several discrete regions at 14.5 dpc and 19.5 dpc but not 10.5 dpc. At 14.5 dpc, expressed in isthmus, pituitary, spinal cord, tongue, intervertebral disk, dorsal root ganglion and pelvis. At 19.5 dpc, expressed in lung and anterior pituitary.
Mainly expressed in the lung. Not detected in brain, heart, liver, kidney and small intestine.
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 (By similarity).
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. Plays a role in mitotic spindle assembly checkpoint (SAC) activation (By similarity).
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 (By similarity). Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).
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 (By similarity).
Binds STK38 and STK38L. Interacts with LATS1 and LATS2 (By similarity). Forms a tripartite complex with STK38 and STK3/MST2 (By similarity).
Phosphorylated by STK3/MST2 and STK4/MST1 and this phosphorylation enhances its binding to LATS1.
F-box-like protein which is required for entry into mitosis. Acts by participating in E3 ligase complexes that mediate the ubiquitination and degradation of WEE1 kinase at G2/M phase (By similarity).
Interacts with SKP1. Part of a SCF (SKP1-cullin-F-box) protein ligase complex (By similarity).
The KEN box is required for the association with the APC/C-Cdh1 complex.
Ubiquitinated and degraded by the APC/C-Cdh1 complex.
G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation.
Homodimer. Interacts with ARRB2. Interacts with KIF7. Interacts with BBS5 and BBS7; the interactions are indicative for the association of SMO with the BBsome complex to facilitate ciliary localization of SMO. Interacts with DLG5 and SDCBP. Interacts with GAS8/DRC4.
In embryo, found in the early neural folds and neural tube, pre-somitic mesoderm and somites, developing limb bud, gut, eye, testes, cartilage, muscle, lung, epiglottis, thymus, tongue, jaw, taste buds, teeth, and skin. In adult, found in multiple tissues including heart, brain, liver, lung, skeletal muscle, kidney and testis.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. SCNN1A subfamily.
Detected in kidney, lung and testis (at protein level). In the testis, detected within the seminiferous tubules but not in the interstitial cells (at protein level).
Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a gamma/SCNN1G subunit (PubMed:9118951). An additional delta/SCNN1D subunit exists only in some organisms and can replace the alpha/SCNN1A subunit to form an alternative channel with specific properties (By similarity). Interacts with NEDD4 (via WW domains) (PubMed:11323714). Interacts with NEDD4L (via WW domains) (PubMed:14556380). Interacts with WWP1 (via WW domains) (By similarity). Interacts with WWP2 (via WW domains) (By similarity). Interacts with the full-length immature form of PCSK9 (pro-PCSK9) (By similarity).
Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride (PubMed:9118951). Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells (PubMed:8382172, PubMed:9118951). Plays an essential role in electrolyte and blood pressure homeostasis, but also in airway surface liquid homeostasis, which is important for proper clearance of mucus. Controls the reabsorption of sodium in kidney, colon, lung and eccrine sweat glands. Also plays a role in taste perception (By similarity).
Expressed in the brain in the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, dorsal and median raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial hypothalamus, paraventricular hypothalamic nucleus, and ventral premammillary nucleus. Not detected in the spleen, lung, liver, skeletal muscle, kidney and testis. Orexin receptor mRNA expression has also been reported in the adrenal gland, enteric nervous system, and pancreas.
Nonselective, high-affinity receptor for both orexin-A and orexin-B neuropeptides. Triggers an increase in cytoplasmic Ca(2+) levels in response to orexin-A binding.
The N-terminal region is required for orexin signaling.
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 (By similarity).
Interacts with IRF2BP1 (By similarity). Forms 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.
Phosphorylation of Thr-148 by MAPK8 in response to different stress conditions such as, UV irradiation, oxidatives stress and anisomycin treatments.
Expressed in many cells in the fungiform and geschmackstreifen taste buds.
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.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. MOCOS subfamily.
Sulfurates the molybdenum cofactor. Sulfation of molybdenum is essential for xanthine dehydrogenase (XDH) and aldehyde oxidase (ADO) enzymes in which molybdenum cofactor is liganded by 1 oxygen and 1 sulfur atom in active form.
Catalyzes the reversible isomerization between hydroxypyruvate and 2-hydroxy-3-oxopropanoate (also termed tartronate semialdehyde).
Belongs to the dynein light chain LC1-type family.
Interacts with ZMYND10 (via C-terminus) (By similarity). Interacts with DNAH5, a outer arm dynein heavy chain (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 (By similarity).
Interacts (via N- and C-terminus) with DDX1. Interacts (via N- and C-terminus) with C14orf166. Interacts with FAM98B. Interacts with PLEKHM1 (via N- and C-terminus).
Positively stimulates PRMT1-induced protein arginine methylation. Involved in skeletal homeostasis. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts.
Belongs to the UTP23/FCF1 family. FCF1 subfamily.
Inhibited by wortmannin (PubMed:8973579). 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 (By similarity). 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 (PubMed:19458041). Interacts with ACBD3. Interacts with ARMH3, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ and SFN (By similarity). Interacts with GGA2 (via VHS domain); the interaction is important for PI4KB location at the Golgi apparatus membrane (By similarity). Interacts with ATG9A.
Phosphorylates phosphatidylinositol (PI) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate (PIP) (PubMed:8973579). May regulate Golgi disintegration/reorganization during mitosis, possibly via its phosphorylation (By similarity). Involved in Golgi-to-plasma membrane trafficking (PubMed:8973579).
Strongly expressed in brain, kidney, lung, small intestine, uterus and adrenal gland. Weaker expression in liver, heart, skeletal muscle, thymus and testis. Not detected in spleen.
Catalyzes the transfer of a geranylgeranyl moiety from geranylgeranyl diphosphate to both cysteines of proteins with the C-terminal sequence -XXCC, -XCXC and -CCXX.
Heterotrimer composed of RABGGTA, RABGGTB and CHM; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHM (component A) mediates peptide substrate binding (PubMed:10745007, PubMed:12620235, PubMed:18399557, PubMed:18756270, PubMed:19894725, PubMed:22480322, PubMed:8505342, PubMed:22963166). The Rab GGTase dimer (RGGT) interacts with CHM (component A) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp) (PubMed:11675392). The CHM:RGGT:Rab complex is destabilized by GGpp (PubMed:11675392). Interaction of RABGGTB with prenylated PTP4A2 precludes its association with RABGGTA and inhibits enzyme activity (By similarity). Interacts with CHODL (By similarity). Interacts with non-phosphorylated form of RAB8A; phosphorylation of RAB8A at 'Thr-72' disrupts this interaction (By similarity).
Most abundant in the heart, brain, spleen and liver. Less in the lung, muscle, kidney and testis; in these tissues, more abundant than the subunit alpha.
E3 ubiquitin-protein ligase that plays an important role in neuronal differentiation, including neurogenesis and gliogenesis, during brain development. During embryonic development initiates neuronal differentiation by inducing cell cycle arrest at the G0/G1 phase through up-regulation of cell-cycle regulatory proteins. Plays a role not only in the fetal period during the development of the nervous system, but also in the adult brain, where it is involved in the maintenance of neural functions and protection of the nervous tissue cells from oxidative stress-induced damage. Exhibits GTPase and E3 ubiquitin-protein ligase activities. Regulates dendritic spine density and synaptic neurotransmission; its ability to hydrolyze GTP is involved in the maintenance of dendritic spine density.
Self-associates. Interacts with SP1 in an oxidative stress-regulated manner. Interacts with SIGMAR1 in an oxidative stress-regulated manner. Interacts with ZBTB16 (via C2H2-type zinc finger domains 1 and 2).
Expressed abundantly in brain and at lower levels in testis and kidney.
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 (By similarity). Interacts with SNAP25.
Part of the MIS12 complex, which is required for kinetochore formation and spindle checkpoint activity. Required to target ZW10 to the kinetochore at prometaphase (By similarity).
Activated by magnesium ions and inhibited by manganese ions. Inhibited by dipyridamole, moderately sensitive to IBMX and inhibited by vinpocetine (By similarity).
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.
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. Involved in the regulation of microtubule polymerization.
Highest in the liver, followed by kidney and testis and much lower in seminal vesicles, spleen, lung and brain.
Homotrimer; The trimer binds only one molecule of glutathione.
In vitro, can be activated by reagents that attack Cys-50 sulfhydryl, such as N-ethylmaleimide and via nitration of Tyr-93 by peroxynitrite.
In vitro, peroxynitrite induces nitration at Tyr-93 which activates the enzyme.
May be involved in BMP2-induced transcription.
General regulator of phagocytosis. Required to uptake Gram negative bacterium by macrophages.
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 (By similarity).
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. 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 (By similarity).
Expressed during the late capillary loop stage of glomerulogenesis. First detected in junctional complexes in podocytes after their migration to the base of cells. Up-regulated upon foot process differentiation.
Expressed in the foot process layer of podocytes of the kidney glomeruli but not in tubules (at protein level). Expressed in the brain.
Interacts (via its WW domains) with DRPLA (By similarity). Interacts with CTNNB1, ACVR2A, SMAD2 and SMAD3 (By similarity). Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). May interact with HTR2A and IGSF9 (By similarity). Interacts with HTR4 (By similarity). Interacts (via guanylate kinase domain) with DLGAP1 (PubMed:9694864). Interacts (via PDZ domains) with GRIN2A, GRID2 and NLGN1 (PubMed:9694864, PubMed:12589829). Interacts with CTNND2 (PubMed:10080919). Interacts with MAGUIN-1 (PubMed:10207009). Interacts (via its second PDZ domain) with PTEN (via unphosphorylated C-terminus); this interaction diminishes the degradation rate of PTEN (PubMed:15951562). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a NGF-dependent manner (PubMed:17724123). Interacts with RAPGEF2; the interaction occurs before or after nerve growth factor (NGF) stimulation (PubMed:10548487). Isoform 1 interacts (via PDZ domain) with KIDINS220 isoform 2 (via C-terminal domain) (PubMed:17724123). Interacts with DDN (PubMed:16751601, PubMed:16464232). Identified in a complex with ACTN4, CASK, IQGAP1, NPHS1, SPTAN1 and SPTBN1 (PubMed:15994232). Interacts with DLL1 (By similarity). Found in a complex with IGSF9B and NLGN2; the interaction with IGSF9B is mediated via the PDZ 5 and PDZ 6 domains, while the interaction with NLGN2 is mediated via the WW1, WW2 and PDZ2 domains (PubMed:23751499). Interacts (via PDZ 6 domain) with USH1G (via SAM domain); the interaction is triggered by phosphorylation of USH1G by CK2 and negatively regulates MAGI2-mediated endocytosis (By similarity).
Seems to act as scaffold molecule at synaptic junctions by assembling neurotransmitter receptors and cell adhesion proteins (PubMed:9694864). Plays a role in nerve growth factor (NGF)-induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth (PubMed:17724123). May play a role in regulating activin-mediated signaling in neuronal cells (By similarity). Enhances the ability of PTEN to suppress AKT1 activation (By similarity). Plays a role in receptor-mediated clathrin-dependent endocytosis which is required for ciliogenesis (By similarity).
Asymmetrically methylated by PRMT1. Symmetrically methylated by PRMT5 (By similarity).
Interacts with PRMT1 and PRMT5. 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. Interacts with WDR77 and ER (By similarity).
Plays an important role in the ligand-dependent activation of estrogen receptor target genes. May play a role in the silencing of fetal globin genes. Recruits the 5FMC complex to ZNF148, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes. Required for 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 methylates H4R3 and transactivates genes involved in glioblastomagenesis (By similarity).
Component of the ER membrane protein complex (EMC). EMC8 and EMC9 are mutually exclusive subunits of the EMC complex.
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.
Interacts with ESR1; Interacts in a manner that is estrogen independent but is enhanced by estrogen. Interacts (via macro domain) with AR.
Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety. Inactive towards proteins bearing poly-ADP-ribose. Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins. Plays a role in estrogen signaling. Binds to androgen receptor (AR) and amplifies the transactivation function of AR in response to androgen. May play an important role in carcinogenesis and/or progression of hormone-dependent cancers by feed-forward mechanism that activates ESR1 transactivation. Could be an ESR1 coactivator, providing a positive feedback regulatory loop for ESR1 signal transduction. Could be involved in invasive growth by down-regulating CDH1 in endometrial cancer cells. Enhances ESR1-mediated transcription activity.
Subject to competitive inhibition by the product ADP-ribose.
Belongs to the eukaryotic-type primase small subunit family.
Homodimer; homodimerization occurs upon GTP-binding and is required for the association with membranous structures. Heterodimer with other family members, including GBP1, GBP3, GBP4 and GBP5.
Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions, but the major reaction product is GDP (By similarity). Exhibits antiviral activity against influenza virus. Promotes oxidative killing and delivers antimicrobial peptides to autophagolysosomes, providing broad host protection against different pathogen classes (By similarity). Confers protection to the protozoan pathogen Toxoplasma gondii (By similarity).
Isoprenylation is required for proper subcellular location.
The L-type calcium channel is composed of four subunits: alpha-1, alpha-2, beta and gamma. Interacts with FASLG (By similarity). Interacts with CBARP (By similarity).
The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting.
Exhibits microtubule-destabilizing activity, which is antagonized by STAT3.
Interacts with STAT3. Interacts with CLU (secreted form); this interaction may act as an important modulator during neuronal differentiation (PubMed:16038898).
N-terminal palmitoylation promotes specific anchoring to the cytosolic leaflet of Golgi membranes and subsequent vesicular trafficking along dendrites and axons. Neuronal Stathmins are substrates for palmitoyltransferases ZDHHC3, ZDHHC7 and ZDHHC15 (By similarity).
Stimulates the secretion of gonadotropins; it stimulates the secretion of both luteinizing and follicle-stimulating hormones.
The precursor is cleaved by ACE, which removes the Gly-Lys-Arg peptide at the C-terminus, leading to mature hormone. The mature form of Gonadoliberin-1 is also cleaved and degraded by ACE.
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 (By similarity).
Interacts with EGFR and promotes EGFR dimerization. Interacts with RHBDF1; may retain EGF in the endoplasmic reticulum and regulates its degradation through the endoplasmic reticulum-associated degradation (ERAD) (By similarity). Interacts with RHBDF2 (By similarity).
Converts testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids (PubMed:1527072). It plays a central role in sexual differentiation and androgen physiology (By similarity).
Expressed in high levels in the prostate and many other androgen-sensitive tissues.
Disulfide-linked heterodimer with the amino acid transport protein SLC3A2/4F2hc.
Expression is seen in jejunum mucosa and the epithelial cells of the jejunum, ileum and colon, as well as in kidney, placenta, brain, testis and skeletal muscle. Expressed in retina, inner blood-retinal barrier of retina, retinal vascular endothelial cells. Also expressed in the intestinal epithelial cell line IEC-6 and in the retinal capillary endothelial cell line TR-iBRB2.
Leucine transport activity is inhibited by 2-amino-bicyclo-(2,2,1)-heptane-2-carboxylate (BCH), glycine, L-isomers of the neutral amino acids and histidine.
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.
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.
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.
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.
Drastically down-regulated in response to PDGF-BB or cell injury, that promote smooth muscle cell proliferation and dedifferentiation. Seems to play a role in the development of the embryonic vascular system.
Highly expressed in the aorta; weakly found in the kidney, thymus, and intestine. Barely detectable in brain, testis, esophagus, lung, liver, aortic adventitia, vena cava, or uterus; not present in heart and skeletal muscle.
Interacts with KAT14. The LIM domain 1 is necessary and sufficient for this interaction (By similarity). Interacts with GLRX3 (By similarity).
Belongs to the adenomatous polyposis coli (APC) family.
Forms homooligomers and heterooligomers with APC2. Interacts with DIAPH1 and DIAPH2. Interacts with PDZ domains of DLG1 and DLG3. Associates with catenins. Binds axin. Interacts with ARHGEF4 (via N-terminus). Interacts with MAPRE1 (via C-terminus); probably required for APC targeting to the growing microtubule plus ends. Interacts with MAPRE2 and MAPRE3 (via C-terminus). Found in a complex consisting of ARHGEF4, APC and CTNNB1. Interacts with SCRIB; may mediate APC targeting to adherens junctions of epithelial cells. Interacts with SPATA13 (via N-terminus and SH3 domain). Interacts with ASAP1 (via SH3 domain). Interacts at the cell membrane with AMER1 and AMER2 (via ARM repeats) (By similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B. Interacts with KHDRBS1 (By similarity). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (By similarity).
The microtubule tip localization signal (MtLS) motif; mediates interaction with MAPRE1 and targeting to the growing microtubule plus ends.
Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)-induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex. It is required for the localization of MACF1 to the cell membrane and this localization of MACF1 is critical for its function in microtubule stabilization (By similarity).
Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is facilitated by Axin. Deubiquitinated by ZRANB1/TRABID (By similarity).
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.
Interacts with EXO1. Interacts with MLH1.
Interacts with MHC class II (MHC-II); selectively recognizes stable complexes of peptide and MHC-II. Interacts with FGL1 (via the Fibrinogen C-terminal domain).
Lymphocyte activation gene 3 protein: Inhibitory receptor on antigen activated T-cells. Delivers inhibitory signals upon binding to ligands, such as FGL1. FGL1 constitutes a major ligand of LAG3 and is responsible for LAG3 T-cell inhibitory function. Following TCR engagement, LAG3 associates with CD3-TCR in the immunological synapse and directly inhibits T-cell activation. May inhibit antigen-specific T-cell activation in synergy with PDCD1/PD-1, possibly by acting as a coreceptor for PDCD1/PD-1. Negatively regulates the proliferation, activation, effector function and homeostasis of both CD8(+) and CD4(+) T-cells. Also mediates immune tolerance: constitutively expressed on a subset of regulatory T-cells (Tregs) and contributes to their suppressive function. Also acts as a negative regulator of plasmacytoid dendritic cell (pDCs) activation. Binds MHC class II (MHC-II); the precise role of MHC-II-binding is however unclear.
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.
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.
Expressed strongly in lung, liver and heart, and at lower levels in kidney, testis, brain, spleen and skeletal muscle.
Inhibited by the chelating agents 1,10-phenanthroline and EDTA. Inhibited by the thiol-containing compounds 2-mercaptoethanol and dithiothreitol. Also inhibited by apstatin, captopril and p-(ch1oromercuri)benzenesulfonic acid. Weakly inhibited by D,L-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and N-[l-(R,S)-carboxy-(2-phenylethyl)]-Ala-Ala-Phe-p-aminobenzoate. Inhibited by ramiprilat and enalaprilat, in a Mn(2+)-dependent manner. Metal ions have a complex substrate- and concentration-dependent effect on activity. Activity towards Arg-Pro-Pro and Gly-Pro-Hyp is stimulated by Mn(2+) ion concentrations of 10-100 uM and then inhibited at Mn(2+) concentrations of 1-2 mM. Mn(2+) concentrations in excess of 2 mM stimulate activity towards Gly-Pro-Hyp but inhibit activity towards Arg-Pro-Pro. Zn(2+) and Co(2+) ions also inhibit activity towards Arg-Pro-Pro at high concentrations. Activity towards bradykinin is inhibited by Mn(2+) concentrations in excess of 1 mM.
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.
By irradiation and dexamethasone (in thymocytes).
Expressed during apoptosis in thymocytes.
High levels in vas deferens and urinary bladder. Lower extent in spinal cord, coeliac ganglion, lung and spleen (probably in the smooth muscle part of both organs).
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.
Belongs to the FKBP-type PPIase family. FKBP1 subfamily.
Interacts with TGFBR1; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation (By similarity). Interacts with ACVR1B and SMAD7. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Interacts directly with RYR2 (PubMed:20431056). Interacts directly with RYR3 (By similarity). Interacts directly with RYR1 (By similarity). Interacts with GLMN; rapamycin and FK506 abolish the interaction with GLMN in a dose dependent manner (By similarity).
Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruits SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (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. Interacts (via C-terminal PDZ domain) with MPP1/p55. Interacts with LRRC4C/NGL1. Interacts with MYO7A. Interacts with RPGR. Interacts with EPS8 (By similarity). Interacts with CASK (PubMed:12641734). Interacts with CIB2 (By similarity). 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). Interacts with ADGRV1/MASS1 (via cytoplasmic region) (By similarity).
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.
Ubiquitous. Highly expressed in heart, spleen, lung and liver. Highly expressed in brain, in the olfactory bulb, thalamus, layers III-V of the cerebral cortex and the molecular layer of cerebellum. Detected in soma and dendrites of thalamic neurons, and in cerebrum in cell bodies and apical dendrites of pyramidal neurons. Expressed in retina and inner ear (PubMed:16434480, PubMed:23055499).
Detected in liver, ovary, kidney, testicle, lung and embryo.
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. N- and C-glycosylations can also facilitate secretion. O-glycosylated proteoglycan. Contains chondroitin sulfate (By similarity).
May be cleaved by a furin endopeptidase. The precursor is sequentially processed (By similarity).
Metalloprotease that may play a role in the degradation of COMP.
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).
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 (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR2A/GRIN2A subfamily.
Channel activity is inhibited by nM concentrations of Zn(2+).
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+). 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:28384476). 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.
Detected in brain cortex, olfactory bulb, hippocampus including the dentate gyrus, striatum, thalamus, superior colliculus, inferior colliculus, midbrain and cerebellum (at protein level) (PubMed:22960932, PubMed:9509416). Detected in brain cortex, hypothalamus and cerebellum (PubMed:1350383).
Expressed during postnatal days P3 to P60, with increased expression after postnatal day 3.
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:1350383, PubMed:8428958, PubMed:28384476, PubMed:16281028, PubMed:23625947, PubMed:24462099, PubMed:27618671, PubMed:27916457, PubMed:28468946, PubMed:28760974, Ref.27). Can also form heterotetrameric channels that contain at least one zeta subunit (GRIN1), at least one epsilon subunit, plus GRIN3A or GRIN3B (PubMed:11160393, PubMed:11588171, PubMed:12391275, PubMed:11929923). In vivo, the subunit composition may depend on the expression levels of the different subunits (Probable). Found in a complex with GRIN1, GRIN3A and PPP2CB (PubMed:11588171). Found in a complex with GRIN1 and GRIN3B (PubMed:14602821). Interacts with AIP1 (PubMed:9694864). 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 (PubMed:7569905, PubMed:9647694). Interacts with LRFN2 (PubMed:16495444). Interacts with RPH3A and DLG4; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (PubMed:26679993). Interacts with SORCS2 (By similarity). Interacts with ARC; preventing ARC oligomerization (PubMed:31080121).
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. 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. 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. Other reports show that PEF1 dissociates from PDCD6 in presence of calcium, and may act as a negative regulator of PDCD6 (By similarity). Also acts as a negative regulator of ER-Golgi transport; possibly by inhibiting interaction between PDCD6 and SEC31 (PubMed:27276012).
Heterodimer; heterodimerizes (via the EF-hand 5) with PDCD6. Dissociates from PDCD6 in presence of calcium.
Ubiquitinated by the BCR(KLHL12) E3 ubiquitin ligase complex.
Detected in brain (at protein level). Isoform 1 and isoform 2 are expressed in brain, kidney, lung, heart and lens fiber.
Interacts with BRSK2. Interacts with CCNY; this increases the CDK16 kinase activity (By similarity). Found in a complex containing CABLES1, CDK17 and TDRD7. Interacts with YWHAH, YWHAQ and YWHAZ. Interacts with NSF. Identified in a complex with NSF, syntaxin-1, synaptotagmin, SYN1, SYP and CDK5R1.
Phosphorylation at Ser-153 inhibits kinase activity.
Protein kinase that plays a role in vesicle-mediated transport processes and exocytosis. Can phosphorylate CCNY at 'Ser-336' (in vitro) Plays a role in the regulation of insulin secretion in response to changes in blood glucose levels. Regulates GH1 release by brain neurons. Required for normal spermatogenesis. Regulates neuron differentiation and dendrite development (By similarity). Phosphorylates NSF, and thereby regulates NSF oligomerization.
Belongs to the melanin-concentrating hormone family.
Expression is strongly increased in hypothalamus between postnatal days 12 and 20, to reach high constant values in adult.
Inhibited by neurogenic stress or osmotic stress.
MCH inhibits ACTH secretion at the end of the light on period which corresponds to the peak of the circadian rhythm in ACTH. Inhibits also stress induced ACTH release during the light off period of the cycle. Involved as a neurotransmitter or neuromodulator in a broad array of neuronal functions. Stimulates sexual behavior when injected into the ventromedial nucleus, this effect is antagonized by NEI. In the medial preoptic area, stimulates anxiety and sexual behavior. Antagonizes inhibitory effect of melanotropin alpha on exploration behavior.
MCH is present in all regions of the brain and in neurointermediate lobe of the pituarity gland, with highest concentrations in the hypothalamus. Also expressed to a much lesser extent in stomach, lamina propria of both duodenum and colon, ovary, thymus, pancreas, adrenal gland and testis (spermatogonia, early spermatocytes and Sertoli cells). Weak expression in heart and lung. The other peptides are expressed at least in Sertoli cells, nei being also expressed in brain, stomach and proximal duodenum. In brain exclusively mature mch and nei peptides are present. In peripheral tissues a large product, encompassing the NEI and MCH domains of the precursor, is found predominantly. At low levels fully processed MCH and NEI peptides are present in gut. No expression in peripheral blood.
NEI can influence differentiation of neuronal processes in brain neurons. Affects the content of neurofilament protein in neuritogenesis (in vitro). May also be a neuromodulatory factor. In behavioral tests, it stimulates exploration and anxiety when injected into the ventromedial nucleus. Also stimulates grooming, locomotion and rearing. May antagonize the inhibitory effect of mch on ACTH release. Reduces dopamine and dopac release in the ventromedial nucleus.
Pro-MCH is processed differentially in the brain and in peripheral organs producing two neuropeptides; NEI and MCH. A third peptide, NGE, may also be produced. Preferential processing in neurons by prohormone convertase 2 (PC2) generates NEI. MCH is generated in neurons of the lateral hypothalmic area by several prohormone convertases including PC1/3, PC2 and PC5/6.
Binds to actin filaments in muscle and non-muscle cells. Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction. Smooth muscle contraction is regulated by interaction with caldesmon. In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments.
Homodimer. Heterodimer of an alpha (TPM1, TPM3 or TPM4) and a beta (TPM2) chain. Interacts with TMOD1.
Adapter protein that links SCN10A to clathrin. Regulates SCN10A channel activity, possibly by promoting channel internalization.
Detected in small neurons in dorsal root ganglia. Detected in C-type fibers of sciatic nerve (at protein level).
Interacts with SCN10A and clathrin. Identified in a complex containing SCN10A, clathrin and SCLT1.
By PDGF through a CREB-dependent transactivation of the NOR1 promoter.
Expressed at high levels in cultured apoptotic neuronal cells and fetal brain, and at low level in adult brain.
Interacts with SIX3 (via homeobox); differentially regulates the transcriptional activities of NR4A3. Interacts with NR3C1 (via nuclear receptor DNA-binding domain); the interactions represses transcription activity of NR4A3 on the POMC promoter Nur response element (NurRE) (PubMed:15591535). Interacts with TRIM28; the interactions potentiates NR4A3 activity on NurRE promoter (PubMed:19321449). Binds DNA as a monomer and homodimer (PubMed:10523643). Interacts with PARP1; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (PubMed:25625556). Interacts with the constituents of DNA-PK heterotrimer PRKDC, XRCC6 and XRCC5; phosphorylates and prevents NR4A3 ubiquitinylation and degradation (By similarity). Interacts with NCOA2; potentiates the activity of the NR4A3. Interacts with NCOA1, NCOA3, MED1 and KAT2B. Interacts with EP300 and NCOA2; mediates the recruitment of MED1 in the coactivator complex (By similarity).
The AF-1 domain mediates transcription activation. The N-terminal region (1-292) directly interacts with the C-terminal LBD (380-627): the interaction is potentiated by AF-1-mediated recruitment of NCOA2.
Transcriptional activator that binds to regulatory elements in promoter regions in a cell- and response element (target)-specific manner (PubMed:7811288). Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes (PubMed:10523643). Plays a role in the regulation of proliferation, survival and differentiation of many different cell types and also in metabolism and inflammation. Mediates proliferation of vascular smooth muscle, myeloid progenitor cell and type B pancreatic cells; promotes mitogen-induced vascular smooth muscle cell proliferation through transactivation of SKP2 promoter by binding a NBRE site (By similarity). Upon PDGF stimulation, stimulates vascular smooth muscle cell proliferation by regulating CCND1 and CCND2 expression (PubMed:16945922). In islets, induces type B pancreatic cell proliferation through up-regulation of genes that activate cell cycle, as well as genes that cause degradation of the CDKN1A (PubMed:24706823). Negatively regulates myeloid progenitor cell proliferation by repressing RUNX1 in a NBRE site-independent manner. During inner ear, plays a role as a key mediator of the proliferative growth phase of semicircular canal development (By similarity). Mediates also survival of neuron and smooth muscle cells; mediates CREB-induced neuronal survival, and during hippocampus development, plays a critical role in pyramidal cell survival and axonal guidance. Is required for S phase entry of the cell cycle and survival of smooth muscle cells by inducing CCND1, resulting in RB1 phosphorylation. Binds to NBRE motif in CCND1 promoter, resulting in the activation of the promoter and CCND1 transcription (By similarity). Also plays a role in inflammation; Upon TNF stimulation, mediates monocyte adhesion by inducing the expression of VCAM1 and ICAM1 by binding to the NBRE consensus site (By similarity). In mast cells activated by Fc-epsilon receptor cross-linking, promotes the synthesis and release of cytokines but impairs events leading to degranulation. Also plays a role in metabolism; by modulating feeding behavior; and by playing a role in energy balance by inhibiting the glucocorticoid-induced orexigenic neuropeptides AGRP expression, at least in part by forming a complex with activated NR3C1 on the AGRP-glucocorticoid response element (GRE), and thus weakening the DNA binding activity of NR3C1. Upon catecholamines stimulation, regulates gene expression that controls oxidative metabolism in skeletal muscle (By similarity). Plays a role in glucose transport by regulating translocation of the SLC2A4 glucose transporter to the cell surface (By similarity). Finally, during gastrulation plays a crucial role in the formation of anterior mesoderm by controlling cell migration (By similarity). Also participates in cardiac hypertrophy by activating PARP1 (PubMed:25625556).
2 transcripts of 2.5 kb and 3.8 kb are expressed at low levels in brain, testis, adrenal gland and thymus.
According to a report, has no detectable intrinsic GTPase activity.
Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form. In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway.
Interacts with RRAGC and RRAGD; heterodimerization stabilizes RRAG proteins. In complex with RRAGC, but not with RRAGA, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (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 (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. Interacts with the GATOR1 complex; inactivates RRAGB. The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor. Interacts with SESN1, SESN2 and SESN3 (By similarity).
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.
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 (By similarity).
Interacts with RAB3A and IHPK1 through the coiled-coil domain. This interaction is competitive. IHPK1 kinase activity is not required for this interaction.
Negligible levels at embryonic stages 9 dpc and 15 dpc. RAB3IL1 levels increase progressively at postnatal ages P3, P7 and P13 with maximal levels in adult brain.
Selectively localized to the brain (at protein level).
Belongs to the eukaryotic ATPase subunit F6 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. Also involved in the restoration of oligomycin-sensitive ATPase activity to depleted F1-F0 complexes (By similarity).
Activity is altered by insulin and estrogen.
Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates (PubMed:8621474, PubMed:8343522). Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate. May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates. Exhibits either endo- or exopeptidase activity depending upon the tissue of origin. When secreted, it acts primarily as an endopeptidase (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.
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.
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 (By similarity). 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 (By similarity). 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. Interacts with PEX19 via its cytoplasmic domain.
The RING-type zinc-finger is degenerated and only coordinates one zinc ions, preventing E3 ubiquitin-protein ligase activity.
Isoform 2 (soluble form) inhibits IL4-induced spleen cell proliferation.
Isoform 2 is expressed in kidney, spleen, lung and liver.
On IL4 binding, phosphorylated on C-terminal tyrosine residues.
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 (By similarity).
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. Interacts with PIK3C3. Interacts with the SH2-containing phosphatases, PTPN6/SHIP1, PTPN11/SHIP2 and INPP5D/SHIP. Interacts with JAK1 through a Box 1-containing region; inhibited by SOCS5. Interacts with SOCS5; inhibits IL4 signaling. Interacts with JAK3. Interacts with CLM1.
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. Interacts with CARD10 (By similarity). Interacts with gap junctions proteins GJB2/Cx26 and GJB4/Cx30 (By similarity).
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 (By similarity). In addition, functions as a critical signaling component in mediating NF-kappa-B activation by acting downstream of EGFR and upstream of CARD10 (By similarity). Contributes to passive conductance current in cochlear glia-like supporting cells, mediated by gap junctions and necessary for hearing (By similarity).
Expressed in primary hippocampal and cortical neurons.
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.
ESCRT-III-like protein involved in cytokinesis, nuclear envelope reassembly and endosomal tubulation (By similarity). Is required for efficient abscission during cytokinesis (By similarity). Involved in recruiting VPS4A and/or VPS4B to the midbody of dividing cells (By similarity). 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 (By similarity). Recruited to the reforming nuclear envelope (NE) during anaphase by LEMD2 (By similarity). Regulates early endosomal tubulation together with the ESCRT-III complex by mediating the recruitment of SPAST (By similarity).
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. Interacts with SPART (via MIT domain); leading to the recruitment of SPART to midbodies. Interacts with SPAST.
Belongs to the universal ribosomal protein uL23 family.
Component of the large ribosomal subunit. Interacts with LYAR and GNL2. Interacts with MDM2; this interaction may promote MDM2-mediated p53/TP53 polyubiquitination. 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. Interacts with IPO8.
Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. Binds a specific region on the 26S rRNA. May promote p53/TP53 degradation possibly through the stimulation of MDM2-mediated TP53 polyubiquitination.
The N-terminal beta-like import receptor binding (BIB) domain mediates interaction with IPO5, IPO7, KPNB1 and TNPO1.
Component of the 40S subunit of the ribosome.
In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family.
Ribosomal protein S27a is part of the 40S ribosomal subunit.
Belongs to the 2H phosphoesterase superfamily. CNPase family.
Catalyzes the formation of 2'-nucleotide products from 2',3'-cyclic substrates (By similarity). May participate in RNA metabolism in the myelinating cell, CNP is the third most abundant protein in central nervous system myelin (By similarity).
May participate in RNA metabolism in the myelinating cell, CNP is the third most abundant protein in central nervous system myelin.
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.
Homodimer. 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). These subunits are bound to an inner core composed of about 48 DLAT and 12 PDHX molecules (by non covalent bonds). 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. Interacts with PDHX.
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). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion. 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. In monomeric form may have additional moonlighting function as serine protease (By similarity). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction (By similarity).
The active site is a redox-active disulfide bond.
Belongs to the complex I NDUFA10 subunit family.
Complex I is composed of 45 different subunits. This a component of the hydrophobic protein fraction.
Phosphorylation at Ser-250 by PINK1 is required for the binding and/or reduction of the complex I substrate ubiquinone.
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) (By similarity). Acts as inhibitor of monocyte chemotaxis (PubMed:15528323). Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed.
Down-regulated in cells transformed by oncogenes.
Highly expressed in the brain, kidney, spleen, and testis and weakly expressed in the lung and liver. Predominantly expressed in differentiated cells as neurons in brain, type I cells in lung and globlet cells in intestine.
Homodimer; can also form homooligomers. Interacts with BMP2; can form higher oligomers with BMP2 (By similarity). Interacts with SLIT1 and SLIT2 in a glycosylation-dependent manner (PubMed:15528323).
Asymmetrically localized to specific cell-cell boundaries in the developing inner ear.
Expression does not persist beyond the early postnatal period in the sensory region of the inner ear.
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).
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).
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. The PAMPs notably include mycobacterial trehalose 6,6'-dimycolate (TDM), a cell wall glycolipid with potent adjuvant immunomodulatory functions. Interacts with signaling adapter Fc receptor gamma chain/FCER1G to form a functional complex in myeloid cells. 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 (Th1) and T-helper 17 (Th17) cell subtypes. Also recognizes alpha-mannose residues on pathogenic fungi of the genus Malassezia and mediates macrophage activation. Through recognition of DAMPs released upon nonhomeostatic cell death, enables immune sensing of damaged self and promotes inflammatory cell infiltration into the damaged tissue.
Expressed in dendritic cells, macrophages, neutrophils and in B-cells.
Monomer and homodimer (By similarity). 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 signaling adapter Fc receptor gamma chain/FCER1G to form a functional complex (PubMed:23921530). Interacts with SAP130 nuclear protein that is released from necrotic cells; the interaction is direct (By similarity).
Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons.
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. 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. Interacts with LSM10 and LSM11 (By similarity).
Involved in both the assembly of spliceosomal snRNPs and the methylation of Sm proteins (By similarity). 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 (By similarity). 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) (By similarity). 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 (By similarity). 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 (By similarity).
Was originally thought to be a chloride channel.
Although related to the Ser/Thr protein kinase family, has no protein kinase activity and acts as a mannose kinase instead.
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 (By similarity).
Binds, as a tetramer, through its N-terminal region, with the bZIP domain of CREB1. 'Arg-314' in the bZIP domain of CREB1 is essential for this interaction. Interaction, via its C-terminal, with TAF4, enhances recruitment of TAF4 to CREB1. Interacts with 14-3-3 proteins, including YWHAE/14-3-3 epsilon. Interacts with calmodulin-dependent catalytic subunit PPP3CA/calcineurin A.
Highly expressed in developing cortical neurons, peaking during dendrite development.
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.
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 (By similarity). 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. 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 (By similarity).
Homodimer. Interacts with polynucleotide kinase (PNK), DNA polymerase-beta (POLB) and DNA ligase III (LIG3). Interacts with APTX and APLF. Interacts with APEX1; the interaction is induced by SIRT1 and increases with the acetylated form of APEX1. Interacts with (poly-ADP-ribosylated) PARP1.
Phosphorylation of Ser-371 causes dimer dissociation. Phosphorylation by CK2 promotes interaction with APTX and APLF (By similarity).
Scaffold protein involved in DNA single-strand break repair by mediating the assembly of DNA break repair protein complexes. Negatively regulates ADP-ribosyltransferase activity of PARP1 during base-excision repair in order to prevent excessive PARP1 activity. Recognizes and binds poly-ADP-ribose chains: specifically binds auto-poly-ADP-ribosylated PARP1, limiting its activity.
Catalyzes the amidation of bile acids (BAs) with the amino acids taurine and glycine (PubMed:12951368, PubMed:624713). More efficient at taurine conjugation of cholyl CoA than glycine conjugation (PubMed:12951368, PubMed:624713). 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 (By similarity). 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 (By similarity). May also act as an acyl-CoA thioesterase that regulates intracellular levels of free fatty acids (By similarity). 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 (By similarity).
Expressed in liver (at protein level); found in hepatocytes, sinusoidal endothelial cells and Kupffer cells.
Highly expressed in placenta. Moderate expression in intestine, heart and brain. In the brain, widely expressed, especially in hippocampus, cerebellum and cerebral cortex. Expression is low in kidney and lung and undetectable in liver.
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.
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. Forms.
Prominently found in brain at both mRNA and protein levels. Moderate expression in testis and lung. Slightly expressed in heart, spleen, skeletal muscle, liver and kidney.
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.
Component of the GPI transamidase complex. May be involved in the recognition of either the GPI attachment signal or the lipid portion of GPI.
Forms a complex with PIGK/GPI8, PIGS, PIGT and GPAA1/GAA1.
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 (By similarity).
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 (By similarity). Interacts (via lumenal domain) with THBS1 (By similarity).
Interacts with XBP1 isoform 2; the interaction occurs in a ER stress-dependent manner. Interacts with LACC1.
N-glycosylated. The glycosylation status may serve as a sensor for ER homeostasis, resulting in ATF6 activation to trigger the unfolded protein response (UPR) (By similarity).
Precursor of the transcription factor form (Processed cyclic AMP-dependent transcription factor ATF-6 alpha), which is embedded in the endoplasmic reticulum membrane. 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).
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. 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'). Binding to ERSE requires binding of NF-Y to ERSE. Could also be involved in activation of transcription by the serum response factor. May play a role in foveal development and cone function in the retina.
Ubiquitinated by RNF186 at Lys-139, which is required for pattern recognition receptor-induced unfolded protein response-associated outcomes.
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 the CRL2(FEM1C) E3 ubiquitin-protein ligase complex.
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 (By similarity).
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 (By similarity).
The twin CX3C motif contains 4 conserved Cys residues that form 2 disulfide bonds in the mitochondrial intermembrane space. However, during the transit of TIMM10 from cytoplasm into mitochondrion, the Cys residues probably coordinate zinc, thereby preventing folding and allowing its transfer across mitochondrial outer membrane (By similarity).
Plays an important role in the differentiation and development of pancreatic islet beta cells. Transcriptional repressor that competes with PAX6 in binding to a common element in the glucagon, insulin and somatostatin promoters (By similarity).
Specifically expressed in pancreatic islets.
Acetylation at Lys-210 and Lys-215 regulates ubiquitination by the SCF(FBXL17) complex. Acetylated at Lys-215 by p300/EP300. Deacetylated at Lys-210 and Lys-215 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:12737817, PubMed:15837430, PubMed:18492485, PubMed:22095282, PubMed:19405910). 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 (By similarity). 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 (By similarity). Methylates RBM15, promoting ubiquitination and degradation of RBM15 (By similarity). Methylates FOXO1 and retains it in the nucleus increasing its transcriptional activity (By similarity). Methylates CHTOP and this methylation is critical for its 5-hydroxymethylcytosine (5hmC)-binding activity (By similarity). Methylates MAP3K5/ASK1 at 'Arg-85' and 'Arg-87' 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 (By similarity). Plays a role in regulating alternative splicing in the heart (By similarity).
Homodimer and heterodimer with PRMT8. Homooctamer; individual homodimers associates to form a homooctamer. Interacts with NFATC2IP. Interacts with ILF3 and SUPT5H. Individual homodimers can associate to form a homohexamer. Interacts with FOXO1; the interaction methylates FOXO1, retaining it in the nucleus and increasing its transcriptional activity. Methylation of FOXO1 is increased with oxidative stress. Interacts with CHTOP; the interaction methylates CHTOP, enabling its interaction with the 5FMC complex (By similarity). Interacts with BTG1, BTG2 and IFNAR1. Interacts with and probably methylates ATXN2L (By similarity). Component of the methylosome, a 20S complex containing at least CLNS1A/pICln, PRMT5/SKB1, WDR77/MEP50, PRMT1 and ERH (By similarity). Interacts with DHX9 (via RGG region) (By similarity). Interacts (via N-terminus) with HABP4 (By similarity). 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 (By similarity).
Polyubiquitinated at Lys-127 by the SCF(FBXL17) complex, leading to its subsequent degradation (By similarity). Ubiquitination is regulated by acetylation at Lys-210 and Lys-215 (By similarity). Polyubiquitinated by E3 ubiquitin-protein ligase TRIM48, leading to suppression of MAP3K5/ASK1 methylation and subsequent MAP3K5 activation (By similarity).
After the establishment of chromosomal sex at fertilization.
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.
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:5871820). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:5871820). 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 (By similarity).
Hexokinase activity is specifically inhibited by 2,6-disubstituted glucosamines.
Monomer (By similarity). Interacts with TIGAR; the interaction increases hexokinase activity in a hypoxia- and HIF1A-dependent manner (By similarity).
The N- and C-terminal halves of the protein contain a hexokinase domain. In contrast to hexokinase-1 and -3 (HK1 and HK3, respectively), both hexokinase domains display catalytic activity. The region connecting the two hexokinase domains is required for the catalytic activity of the N-terminal hexokinase domain. The N-terminal half regulates stability of the whole enzyme.
Detected in brain and liver (at protein level). Ubiquitously expressed.
Plays a role in endocytosis and/or membrane trafficking at the trans-Golgi network (TGN) (By similarity). May act by linking the adapter protein complex AP-1 to other proteins (By similarity). Component of clathrin-coated vesicles (By similarity). 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 (By similarity).
Self-associates (By similarity). Interacts with GGA1 (via GAE domain) (By similarity). Interacts with GGA2 and GGA3 (By similarity). Interacts with AP1G1 (via GAE domain), a subunit of adapter protein complex AP-1 (By similarity). Interacts with AP1G2 (via GAE domain) a subunit of adapter protein complex AP-1 (By similarity). Component of the aftiphilin/p200/gamma-synergin complex, at least composed of AFTPH/aftiphilin, HEATR5B/p200a and SYNRG/gamma-synergin, which plays a role in the AP1G1/AP-1-mediated trafficking of transferrin from early to recycling endosomes (By similarity). Within the complex interacts with AFTPH/aftiphilin and HEATR5B/p200a; the interactions are direct (By similarity). Interacts (via EH domain) with SCAMP1 (PubMed:10777571).
The DFXDF motifs mediate the interaction with gamma-appendage subunits AP1G1 and AP1G2.
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.
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.
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.
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 (By similarity).
The IGFBP N-terminal domain mediates interaction with TSC2 substrate.
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.
Homotrimer. Interacts with IRS1, JAK1, NRP1, PIK3R1, PLEC and TMF1. Interacts with PPP1CA and regulates its phosphorylation at 'Thr-320'. 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 (By similarity). Interacts with ARHGDIA.
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 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 clearly depends on cell type and stimulus (By similarity). Plays a role in synapse organization, trafficking of synaptic vesicles, the generation of excitatory postsynaptic currents and neuron-neuron synaptic transmission.
AK6 and TAF9 were initially considered as products of the same gene since they share two exons. However, they are translated from different initiation codons and reading frames and encode unrelated proteins. This arrangement is conserved in some mammalian species.
Component of the TFIID basal transcription factor complex, composed of TATA-box-binding protein TBP, and a number of TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13. Component of the TATA-binding protein-free TAF complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex. 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. The STAGA transcription coactivator-HAT complex consists at least of SUPT3H, GCN5L2, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9. Binds N-terminal domain of p53/TP53 which is essential for transcription. 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. Binds TFIIB and the Herpes simplex virus activator VP16. Forms a heterodimer with TAF6 in a complex with the TAF4B-TAF12 heterodimer. Also interacts with TAF5. Binds directly DNA. Increased DNA binding when complexed with TAF6.
The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription. 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). 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. TAF9 is also a component of the TBP-free TAFII complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex. TAF9 and its paralog TAF9B are involved in transcriptional activation as well as repression of distinct but overlapping sets of genes. Essential for cell viability. May have a role in gene regulation associated with apoptosis.
Forms homodimers. Monomers and dimers are able to bind DNA, but the off-rate is faster for monomers (By similarity). 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:15665000). Acts synergistically with NEUROD1/BETA2 and PDX1 (By similarity). Binds the insulin enhancer C1/RIPE3b element (PubMed:15665000). Binds to consensus TRE-type MARE 5'-TGCTGACTCAGCA-3' DNA sequence (By similarity).
Up-regulated by glucose in Langerhans islets (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. 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 MYST1. 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 (By similarity). Forms a complex with MSL1 and NUPR1 (By similarity).
Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. 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 (By similarity).
Interacts with CDK1 (By similarity). Interacts with CDK2. May interact with CDKN1B/KIP1. Identified in a complex with CDK2 and CDKN1B/KIP1, where it interacts primarily with CDK2 (By similarity).
Regulates the G1/S phase transition of the cell cycle by binding and activating CDK1 and CDK2. 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. Interferes with CDKN1B-mediated inhibition of CDK2. Mediates cell survival during the DNA damage process through activation of CDK2.
The C-terminus is required for CDK2-activation, but not CDK2-binding.
Homotrimer (By similarity). Functional P2XRs are organized as homomeric and heteromeric trimers (PubMed:7566120).
Receptor for ATP that acts as a ligand-gated cation channel (PubMed:7566120, PubMed:7566119). Plays a role in sensory perception. Required for normal perception of pain. Required for normal taste perception (By similarity).
Selectively expressed in sensory ganglia.
Homodimer. Interacts with UBE4B and SAP30L (By similarity). Interacts with SCOC and ULK1; SCOC interferes with ULK1-binding to FEZ1 (By similarity). Directly interacts with SCOC and UVRAG. Stabilizes the interaction between SCOC and UVRAG during amino acid starvation (By similarity). Interacts with the NH2-terminal variable region (V1) of PKC zeta and weakly with that of PKC epsilon.
May be involved in axonal outgrowth as component of the network of molecules that regulate cellular morphology and axon guidance machinery. 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 (By similarity).
Belongs to the class I-like SAM-binding methyltransferase superfamily. EFM5 family.
Protein-lysine methyltransferase that selectively catalyzes the trimethylation of EEF1A at 'Lys-79'.
Was originally thought to be an N(6)-adenine-specific DNA methyltransferase based on primary sequence and predicted secondary structure.
Detected in jejunum (PubMed:8404647, PubMed:9820812). Detected in kidney, skeletal muscle, brain and adipose tissue (at protein level) (PubMed:9820812). Detected in small intestine and in kidney, and at much lower levels in brain. Detected in enterocytes in duodenum, jejunum, and ileum (PubMed:8333543).
Detected in small intestine during embryogenesis, but expression is much higher in adult.
Fructose uptake is inhibited by mercury ions (PubMed:26416735). Fructose uptake is only slightly inhibited by cytochalasin B (PubMed:8333543, PubMed:9820812).
Functions as a fructose transporter that has only low activity with other monosaccharides (PubMed:26416735, PubMed:8333543, PubMed:9820812). Can mediate the uptake of deoxyglucose, but with low efficiency (PubMed:8333543). Essential for fructose uptake in the small intestine (By similarity). Plays a role in the regulation of salt uptake and blood pressure in response to dietary fructose (By similarity). Required for the development of high blood pressure in response to high dietary fructose intake (By similarity).
Up-regulated in jejunum by a diet with a high fructose content (at protein level) (PubMed:8404647, PubMed:9820812). Up-regulated in kidney by a diet with a high fructose content (at protein level) (PubMed:9820812). Up-regulated in jejunum by a diet with a high fructose content (PubMed:8404647).
Belongs to the complex I NDUFS5 subunit family.
Probable sodium-dependent amino acid/proton antiporter, could be a neuronal transporter for glutamate.
Possible tumor suppressor which may play a role in cell growth.
Acts as a positive regulator of apoptosis. Phosphorylates myosin light chains.
Highly expressed in thymus, spleen, and testis, lower levels present in the brain.
Interacts with CHP1; the interaction induces CHP1 to translocate from the Golgi to the nucleus.
Homodimer. Interacts with SNX1, SNX2 and SNX4 (By similarity).
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 (By similarity).
Acyltransferase which efficiently conjugates very long-chain and long-chain fatty acids to taurine. Shows no conjugation activity in the presence of glycine (By similarity).
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 (By similarity).
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 (By similarity).
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.
This protein co-purified with the prolactin receptor.
Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids (11beta-hydroxysteroid) such as corticosterone, to inactive 11-ketoglucocorticoids (11-oxosteroid) such as 11-dehydrocorticosterone, in the presence of NAD(+) (PubMed:7649078). Functions as a dehydrogenase (oxidase), thereby decreasing the concentration of active glucocorticoids, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids (PubMed:7649078, PubMed:34028587). Plays an important role in maintaining glucocorticoids balance during preimplantation and protects the fetus from excessive maternal corticosterone exposure (PubMed:34028587). 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 (By similarity). 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 (By similarity). Converts 7-beta-25-dihydroxycholesterol to 7-oxo-25-hydroxycholesterol in vitro (By similarity). 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 (By similarity).
Highly expressed in kidney, adrenal gland and distal colon, and at much lower levels in lung, hypothalamus, hippocampus, and midbrain.
Homozygous knockout pups have reduced Na(+) and water content in the skin at birth, but retain higher levels of Na(+) and water in the skin throughout development and into adulthood at the expense of K(+), manifesting hypokalaemia by 15 days of age and contributing to salt sensitive hypertension.
Inhibited by glycyrrhetinic acid (By similarity). Induced by progesterone, through the Ihh signaling pathway (By similarity).
Interacts with ligand-free cytoplasmic NR3C2.
Rats and mice do not produce appreciable cortisol, because they do not express the 17-alpha hydroxylase (Cyp17a1) enzyme in the adrenals.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. In this context, interacts with GNB2 (By similarity). Interacts with UNC5B (By similarity). Interacts with GPSM1 (PubMed:11121039). Interacts with RGS12 and RGS14 (PubMed:11387333). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:21653697). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif) (By similarity). Interacts (inactive GDP-bound form) with CCDC8A/GIV (via GBA motif) (PubMed:19211784).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. May play a role in cell division.
Associates with GIRK2, GIRK3 or GIRK4 to form a G-protein activated heteromultimer pore-forming unit. The resulting inward current is much larger (By similarity).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ3 subfamily.
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. This receptor plays a crucial role in regulating the heartbeat.
Acetylated by EP300; acetylation leads both to the decreased of SIRT2-mediated alpha-tubulin deacetylase activity and SIRT2-mediated down-regulation of TP53 transcriptional activity.
Belongs to the sirtuin family. Class I subfamily.
Expressed in the cerebellum, cerebral cortex and cervival spinal cord. Expressed in Purkinje cells, oligodendrocytes and Schwann cells (at protein level). Expressed in the central nervous system (CNS).
Has some ability to deacetylate histones in vitro, but seeing its subcellular location, this is unlikely in vivo.
In oligodendrocytes during differentiation of CG-4 cells.
Inhibited by Sirtinol, A3 and M15 small molecules. Inhibited by nicotinamide. Inhibited by a macrocyclic peptide inhibitor S2iL5. Inhibited by EP300-induced acetylation (By similarity).
Interacts with CDC20, FOXO3 and FZR1 (By similarity). Associates with microtubules in primary cortical mature neurons (By similarity). Homotrimer. Interacts (via both phosphorylated, unphosphorylated, active or inactive forms) with HDAC6; the interaction is necessary for the complex to interact with alpha-tubulin, suggesting that these proteins belong to a large complex that deacetylates the cytoskeleton. Interacts with FOXO1; the interaction is disrupted upon serum-starvation or oxidative stress, leading to increased level of acetylated FOXO1 and induction of autophagy (By similarity). Interacts with RELA; the interaction occurs in the cytoplasm and is increased in a TNF-alpha-dependent manner. Interacts with HOXA10; the interaction is direct. Interacts with YWHAB and YWHAG; the interactions occur in a AKT-dependent manner and increase SIRT2-dependent TP53 deacetylation. Interacts with MAPK1/ERK2 and MAPK3/ERK1; the interactions increase SIRT2 stability and deacetylation activity. Interacts (phosphorylated form) with KMT5A isoform 2; the interaction is direct, stimulates KMT5A-mediated methyltransferase activity on histone at 'Lys-20' (H4K20me1) and is increased in a H(2)O(2)-induced oxidative stress-dependent manner. Interacts with G6PD; the interaction is enhanced by H(2)O(2) treatment. Interacts with a G1/S-specific cyclin E-CDK2 complex. Interacts with AURKA, CDK5R1 (p35 form) and CDK5 and HIF1A. Interacts with the tRNA ligase SARS1; recruited to the VEGFA promoter via interaction with SARS1 (By similarity). Interacts with BEX4; negatively regulates alpha-tubulin deacetylation by SIRT2 (By similarity).
NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors (PubMed:17344398). Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by KMT5A leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates KMT5A modulating KMT5A chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates histone H4 at 'Lys-16' (H4K16ac) at the VEGFA promoter and thereby contributes to regulate expression of VEGFA, a key regulator of angiogenesis. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy (By similarity). Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation (By similarity). Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor (PubMed:22943040). In addition to protein deacetylase activity, also has activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as ARF6 and KRAS, thereby regulating their association with membranes (By similarity).
Phosphorylated at phosphoserine and phosphothreonine. Phosphorylated at Ser-330 by a mitotic kinase CDK1/cyclin B at the G2/M transition; phosphorylation regulates the delay in cell-cycle progression. Phosphorylated at Ser-330 by a mitotic kinase G1/S-specific cyclin E/Cdk2 complex; phosphorylation inactivates SIRT2-mediated alpha-tubulin deacetylation and thereby negatively regulates cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Phosphorylated by cyclin A/Cdk2 and p35-Cdk5 complexes and to a lesser extent by the cyclin D3/Cdk4 and cyclin B/Cdk1, in vitro. Dephosphorylated at Ser-330 by CDC14A and CDC14B around early anaphase (By similarity).
Catalyzes the reversible hydration of carbon dioxide.
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.
Interacts (via LDL-receptor class A domains) with TCN2.
Receptor for transcobalamin saturated with cobalamin (TCbl). Plays an important role in cobalamin uptake. Plasma membrane protein that is expressed on follicular dendritic cells (FDC) and mediates interaction with germinal center B cells. Functions as costimulator to promote B cell responses to antigenic stimuli; promotes B cell differentiation and proliferation. 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). CD320 augments the proliferation of PC precursors generated by IL-10.
Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney (By similarity).
Monomer. May also exist as a heterodimer; with ERAP2. Interacts with RBMX (By similarity).
Belongs to the IspD/TarI cytidylyltransferase family. IspD subfamily.
Cytidylyltransferase required for protein O-linked mannosylation (By similarity). Catalyzes the formation of CDP-ribitol nucleotide sugar from D-ribitol 5-phosphate. 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 (By similarity). 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 (By similarity). Not involved in dolichol production (By similarity).
Putative C to U editing enzyme whose physiological substrate is not yet known.
Activated by the non-canonical Wnt signaling pathway, in which WNT5A leads to activation of MAP3K7/TAK1 and HIPK2, which subsequently phosphorylates and activates this protein. Activated by dimerization and subsequent intermolecular autophosphorylation on Thr-298. Other cytokines such as IL6 may also activate this regulatory circuit (By similarity).
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 (By similarity).
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. Forms a transcriptional repressor complex with CHD7, PPARG and SETDB1. Interacts with RNF138/NARF (By similarity). Interacts with ATF5; the interaction stabilizes ATF5 at the protein level in a kinase-independent manner (By similarity).
Phosphorylated on Thr-298. Intermolecular autophosphorylation on Thr-298 activates the enzyme (By similarity).
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. Activation of this pathway causes binding to and phosphorylation of the histone methyltransferase SETDB1. The NLK-SETDB1 complex subsequently interacts with PPARG, leading to methylation of PPARG target promoters at histone H3K9 and transcriptional silencing. The resulting loss of PPARG target gene transcription inhibits adipogenesis and promotes osteoblastogenesis in mesenchymal stem cells (MSCs). 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.
Belongs to the uroporphyrinogen decarboxylase family.
E2-dependent E3 ubiquitin-protein ligase that functions as a RIGI coreceptor in the sensing of viral RNAs in cell cytoplasm and the activation of the antiviral innate immune response. Together with the UBE2D3, UBE2N and UB2V1 E2 ligases, catalyzes the 'Lys-63'-linked polyubiquitination of RIGI oligomerized on viral RNAs, an essential step in the activation of the RIG-I signaling pathway. Through a ubiquitin-independent parallel mechanism, which consists in bridging RIGI filaments forming on longer viral RNAs, further activates the RIG-I signaling pathway. This second mechanism that synergizes with the ubiquitin-dependent one would thereby allow an RNA length-dependent regulation of the RIG-I signaling pathway. Associated with the E2 ligase UBE2N, also constitutively synthesizes unanchored 'Lys-63'-linked polyubiquitin chains that may also activate the RIG-I signaling pathway.
Homodimer. Interacts (homodimer) with RIGI (double-stranded RNA-bound oligomeric form); involved in both RIGI ubiquitination, oligomerization into filaments associated with viral RNAs and the bridging of these filaments. Interacts with UBE2D3 and UBE2N; E2 ubiquitin ligases involved in RNF135-mediated ubiquitination of RIGI and activation of the RIG-I signaling pathway. Interacts with PCBP2.
The B30.2/SPRY domain mediates the interaction with the substrate RIGI.
The coiled-coil domains mediate homodimerization and the bridging of viral RNA-associated RIGI filaments.
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. 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. Also catalyzes pseudouridylation of some tRNAs, including synthesis of pseudouridine(55) from uracil-55, in the psi GC loop of a subset of tRNAs.
Expressed in the head and flagellum of epididymal sperm but not in testicular sperm (at protein level). Kidney > liver > heart > muscle > brain.
Plays a role in valine and pyrimidine metabolism. Binds fatty acyl-CoA.
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 and liver. Weakly or not expressed in brain, heart, lung, spleen, epididymis and testis.
Growth regulator. Inhibits the proliferation of a number of tumor cell lines. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells (By similarity). Uses only type II OSM receptor (heterodimers composed of OSMR and IL6ST). Involved in the maturation of fetal hepatocytes, thereby promoting liver development and regeneration.
Propeptide processing is not important for receptor binding activity but may be important growth-inhibitory activity.
Widely expressed. Expressed at higher levels in liver, skin and spleen.
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 (By similarity).
Syntaxin that may be involved in targeting and fusion of Golgi-derived retrograde transport vesicles with the ER.
Odorant receptor. Activated by a lily-derived aldehyde as well as other odorants. May signal through an inositol 1,4,5-trisphosphate (IP3) second messenger system.
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. Interacts (via the biotin carboxylation domain) with SIRT4 (By similarity).
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.
Cell-cycle-regulated enzyme of importance in nucleotide metabolism. Catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. Transcriptional regulation limits expression to the S phase of the cell cycle and transient expression coincides with the oscillation in the intracellular dTTP concentration.
Homotetramer. Tetramerization from dimerization is induced by ATP and increases catalytic efficiency due to a high affinity for thymidine. Tetramerization is inhibited by phosphorylation at Ser-13. Interacts (via the KEN box) with FZR1.
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.
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.
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.
Belongs to the potassium channel family. S (TC 1.A.1.2) subfamily. Kv9.1/KCNS1 sub-subfamily.
Heteromultimer with KCNB1 and KCNB2. Does not form homomultimers.
Highly expressed in brain, but not in the other tissues tested (PubMed:9704029).
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.
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 (By similarity). Involved in the 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.
Abundant expression in lung, spleen and thymus, and detected faintly in brain, liver, adrenal gland and heart at protein level.
Proton-coupled amino-acid transporter that transports free histidine and certain di- and tripeptides, and is involved in innate immune response (PubMed:11336635). Also able to transport carnosine (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 (By similarity).
Homodimer; disulfide-linked. Interacts with PVR (By similarity).
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 (By similarity).
Expressed in Schwann cells (PubMed:32169171). Expressed (at protein level) in liver (PubMed:1400324).
Homodimer. The enzyme contains three components A, B and C, the latter two being produced from the first by a proteolytic cleavage. Interacts with LONP2 (By similarity).
Involved in the initial and rate-limiting step of peroxisomal beta-oxidation of straight-chain saturated and unsaturated very-long-chain fatty acids. Catalyzes the desaturation of fatty acyl-CoAs such as palmitoyl-CoA (hexadecanoyl-CoA) to 2-trans-enoyl-CoAs ((2E)-enoyl-CoAs) such as (2E)-hexadecenoyl-CoA, and donates electrons directly to molecular oxygen (O(2)), thereby producing hydrogen peroxide (H(2)O(2)).
Is active against a much broader range of substrates and shows activity towards long-chain acyl-CoAs.
Shows highest activity against medium-chain fatty acyl-CoAs. Shows optimum activity with a chain length of 10 carbons (decanoyl-CoA) in vitro.
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).
Detected in kidney, in proximal tubules.
Down-regulated in kidneys from a strain of spontaneously hypertensive rats (SHR). Down-regulated after unilateral ureteral obstruction or unilateral nephrectomy.
First detected in kidney from 1 week old rats. Not detectable in fetal kidney and in kidney from newborn rats.
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 (By similarity). Interacts with STAM (By similarity). Interacts with STAM2 (By similarity). Interacts with EPS15; the interaction is direct, calcium-dependent and inhibited by SNAP25 (PubMed:10809762). Identified in a complex with STAM and LITAF (By similarity). Found in a complex with STAM and E3 ligase ITCH and DTX3L (By similarity). 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 (By similarity). Interacts with NF2; the interaction is direct (By similarity). Interacts with ubiquitin; the interaction is direct (By similarity). Interacts with VPS37C (By similarity). Interacts with SMAD1, SMAD2 and SMAD3 (By similarity). Interacts with TSG101; the interaction mediates the association with the ESCRT-I complex (By similarity). Interacts with SNAP25; the interaction is direct and decreases with addition of increasing concentrations of free calcium (PubMed:9039916, PubMed:10825299). Interacts with SNX1; the interaction is direct (PubMed:11110793). Component of a 550 kDa membrane complex at least composed of HGS and SNX1 but excluding EGFR (PubMed:11110793). Interacts with TRAK2 (PubMed:17062640). Interacts with TRAK1 (By similarity). Component of the CART complex, at least composed of ACTN4, HGS/HRS, MYO5B and TRIM3 (By similarity). Interacts (via UIM domain) with UBQLN1 (via ubiquitin-like domain) (By similarity). Interacts with ARRDC3 (By similarity). Identified in a complex containing at least ARRDC4, AVPR2 and HGS (By similarity). Interacts with LAPTM4B; promotes HGS ubiquitination (By similarity).
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. 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 (By similarity). May contribute to the efficient recruitment of SMADs to the activin receptor complex.
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. This phosphorylation occurs in response to EGF. A minor site of phosphorylation on Tyr-329 is detected. Protein phosphorylation may also be triggered in response to IL-2, GM-CSF and HGF (By similarity).
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 (By similarity).
May be proteolytically processed in neuron-like cells.
May be signaling molecules that resemble neuropeptides and that act by binding to alpha-neurexins and possibly other receptors.
Heterodimer with MMACHC. Forms a multiprotein complex with MMACHC, MTR and MTRR.
Involved in cobalamin metabolism and trafficking. Plays a role in regulating the biosynthesis and the proportion of two coenzymes, methylcob(III)alamin (MeCbl) and 5'-deoxyadenosylcobalamin (AdoCbl). Promotes oxidation of cob(II)alamin bound to MMACHC. 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.
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 (By similarity).
Belongs to the bacterial ribosomal protein bL36 family.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.1/KCNH8 sub-subfamily.
Detected in superior cervical, mesenteric and coeliac ganglia. Expressed in brain (piriform cortex, olfactory tubercle, cerebral cortex, hippocampus pyramidial cells and dentate gyrus and basal ganglia of caudate/putamen and accumbens nucleus). Expressed in pituitary.
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.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes (By similarity). 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 (By similarity). 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 (By similarity). CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively (By similarity). Essential to maintain the survival of epiblast cells and thus the development of the postimplantation embryo (By similarity).
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 (By similarity). In the complex, it probably interacts directly with COPS1, COPS4, COPS8 and COPS9 (By similarity). Interacts with CK2 and PKD (By similarity). Interacts with the translation initiation factor EIF3S6 and IKBKG (By similarity). Interacts with ERCC6 (By similarity).
Acetylation at Lys-205 and Lys-702 by KAT5 promotes its transcription activator activity.
Brain, not in liver, very low in other tissues. The long (neuron-specific) form is expressed only in brain.
Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP (By similarity). Interacts (via PID domain 2) with APP (with the intracellular domain of the amyloid-beta precursor protein) (By similarity). Interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the transcription activation activity (By similarity). Interacts (via PID domain 1) with KAT5/TIP60 (PubMed:19282473). 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 (By similarity). Interacts with MAPK8 (By similarity). Interacts (via PID domain 1) with TSHZ3 (via homeobox domain) (PubMed:19343227). Interacts with SET (By similarity). Found in a trimeric complex with HDAC1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (By similarity). Interacts (via WWW domain) with NEK6 (By similarity). Interacts (via WWW domain) with ABL1. Interacts with RNF157 (By similarity).
Phosphorylation at Ser-611 by SGK1 promotes its localization to the nucleus (PubMed:18304449). Phosphorylated following nuclear translocation. Phosphorylation at Tyr-547 by ABL1 enhances transcriptional activation activity and reduces the affinity for RASD1/DEXRAS1 (By similarity).
Polyubiquitination by RNF157 leads to degradation by the proteasome.
Transcription coregulator that can have both coactivator and corepressor functions. Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. 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. Required for histone H4 acetylation at double-strand breaks (DSBs) (By similarity). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its transcription activation activity (PubMed:19282473). Functions in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s) (By similarity). Involved in hippocampal neurite branching and neuromuscular junction formation, as a result plays a role in spatial memory functioning. Plays a role in the maintenance of lens transparency. May play a role in muscle cell strength (By similarity).
Belongs to the glycosyltransferase 90 family.
Dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose from UDP-glucose and UDP-xylose, respectively, to a serine residue found in the consensus sequence of C-X-S-X-P-C. Specifically targets extracellular EGF repeats of protein such as CRB2, F7, F9 and NOTCH2 (By similarity). Acts as a positive regulator of Notch signaling by mediating O-glucosylation of Notch, leading to regulate muscle development (By similarity). Notch glucosylation does not affect Notch ligand binding (By similarity). Required during early development to promote gastrulation: acts by mediating O-glucosylation of CRB2, which is required for CRB2 localization to the cell membrane (By similarity).
Broadly expressed, with highest levels in pancreatic islets, testis and bladder. Present in the islets of Langerhans (at protein level).
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. 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. By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes. 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.
BH1 and BH2 domains are required for the interaction with BAX and for anti-apoptotic activity.
Expressed in a variety of tissues, with highest levels in reproductive tissues. In the adult brain, expression is localized in mitral cells of the olfactory bulb, granule and pyramidal neurons of hippocampus, pontine nuclei, cerebellar granule neurons, and in ependymal cells. In prenatal brain, expression is higher and localized in the neuroepithelium and in the cortical plate.
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 (By similarity). 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 (By similarity). Interacts with GIMAP3/IAN4, GIMAP4/IAN1 and GIMAP5/IAN5 (By similarity). Interacts with BCAP31. Interacts with IRF3; the interaction is inhibited by Sendai virus infection. Interacts with BECN1; thereby inhibiting autophagy in non-starvation conditions. Interacts with AMBRA1; thereby inhibiting autophagy (By similarity).
Monoubiquitinated by PRKN, leading to an increase in its stability. Ubiquitinated by SCF(FBXO10), leading to its degradation by the proteasome.
Phosphorylation/dephosphorylation on Ser-70 regulates anti-apoptotic activity. 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. In the absence of growth factors, BCL2 appears to be phosphorylated by other protein kinases such as ERKs and stress-activated kinases. Phosphorylated by MAPK8/JNK1 at Thr-69, Ser-70 and Ser-84, wich stimulates starvation-induced autophagy (By similarity). 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 (By similarity).
Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. 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). Also acts as an inhibitor of autophagy: interacts with BECN1 and AMBRA1 during non-starvation conditions and inhibits their autophagy function. May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release.
The BH3 motif is required 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.
Expressed in a circadian manner in the suprachiasmatic nucleus (SCN) of the brain.
Expressed in heart, spleen, lung, liver, muscle, kidney, uterus and gut. Highly expressed in the cerebral cortex, especially in the fifth layer, thalamus, superior colliculus, olfactory bulb, piriform cortex, hippocampus and hypothalamic nuclei.
Homodimer. Heterodimer with BHLHE41/DEC2. Interacts with TCF3/E47. Interacts with ubiquitin-conjugating enzyme UBE2I/UBC9. Interacts with HDAC1, SUMO1, RXRA and BMAL1 (By similarity).
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. 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 PER1/2 and in turn is repressed by PER1/2 and CRY1/2. 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. 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 and NR1H3/LXRA transactivation activity. May be involved in the regulation of chondrocyte differentiation via the cAMP pathway (By similarity). Represses the transcription of NR0B2 and attentuates the transactivation of NR0B2 by the CLOCK-BMAL1 complex (By similarity). Drives the circadian rhythm of blood pressure through transcriptional repression of ATP1B1 in the cardiovascular system (By similarity).
Ubiquitinated; which may lead to proteasomal degradation.
Probable cell adhesion protein involved in leukocyte transmigration across the blood-brain barrier. Does not express any beta-galactosyltransferase activity in vitro.
Transcription regulator which may participate in NGFR/p75(NTR)-mediated apoptosis. Probably acts as a 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 (By similarity).
Belongs to the GST superfamily. Kappa family.
Glutathione S-transferase that catalyzes the conjugation of glutathione to exogenous and endogenous compounds.
Acetylated by EP300. Lys-210 as is the major acetylation site for EP300; the dynamicly regulated acetylation inhibits heterodimerization with RXRA and transactivation activity. Deacetylated by SIRT1.
Heterodimer of NR1H4 and RXR activated by farnesol.
Heterodimer with RXRA; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (By similarity). 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, EP300 and SMARCD1. Interacts with XRCC5 and XRCC6; decreasing NR1H4/FXR transactivation activity towards ABCB11/BSEP. Interacts with PAGR1 AND NCOA6; indicative for an association with an MLL2/MLL3 complex (ASCOM).
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. 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. 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). 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). 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). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression. The function also involves the coordinated induction of hepatic KLB/beta-klotho expression. 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. 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). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element. Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase). 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). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance. Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier. Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells. 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. 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.
Methylation may increase transactivation of target genes.
Phosphorylation by PKC/PRKCA increases transactivation activity by promoting association with PPARGC1A.
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 (By similarity).
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 and SRSF9. 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. Interacts with VGF-derived peptide TLQP-21 (PubMed:24106277).
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. 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. May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription. May play a role in antibacterial defense.
Both EF-hands are required for function.
Expressed predominantly in whole brain and kidney, with limited expression in heart, lung, liver, and skeletal muscle and no expression in spleen and testis. Also expressed in pituitary gland, adrenal gland, digestive tract, and reproductive organs.
Mediates cell-cell adhesion in a calcium-dependent manner. Able to inhibit growth in several cell lines.
Probably digested extracellularly by an unknown serine protease generating extremely hydrophobic bioactive peptides.
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). May play a role in DNA damage response and may participate in cell proliferation and anchorage-independent cell growth.
Part of a complex that contains DCUN1D5, CUL1 and RBX1; this interaction is bridged by CUL1. 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. Interacts (via DCUN1 domain) with UBE2M (N-terminally acetylated form) and probably with UBE2F (N-terminally acetylated form). May also interact with regulators or subunits of cullin-RING ligases such as RBX1, RNF7, ELOB and DDB1; these interactions are bridged by cullins. 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.
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 (By similarity).
The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins. 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.
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 (By similarity). It cleaves after Asp (PubMed:9765264). 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 (By similarity). Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution (By similarity). Cleaves caspase-3 and -9 (CASP3 and CASP9, respectively) to give rise to active enzymes mediating apoptosis (PubMed:9765264). Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair (By similarity).
Inactivated by the serine protease inhibitor diisopropylfluorophosphate.
By polycyclic hydrocarbons (Governed by the aromatic hydrocarbon-responsive (AH) locus).
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:1703398, PubMed:7862630). 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 (By similarity). Alternatively, can activate quinones and their derivatives by generating redox reactive hydroquinones with DNA cross-linking antitumor potential (By similarity). 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 (By similarity).
Homodimer (PubMed:7568029). 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 (By similarity). 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 (By similarity). 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 (By similarity).
PubMed:2480957 sequence seems incorrectly to be attributed to a mouse sequence while it really seems to correspond to the rat sequence.
Quinone reductase accepts electrons from both NADH and NADPH with equal efficiency.
This protein is inhibited by dicoumarol.
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.
Interacts with PROM1. Interacts with BACE1.
May have a lysine N-acetyltransferase activity catalyzing peptidyl-lysine N6-acetylation of various proteins (By similarity). Thereby, may regulate apoptosis through the acetylation and the regulation of the expression of PROM1 (By similarity). May also regulate amyloid beta-peptide secretion through acetylation of BACE1 and the regulation of its expression in neurons (By similarity). May play a role in regulation of gastrulation (PubMed:11397015).
Has omega-amidase activity. 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.
Fei et al (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.
Highly expressed in liver (PubMed:10619430). Expressed in skeletal muscle. Expressed in kidney, heart and brain (PubMed:10619430). Not detected in gut, lung or spleen (PubMed:10619430). Expressed ubiquitously in hepatocytes in liver whereas in kidney expression is restricted to the medulla (PubMed:10619430). Within brain, expressed in glial cells (PubMed:10619430). In the cerebellum, expressed on Bergmann glial fibers in the molecular layer and astrocytes in the granule layer (PubMed:10619430). Expressed in brain kidney and liver (at protein level) (PubMed:15716335). In the adult kidney, highly expressed in the outer strip of the outer medulla and medullary rays penetrating into the kidney cortex (at protein level) (PubMed:15716335).
Induced by chronic metabolic acidosis (CMA).
L-glutamine efflux and L-glutamine uptake are regulated by CO2/HCO3(-) through SLC4A4 leading to modulation of cytosolic pH and Na(+)concentration.
Phosphorylation at Ser-52 induces internalization and sequestration into an intracellular reservoir (PubMed:21525297, PubMed:29561757). During dephosphorylation by protein phosphatases, can recycle back to the plasma membrane and regain activity. Prolonged phosphorylation results in its degradation (PubMed:21525297).
Symporter that cotransports specific neutral amino acids and sodium ions, coupled to an H(+) antiporter activity (PubMed:10619430, PubMed:16249471, PubMed:17148440, PubMed:19596860, PubMed:28272791, PubMed:29561757, PubMed:11850497, PubMed:21525297, PubMed:11742981, 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 (PubMed:10619430, PubMed:29561757, PubMed:28272791). 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:10619430, PubMed:16249471, PubMed:17148440, PubMed:19596860, PubMed:28272791, PubMed:29561757, PubMed:11850497, PubMed:21525297, PubMed:11742981, PubMed:10823827). The transport is electroneutral coupled to the cotransport of 1 Na(+) and the antiport of 1 H(+), pH dependent, saturable, Li(+) tolerant and functions in both direction depending on the concentration gradients of its substrates and cotransported ions (PubMed:10619430, PubMed:16249471, PubMed:17148440, PubMed:19596860, PubMed:28272791, PubMed:11850497, PubMed:11742981, PubMed:10823827, PubMed:17909850). 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 (PubMed:11742981). In addition, may play a role in nitrogen metabolism, amino acid homeostasis, glucose metabolism and renal ammoniagenesis (By similarity).
Fatty acylated. Heavily palmitoylated in the cysteine string motif (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-alpha subfamily 1 members, predominantly to G(i)-alpha-3. Activity on G(z)-alpha is inhibited by phosphorylation and palmitoylation of the G-protein (By similarity).
Interacts with GIPC PDZ domain. Interacts with GNAO1.
Phosphorylated, mainly on serine residues.
Catalyzes the hydroxylation of 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinol (DMQH2) during ubiquinone biosynthesis. Has also a structural role in the COQ enzyme complex, stabilizing other COQ polypeptides. Involved in lifespan determination in a ubiquinone-independent manner.
Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9. Interacts with ADCK4 and COQ6. Interacts with COQ9.
Activated by autophosphorylation at Tyr-1162, Tyr-1166 and Tyr-1167 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 (By similarity). Dephosphorylated by PTPN1 (By similarity).
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-1166 is predominantly phosphorylated first, followed by phosphorylation of Tyr-1162 and Tyr-1167. While every single phosphorylation increases kinase activity, all three tyrosine residues in the kinase activation loop (Tyr-1162, Tyr-1166 and Tyr-1167) 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-981 is required for IRS1- and SHC1-binding. Phosphorylation of Ser-1279 by GSK-3beta restrains kinase activity and promotes cell surface expression, it requires a priming phosphorylation at Ser-1283 (By similarity). Dephosphorylated by PTPN1.
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 (By similarity).
Polyubiquitinated at Lys-1169 and Lys-1172 through both 'Lys-48' and 'Lys-29' linkages, promoting receptor endocytosis and subsequent degradation by the proteasome. Ubiquitination is facilitated by pre-existing phosphorylation (By similarity).
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 (By similarity). When present in a hybrid receptor with INSR, binds IGF1 (By similarity).
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 (By similarity). Interacts with SOCS1, SOCS2 and SOCS3 (By similarity). Interacts with 14-3-3 proteins (By similarity). Interacts with NMD2 (By similarity). Interacts with MAP3K5 (By similarity). Interacts with STAT3. Found in a ternary complex with IGF1 and ITGAV:ITGB3 or ITGA6:ITGB4 (By similarity). Interacts (nascent precursor form) with ZFAND2B (By similarity).
Expressed in the ganglion cell layer of the retina in the eye and in the ventral zone of the dorsal thalamus of the CNS.
Potential regulator of neural basic helix-loop-helix genes. It may down-regulate expression of ASCL1 and, within the thalamus, up-regulate NGN2, thereby regulating distinct patterns of neuronal differentiation.
Transiently expressed during embryonic development of the nervous system, detected at 11.5 dpc and declining after 15.5 dpc.
Exhibits both phospholipase A1/2 and acyltransferase activities (By similarity). 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 (By similarity). Shows O-acyltransferase activity, catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid (By similarity).
Belongs to the NAD(P)-dependent epimerase/dehydratase family.
Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The reaction with UDP-Gal plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6-phosphate. It contributes to the catabolism of dietary galactose and enables the endogenous biosynthesis of both UDP-Gal and UDP-GalNAc when exogenous sources are limited. Both UDP-sugar interconversions are important in the synthesis of glycoproteins and glycolipids.
Expressed in aortic endothelial cells, with low expression in the descending thoracic aorta and the outer curvature of the aortic arch, where pulsatory shear stress exists, and high in the inner curvature of the aortic arch, where oscillatory shear stress prevails (at protein level) (PubMed:28167758). Expressed predominantly in gastric mucosa and at much lower levels in the intestine (PubMed:8248184).
The GATA-type zinc fingers mediate interaction with LMCD1.
Transcriptional activator that regulates SEMA3C and PLXNA2. May regulate genes that protect epithelial cells from bacterial infection. Involved in gene regulation specifically in the gastric epithelium. Involved in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions.
Involved in the lipid remodeling steps of GPI-anchor maturation.
Interacts with PTPRF. Interacts with DLG4 (By similarity).
Mainly expressed in the brain. Widespread distribution in various brain regions (at protein level). Detected both embryonically and postnatally with stronger expression in postnatal stages.
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.
The extreme C-terminus binds to the first 2 PDZ domains of DLG4.
Detected in serum and cerebrospinal fluid (at protein level). Highly expressed in the choroid plexus. Detected at lower levels in the liver.
Homotetramer. Dimer of dimers. In the homotetramer, subunits assemble around a central channel that can accommodate two ligand molecules. Interacts with RBP4.
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 (By similarity).
This protein binds retinol-binding protein at levels similar to, and the thyroid hormones at levels much higher than, the human protein.
Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Belongs to the bacterial ribosomal protein bL27 family.
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 (By similarity). Interacts (via PDZ domains) with ACE2 (via PDZ-binding motif); the interaction may enhance ACE2 membrane residence (By similarity).
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. Involved in sperm capacitation. May participate in the regulation of the chloride and bicarbonate homeostasis in spermatozoa. 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 (By similarity).
Belongs to the small G protein signaling modulator family.
Expressed in brain, liver, kidney and testis. Moderately expressed in heart, very weakly in lung and muscle. Not expressed in spleen.
Interacts with GJA1. Interaction with GJA1 induces its degradation. Interacts (via RUN domain) with NF2 (via C-terminus). Interacts with RAB3A, RAB4A, RAB5A, RAB8A, RAB11A, RAP1A, RAP1B, RAP2A, RAP2B and PDCD6I. No interaction with RAB27A. No interaction with GJB1 or GJD2.
May play a cooperative role in NF2-mediated growth suppression of cells. May act as a modulator of small G protein RAB- and RAP-mediated neuronal signal transduction and vesicular transportation pathways (By similarity).
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) (By similarity). Interacts with MARCHF11.
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 (By similarity).
Highly expressed in brain; also expressed in liver and kidney.
Oxysterol 7alpha-hydroxylase that mediates formation of 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC) from 25-hydroxycholesterol. Plays a key role in cell positioning and movement in lymphoid tissues: 7-alpha,25-dihydroxycholesterol (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.
Homotetramer. 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.
Highly expressed in brain and lung. Expressed at lower levels in colon, heart, kidney, liver, small intestine, spleen, testis and thymus. Isoform 1 and isoform 2 are the major isoforms in brain while isoform 5 and isoform 6 are the major isoforms in lung, spleen, testis and thymus.
Homodimerizes, the dimers can polymerize end-to-end to form filamentous structures. Interacts with AKAP9, ARHGAP17, DAAM1, DIAPH1, DIAPH2, DNM1, DNM2, DNM3, FASLG/FASL, and SNX2. May interact with TNKS (By similarity). Interacts specifically with GTP-bound RND2 and CDC42. Interacts with PDE6G, WASL/N-WASP and microtubules.
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 (By similarity). May act as a link between RND2 signaling and regulation of the actin cytoskeleton. Isoform 1 and isoform 2 promote RND2-induced neurite branching in neuronal cells.
Dorsalizing factor. Key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta family bone morphogenetic proteins (BMPs) and sequestering them in latent complexes.
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. 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 (By similarity).
Interacts with NBAS and KNTC1/ROD; the interactions are mutually exclusive and indicative for its association in two different vesicle tethering complexes (By similarity). Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH (By similarity). 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) (By similarity). Interacts directly with RINT1/TIP20L bound to BNIP1/SEC20L (By similarity). Interacts with C19orf25 and ZWINT (By similarity). Interacts with ZFYVE1 (By similarity). Interacts with RAB18 and this interaction is enhanced in the presence of ZFYVE1 (By similarity).
Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates (PubMed:17696782). Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins (By similarity). 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 (By similarity). Regulates autophagy via the deubiquitination of 'Lys-402' of BECN1 leading to the stabilization of BECN1 (By similarity).
Interacts with STUB1/CHIP (when monoubiquitinated) (By similarity). Interacts with DNA repair proteins RAD23A and RAD23B. Interacts with BECN1 (via its poly-Gln domain) (By similarity). Interacts with PRKN, UBR2, VCP and tubulin (By similarity).
Monoubiquitinated by UBE2W, possibly leading to activate the deubiquitinating enzyme activity (By similarity).
The UIM domains bind ubiquitin and interact with various E3 ubiquitin-protein ligase, such as STUB1/CHIP (By similarity). They are essential to limit the length of ubiquitin chains (By similarity).
Ubiquitously expressed (PubMed:10732811).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Gamma-aminobutyric acid receptor (TC 1.A.9.5) subfamily. GABRA2 sub-subfamily.
In the male reproductive tract, binds to sperm heads where it modulates sperm capacitance by inhibiting calcium uptake and nitrogen oxide (NO) production (By similarity).
Serine protease inhibitor which exhibits anti-trypsin activity (PubMed:3202973, PubMed:3597401). In the pancreas, protects against trypsin-catalyzed premature activation of zymogens (By similarity).
Expressed in brain, with highest levels in the olfactory bulb, striatum, cerebral cortex, hippocampus and cerebellum. Also expressed in pancreatic islet cells.
Interacts with the N-termini of STX1A and/or STX1B1 and DOC2A (PubMed:8999968, PubMed:9195900, PubMed:9736751). Interacts with BSN (PubMed:12163476, PubMed:14734538). Interacts with RIMS1 which recruits UNC13A to the active zone (PubMed:11343654, PubMed:16704978). Forms homodimers via its first C2 domain. Also interacts via this domain with the zinc finger domain of RIMS2 (PubMed:16052212, PubMed:16732694). Part of a complex consisting of ERC2, RIMS1 and UNC13A (PubMed:12163476). Also part of a complex consisting of UNC13A, RIMS2 and RAB3A. Interacts with FBXO45 (via SRY domain); leading to the degradation of UNC13A by the proteasome (By similarity).
Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release (By similarity). Also involved in secretory granule priming in insulin secretion. Plays a role in dendrite formation by melanocytes (By similarity).
The C-terminal region containing both MHD domains and the third C2 domain is required for synaptic vesicle priming activity.
Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.
Interacts with CLU/clusterin. Interacts with UBXN10; the interaction is direct.
Required for cilia biogenesis. Appears to function within the multiple intraflagellar transport complex B (IFT-B). Key regulator of hedgehog signaling.
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. Lacks carboxypeptidase activity. Lacks dipeptidyl-peptidase IV type activity.
Detected on apical villi on the brush border membrane of ileum enterocytes (at protein level) (PubMed:9388249). Mainly expressed in the distal small intestine (PubMed:9388249).
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 (By similarity). The EARP complex interacts with EIPR1 (PubMed:27191843, PubMed:27440922). Interacts with VPS51 and VPS53 in an EIPR1-independent manner (By similarity).
Expressed in a wide variety of organs including brain, spleen, liver, muscle and kidney.
Homotrimer (By similarity). Interacts with CXCR2 extracellular domain (By similarity). Interacts with the CD74 extracellular domain, USO1, COPS5 and BNIPL (By similarity).
Pro-inflammatory cytokine involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti-inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity.
Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CXCL11 and CXCL12/SDF1 (By similarity). 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:20018651). Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness. In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival. 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. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development. Regulates axon guidance in the oculomotor system through the regulation of CXCL12 levels (By similarity).
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. 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. Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness. In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival. 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. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development.
Belongs to the G-protein coupled receptor 1 family. Atypical chemokine receptor subfamily.
By ischemia. Up-regulated in the cingulate, retrosplenial and frontal areas of the cortex ipsilateral to middle cerebral artery occlusion (MCAO) by 163% at 6 hours, 220% at 2 days and 89% at 4 days after ischemia-onset, with expression reduced back to control level at 10 days after MCAO. Expression is almost undetectable in the infarct area between days 2 and 10 after MCAO.
Expressed in the ventral and dorsal parts of telencephalon at all developmental stages of brain analyzed (14 dpc to P56). Strong expression detected in the cranial connective tissue surrounding the brain at 14 dpc to 15 dpc. In the cortex, expressed mainly in the marginal zone at preplate stage (14 dpc), with expression increasing strongly in the marginal zone/layer I between 15 dpc and 18 dpc and declining rapidly in layer I after P0. Expression emerges in the lateral part of cortical plate at 15 dpc and increases in the medial and lateral parts between 15 dpc and 17 dpc. Expression not detected in the cortical ventricular and subventricular zones at the early embryonic stages but emerges at 18 dpc. Expressed in GABAergic precursors and in some reelin-expressing Cajal-Ratzius cells, in neurons forming the cortical plate and sparsely in the developing dentate gyrus and cerebellar external germinal layer. In the ventral telencephalon, expressed in the germinative zone of the ganglionic eminences and in GABAergic neurons forming the caudate putamen between 14 dpc and 18 dpc.
Expressed in vascular smooth muscle cells (at protein level). In brain, expressed in blood vessels, pyramidal cells in hippocampal subfield CA3, mature dentate gyrus granule cells, ventricle walls, olfactory bulb, accumbens shell, supraoptic, lateroanterior and ventromedial hypothalamic nuclei, medial region of thalamus, and motor nuclei, central gray and raphe magnus nucleus of brain stem. Detected in primary neurons, GABAergic neurons, astrocytes, cerebral cortex, ventral striatum and choroid plexus. Not detected in mesencephalon.
Homodimer. Can form heterodimers with CXCR4; heterodimerization may regulate CXCR4 signaling activity. Interacts with ARRB1 and ARRB2.
The C-terminal cytoplasmic tail, plays a key role in: correct trafficking to the cell membrane, recruitment of beta-arrestin, ubiquitination, and in chemokine scavenging and signaling functions. The Ser/Thr residues and the Lys residues in the C-terminal cytoplasmic tail are essential for beta-arrestin recruitment and ubiquitination respectively.
The Ser/Thr residues in the C-terminal cytoplasmic tail may be phosphorylated.
Ubiquitinated at the Lys residues in its C-terminal cytoplasmic tail and is essential for correct trafficking from and to the cell membrane. Deubiquitinated by CXCL12-stimulation in a reversible manner.
Guanine nucleotide exchange factor (GEF), which can activate some, but not all, G-alpha proteins by exchanging bound GDP for free GTP. Able to potentiate G(olf)-alpha-dependent cAMP accumulation suggesting that it may be an important component for odorant signal transduction (Probable).
Interacts with GDP-bound G alpha proteins GNAI1, GNAL, GNAS and GNAQ. Does not interact with G-alpha proteins when they are in complex with subunits beta and gamma.
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. 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. 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.
Interacts with NOTCH1 (via extracellular region).
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 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).
Expressed in brain, lung, thymus, bladder and skeletal muscle. Up-regulatedd during prostate degeneration.
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. 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). 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 (By similarity). Mediates TNF/TRAF2-induced MAP3K5-JNK activation, while it inhibits CHUK-NF-kappa-B signaling. Functions as a Ras GTPase-activating protein. May act as a tumor suppressor gene.
In response to TNF-alpha-induction, phosphorylated at Ser-535; 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 (via NPXY motif) with DAB2 (via PID domain). Interacts (via PH domain) with ERN1. 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 (By similarity). Interacts with DAB1 and DAB2.
Homodimer. Interacts with CDK16 (By similarity). Interacts with RGS7 (phosphorylated form). 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 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (By similarity). Interacts with SLITRK1 (By similarity). Interacts with RIPOR2 (By similarity). Interacts with INAVA; the interaction increases upon PRR (pattern recognition receptor) stimulation and is required for cellular signaling pathway activation and cytokine secretion (By similarity). Interacts with MARK2, MARK3 and MARK4 (By similarity). Interacts with MEFV (By similarity).
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. At the cell membrane, can promote and as well inhibit cullins neddylation.
Part of a complex containing DCUN1D3, CUL3 and RBX1. 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. Interacts preferentially with CUL3; this interaction triggers the relocalization of CUL3 to the cell membrane where CUL3 is neddylated. Interacts (via DCUN1 domain) with RBX1. May also interact with regulators or subunits of cullin-RING ligases such as RNF7, ELOB and DDB1; these interactions are bridged by cullins. Interacts (via DCUN1 domain) with CAND1; this interaction is bridged by cullins and strongly inhibits cullin neddylation. These CAND-cullin-DCNL complexes can only be neddylated in the presence of a substrate adapter. Interacts (via DCUN1 domain) with the N-terminally acetylated form of UBE2M and UBE2F.
The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins. 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. This domain is also involved in CAND1-, cullins- and RBX1-binding.
Acetylated on multiple sites upon stimulation with LPS (By similarity). Acetylation on lysine residues in the nuclear localization signals (NLS 1 and NLS 2) leads to cytoplasmic localization and subsequent secretion (PubMed:14532127). Acetylation on Lys-3 results in preferential binding to DNA ends and impairs DNA bending activity (PubMed:17269659).
Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers.
In the cytoplasm proposed to dissociate the BECN1:BCL2 complex via competitive interaction with BECN1 leading to autophagy activation (By similarity). 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:22869893). 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. Promotes extracellular DNA-induced AIM2 inflammasome activation implicating AGER/RAGE (By similarity). 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:10952726, PubMed:20547845, PubMed:22869893). Promotes secretion of interferon-gamma by macrophage-stimulated natural killer (NK) cells in concert with other cytokines like IL-2 or IL-12. TLR4 is proposed to be the primary receptor promoting macrophage activation and signaling through TLR4 seems to implicate LY96/MD-2 (By similarity). 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:23508573). Contributes to tumor proliferation by association with ACER/RAGE (PubMed:10830965). Can bind to IL1-beta and signals through the IL1R1:IL1RAP receptor complex (By similarity). Binding to class A CpG activates cytokine production in plasmacytoid dendritic cells implicating TLR9, MYD88 and AGER/RAGE and can activate autoreactive B cells (By similarity). 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 (By similarity). 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 (PubMed:18277947). Released HMGB1:nucleosome complexes formed during apoptosis can signal through TLR2 to induce cytokine production. 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 (By similarity). 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. Can be proteolytically cleaved by a thrombin:thrombomodulin complex; reduces binding to heparin and pro-inflammatory activities (By similarity).
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:22869893). 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 (By similarity). Interacts with AGER (PubMed:12183440). Interacts with PTPRZ1 isoform 3/phosphacan (PubMed:9507007). Interacts with SREBF1, TLR2, TLR4, TLR9, APEX1, FEN1, POLB, TERT, IL1B, MSH2, XPA, XPC, HNF1A, TP53 (By similarity). Interacts with CD24; the probable CD24:SIGLEC10 complex is proposed to inhibit HGMB1-mediated tissue damage immune response. Interacts with THBD; prevents HGMB1 interaction with ACER/RAGE and inhibits HGMB1 pro-inflammatory activity. Interacts with HAVCR2; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response (By similarity). Interacts with XPO1; mediating nuclear export (PubMed:14532127).
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. 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. 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 proangiogenic activity. May be involved in platelet activation. Binds to phosphatidylserine and phosphatidylethanolamide (PubMed:11154118). Bound to RAGE mediates signaling for neuronal outgrowth (PubMed:1885601, PubMed:2461949, PubMed:7592757, PubMed:12183440). May play a role in accumulation of expanded polyglutamine (polyQ) proteins.
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 (PubMed:2922595, PubMed:11513603). 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:12486007). May be involved in nucleotide excision repair (NER), mismatch repair (MMR) and base excision repair (BER) pathways, and double strand break repair such as non-homologous end joining (NHEJ) (PubMed:10866811). 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 (PubMed:24551219). 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 (By similarity). May be involved in mitochondrial quality control and autophagy in a transcription-dependent fashion implicating HSPB1 (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.
Poly-ADP-ribosylated by PARP1 when secreted following stimulation with LPS.
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.
Was reported that 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. However, this work was later retracted, although the roles of different redox forms in some functional activities is supported by other papers.
Synthesis and degradation of fructose 2,6-bisphosphate.
The most important regulatory mechanism of these opposing activities is by phosphorylation and dephosphorylation of the enzyme.
Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:26669264). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm (By similarity). Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol (By similarity). Upon binding of c-di-GMP or cGAMP, STING1 oligomerizes, translocates from the endoplasmic reticulum and is phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent anti-viral state (PubMed:26669264). In addition to promote the production of type I interferons, plays a direct role in autophagy (By similarity). Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (By similarity). The ERGIC serves as the membrane source for WIPI2 recruitment and LC3 lipidation, leading to formation of autophagosomes that target cytosolic DNA or DNA viruses for degradation by the lysosome (By similarity). The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation (By similarity). Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy (By similarity). Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (PubMed:26669264). The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the STING1-bound conformation and pays low energy costs in changing into the active conformation (By similarity). May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons (By similarity). May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity).
Homodimer; forms a homodimer in absence of cyclic nucleotide (c-di-GMP or cGAMP); 'Lys-63'-linked ubiquitination at Lys-151 is required for homodimerization (PubMed:26669264). Homotetramer; in presence of cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and higher-order oligomers through side-by-side packing (By similarity). Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (By similarity). Interacts with RIGI, MAVS and SSR2 (By similarity). Interacts with RNF5 and TRIM56 (By similarity). Interacts with TBK1; when homodimer, leading to subsequent production of IFN-beta (By similarity). Interacts with IFIT1 and IFIT2 (By similarity). Interacts with TRIM29; this interaction induces STING1 ubiquitination and subsequent degradation (By similarity). Associates with the MHC-II complex (By similarity).Interacts with STEEP; the interaction is increased upon cGAMP binding and promotes STING1 translocation to COPII vesicles (By similarity). Interacts with SEC24A, SEC24B and SEC24C; promoting translocation to COPII vesicles (By similarity). Interacts (when ubiquitinated) with SQSTM1; leading to relocalization to autophagosomes (By similarity). Interacts with SURF4 (By similarity). Interacts with HNRNPA2B1 (By similarity). Interacts with ZDHHC1; ZDHHC1 constitutively interacts with STING1 and in presence of DNA viruses activates it by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (By similarity). Interacts with ZDHHC11; in presence of DNA viruses promotes the recruitment of IRF3 to STING1 (By similarity). Interacts with TOMM70 (By similarity).
In absence of cGAMP, the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly (By similarity). In absence of cyclic nucleotide (c-di-GMP or cGAMP), the protein is autoinhibited by an intramolecular interaction between the cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT) (By similarity). Following cGAMP-binding, the cyclic dinucleotide-binding domain (CBD) is closed, leading to a 180 degrees rotation of the CBD domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the CBD dimer, which leads to the formation of the STING1 tetramer and higher-order oligomers through side-by-side packing (By similarity). The N-terminal part of the CBD region was initially though to contain a fifth transmembrane region (TM5) but is part of the folded, soluble CBD (By similarity).
In contrast to mouse protein, not activated by anticancer molecule 5,6-dimethylxanthenone 4-acetic acid (DMXAA).
Palmitoylation takes place in the Golgi apparatus and creates a platform for the recruitment of TBK1.
Phosphorylation by TBK1 leads to activation and production of IFN-beta. Following cyclic nucleotide (c-di-GMP or cGAMP)-binding, activation and translocation from the endoplasmic reticulum, STING1 is phosphorylated by TBK1 at Ser-366 in the pLxIS motif. The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines (By similarity). Phosphorylated on tyrosine residues upon MHC-II aggregation (By similarity). Dephosphorylation by PPP6C leads to inactivation and decreased production of IFN-beta (By similarity). Phosphorylation at Ser-358 is also required to activate IRF3 (By similarity).
Sumoylated at Lys-338 by TRIM38 during the early phase of viral infection, promoting its stability by preventing its relocalization to autophagosomes and subsequent degradation. Desumoylated by SENP2 during the late phase of viral infection.
The N-terminal domain interacts with glycerophospholipids and phospholipids.
The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of STING1 recruits IRF3. IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines.
Ubiquitinated (By similarity). Ubiquitinated via 'Lys-63'-linked ubiquitin chains in response to double-stranded DNA treatment, leading to relocalization to autophagosomes and subsequent degradation; this process is dependent on SQSTM1 (By similarity). 'Lys-63'-linked ubiquitination mediated by TRIM56 at Lys-151 promotes homodimerization and recruitment of the antiviral kinase TBK1 and subsequent production of IFN-beta. 'Lys-48'-linked polyubiquitination at Lys-151 occurring after viral infection is mediated by RNF5 and leads to proteasomal degradation. 'Lys-11'-linked polyubiquitination at Lys-151 by RNF26 leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-48'-linked polyubiquitination (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.
Interacts (via C-terminal domain) with PHB2.
Forms a stable heterodimer with MND1. Interacts with PSMC3/TBP1 (By similarity). Interacts with the DNA-binding domain of the nuclear receptors NR3C1/GR, ESR2/ER-beta, THRB and RXRA.
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 (By similarity). Plays a role as a coactivator in nuclear receptor-mediated transcription.
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).
Binds TFR through the extracellular domain in a pH-dependent manner.
Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.
Belongs to the quiescin-sulfhydryl oxidase (QSOX) family.
Catalyzes the oxidation of sulfhydryl groups in peptide and protein thiols to disulfides with the reduction of oxygen to hydrogen peroxide (PubMed:11278790). Plays a role in disulfide bond formation in a variety of extracellular proteins. In fibroblasts, required for normal incorporation of laminin into the extracellular matrix, and thereby for normal cell-cell adhesion and cell migration (By similarity).
Isoform 3: Detected in seminal vesicle fluid (at protein level) (PubMed:11278790, PubMed:12354420). Isoform 1: Detected in brain, hypophysis, heart, testis and the seminal vesicle. Isoform 3: Highly expressed in the seminal vesicles followed by testis, heart, brain, thymus, hypophysis and lung. Also expressed in prostate, kidney, spleen, liver.
N-glycosylated. O-glycosylated on Thr and Ser residues.
Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.8/SCN10A subfamily.
Down-regulated after axotomy in dorsal root ganglia.
Expressed in dorsal root ganglia at 15 dpc onwards.
Expressed in dorsal root ganglia, trigeminal ganglia, nodose ganglia and sciatic nerve.
Lacks the cysteine which covalently binds the conotoxin GVIIJ. This cysteine (position 815) is speculated in other sodium channel subunits alpha to be implied in covalent binding with the sodium channel subunit beta-2 or beta-4.
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. Interacts with NEDD4 and NEDD4L.
Ubiquitinated by NEDD4L; which promotes its endocytosis.
Highly expressed in the CNS, in particular in neurons of the caudate putamen, diagonal band, the paraventricular nucleus of the thalamus, part of the hypothalamus, in cranial motor nuclei, inferior olive, and substantia gelatinosa of the spinal tract trigeminal nucleus. Not detected in cerebral cortex, hippocampus and cerebellum.
May contribute to the degradation of peptide hormones and be involved in the inactivation of neuronal peptides. Cleaves the synthetic substrate Z-Gly-Gly-Leu-pNA and releases pNA. May protect against C2-ceramide-induced apoptosis.
Belongs to the tyrosyl-DNA phosphodiesterase family.
DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate (By similarity).
Belongs to the prenylcysteine oxidase family.
Prenylcysteine oxidase that cleaves the thioether bond of prenyl-L-cysteines, such as farnesylcysteine and geranylgeranylcysteine (By similarity). 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 (By similarity).
Belongs to the DEAD box helicase family. DDX47/RRP3 subfamily.
Oligomeric complex that consists of at least the alpha, beta, beta', gamma, delta, epsilon and zeta subunits. Probably interacts with PEX11A. Interacts with JAGN1 (By similarity). Interacts with SCYL1.
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.
Belongs to the TRAFAC class YlqF/YawG GTPase family. NOG2 subfamily.
GTPase that associates with pre-60S ribosomal subunits in the nucleolus and is required for their nuclear export and maturation.
Slightly by zinc in the intestine, but not the liver.
Widely expressed (PubMed:7882967). Detected in duodenum and jejunum but not in ileum and colon (at protein level) (PubMed:9560190). Expressed by neuroglial cells (at protein level) (PubMed:15378655).
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:7882967, PubMed:19095042, PubMed:24951051). 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 (PubMed:15378655, PubMed:16741752, PubMed:19767393). 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 (By similarity).
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.
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (By similarity). The PAF1 complex interacts with PHF5A. Within the PAF1 complex interacts directly with PHF5A (By similarity). Interacts with POLR2A, CPSF1, CPSF4, CSTF2, KMT2A/MLL1 and CTNNB1. Interacts with a Set1-like complex that has histone methyltransferase activity and methylates histone H3. Found in a complex with BCL9L or BCL9, CDC73, CTNNB1 and PYGO1 indicative for the participation in a nuclear Wnt signaling complex. Interacts with PTPN11 (By similarity). Interacts with SETD5 (By similarity).
Phosphorylated. Dephosphorylated by PTPN11.
Tumor suppressor probably involved in transcriptional and post-transcriptional control pathways. May be involved in cell cycle progression through the regulation of cyclin D1/PRAD1 expression. 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. 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. Connects PAF1C with the cleavage and polyadenylation specificity factor (CPSF) complex and the cleavage stimulation factor (CSTF) complex, and with Wnt signaling. Involved in polyadenylation of mRNA precursors (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 (By similarity).
Binds CLEC2I/Clr-g leading to activation of natural killer cells or stimulation of IL-2 production and proliferation of T-cells in response to antigen stimulation. May contribute to the formation of the immunological synapse between T-cells and antigen-presenting dendritic cells (By similarity).
Expressed in natural killer cells and a subset of T-cells.
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. Interacts with ALKBH4.
Interacts (via FERM domain) with ARHGEF18 (via C-terminus); the interaction activates ARHGEF18.
May be negatively regulated by phosphorylation.
Up-regulates the activity of the Rho guanine nucleotide exchange factor ARHGEF18. Involved in the regulation of the circumferential actomyosin belt in epithelial cells. Promotes cellular adhesion, migration and motility in vitro and may play a role in wound healing. May have a role in mediating cytoskeletal changes associated with steroid-induced cell differentiation.
Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes (By similarity). 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 (By similarity). Also involved in the deneddylation of non-cullin subunits such as STON2 (By similarity). The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1, IRF8/ICSBP and SNAPIN, possibly via its association with CK2 and PKD kinases (By similarity). CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively (By similarity).
Component of the CSN complex, composed of COPS1/GPS1, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7 (COPS7A or COPS7B), COPS8 and COPS9 (By similarity). In the complex, it probably interacts directly with COPS1, COPS2, COPS3, COPS5, COPS6, COPS7 (COPS7A or COPS7B) and COPS8 (By similarity). Interacts with TOR1A; the interaction is direct and associates TOR1A and SNAPIN with the CSN complex (PubMed:21102408). Interacts with STON2; controls STON2 neddylation levels (PubMed:21102408). Interacts with ERCC6 (By similarity).
Interacts with ABT1. Forms a complex with ABT1 and suppresses the ABT1-induced activation of polymerase II-directed transcription in mammalian cells. Disrupts the interaction between ABT1 and TATA-binding protein (TBP), and suppresses the ABT1-induced activation of polymerase II-directed basal transcription in vitro.
May constitute a novel regulatory system for basal transcription. Negatively regulates ABT1.
Allosterically activated by various compounds including ATP, 2,3-BPG/2,3-Bisphosphoglyceric acid and Ap4A/P1,P4-bis(5'-adenosyl) tetraphosphate (PubMed:6260203). Binding of an allosteric activator is a prerequisiste to magnesium and substrate binding (By similarity). Inhibited by inorganic phosphate (PubMed:6260203).
Broad specificity cytosolic 5'-nucleotidase that catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates (PubMed:6260203). 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 (By similarity). Has the highest activities for IMP and GMP followed by dIMP, dGMP and XMP (PubMed:6260203). Could also catalyze the transfer of phosphates from pyrimidine monophosphates but with lower efficiency (By similarity). Through these activities regulates the purine nucleoside/nucleotide pools within the cell (PubMed:6260203).
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:28012039). SCN1B strongly enhances the presence of the pore-forming alpha subunit at the cell surface (By similarity). 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 (PubMed:28012039). Potently inhibited by tetrodotoxin and saxitoxin (PubMed:16303569, PubMed:23077250).
Component of a voltage-sensitive sodium channel complex that consists of a pore-forming alpha subunit and one or more regulatory beta subunits. Interacts with SCN1B (PubMed:28012039). 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-1321 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 (PubMed:2559760, PubMed:16303569, PubMed:28012039). Alternates between resting, activated and inactivated states (PubMed:28012039). Required for normal muscle fiber excitability, normal muscle contraction and relaxation cycles, and constant muscle strength in the presence of fluctuating K(+) levels (By similarity).
Acetylation at Lys-471 activates malonyl-CoA decarboxylase activity. Deacetylation at Lys-471 by SIRT4 represses activity, leading to promote lipogenesis (By similarity).
Catalyzes the conversion of malonyl-CoA to acetyl-CoA. In the fatty acid biosynthesis MCD selectively removes malonyl-CoA and thus assures that methyl-malonyl-CoA is the only chain elongating substrate for fatty acid synthase and that fatty acids with multiple methyl side chains are produced. In peroxisomes it may be involved in degrading intraperoxisomal malonyl-CoA, which is generated by the peroxisomal beta-oxidation of odd chain-length dicarboxylic fatty acids. Plays a role in the metabolic balance between glucose and lipid oxidation in muscle independent of alterations in insulin signaling. May play a role in controlling the extent of ischemic injury by promoting glucose oxidation.
Expressed in liver, heart, skeletal muscles and adipose tissues (at protein level). Ubiquitous. Strongly expressed in liver, kidney, heart, skeletal muscle and adipose tissues. Weakly expressed in brain.
Homotetramer. Dimer of dimers. The two subunits within a dimer display conformational differences suggesting that at any given moment, only one of the two subunits is competent for malonyl-CoA binding and catalytic activity. Under oxidizing conditions, can form disulfide-linked homotetramers (in vitro). Associates with the peroxisomal targeting signal receptor PEX5 (By similarity).
Interchain disulfide bonds may form in peroxisomes (Potential). Interchain disulfide bonds are not expected to form in the reducing environment of the cytoplasm and mitochondria.
Malonyl-CoA decarboxylase activity does not require any cofactors or divalent metal ions.
May be produced by alternative initiation at Met-39 of isoform mitochondrial. Alternatively, represents a proteolytic processed form of the mitochondrial form (PubMed:10947976).
Detected in neonatal submandibular and parotid gland secretion but not in sublingual gland secretion (at protein level). In submandibular gland, expressed at high levels in the first postnatal week, with expression diminishing thereafter.
Expressed in parotid, submandibular and sublingual glands.
Has strong antibacterial activity against P. aeruginosa.
Plays a role in the initiation of autophagy. In the retina, might be involved in the process of photoreceptor cells renewal and recycling to preserve visual function. Induces apoptotic cell death when coexpressed with DRAM1.
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.
Belongs to the CND2 H2 (condensin-2 subunit 2) family.
Component of the condensin-2 complex, which contains the SMC2 and SMC4 heterodimer, and three non SMC subunits, NCAPG2, NCAPH2 and NCAPD3 that probably regulate the complex.
Regulatory subunit of the condensin-2 complex, a complex that seems to provide chromosomes with an additional level of organization and rigidity and in establishing mitotic chromosome architecture (By similarity). May promote the resolution of double-strand DNA catenanes (intertwines) between sister chromatids. Condensin-mediated compaction likely increases tension in catenated sister chromatids, providing directionality for type II topoisomerase-mediated strand exchanges toward chromatid decatenation. Required for decatenation of chromatin bridges at anaphase. Early in neurogenesis, may play an essential role to ensure accurate mitotic chromosome condensation in neuron stem cells, ultimately affecting neuron pool and cortex size (By similarity). Seems to have lineage-specific role in T-cell development (By similarity).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Kinesin II subfamily.
Microtubule-based anterograde translocator for membranous organelles.
Expressed in the floor plate of the spinal cord at 11 dpc and also in the ventricular zone at 16 dpc, but not in adult. In the brain, expression is more significant at 16 dpc than at adult, with high expression in the cortex, pontine area and choroid plexus. Detected in the otocyst at 16 dpc.
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 (By similarity).
Highly expressed in the kidney and adrenal gland. In the kidney, it is expressed in arteriolar smooth muscle cells and in epithelial cells of individual segments (at protein level).
Homodimer; disulfide-linked. Interacts with PDGFRA homodimers, and with heterodimers formed by PDGFRA and PDGFRB. Interacts (via CUB domain) with PLAT (via kringle domain) (By similarity).
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 (By similarity).
Up-regulated in mesangial, visceral epithelial, and interstitial cells after predominant injury to these cells. Expression levels increase in hepatic cells undergoing in vitro transdifferentiation, which represents a model for hepatic fibrogenesis. Expression induced by indoxyl sulfate. Expression induced by angiotensin-2 via EGR1 in smooth muscle cells in neonatal but not in adult rats.
Homodimer and homooligomer (PubMed:19755150). Interacts with the cytoplasmic part of DCC (PubMed:10399920). Interacts with MAGED1 (PubMed:12598531). Interacts with PRKCABP, possibly mediating some interaction with PKC (PubMed:14672991). Interacts (via extracellular domain) with FLRT2 (via extracellular domain) (By similarity). Interacts (via extracellular domain) with FLRT3 (via extracellular domain) (By similarity).
Mainly expressed in regions of differentiating neurons. Expressed at early stages of neural tube development in the ventral spinal cord. In developing hindbrain, it colocalizes with a number of cranial motor neuron subpopulations from embryonic E11 to E14, while DCC is expressed by motor neurons at E12. Also expressed in non-neural structures, such as the basal plane of the hindbrain and midbrain, in the developing hypothalamus, thalamus and in the pallidum.
Phosphorylated on cytoplasmic tyrosine residues (By similarity). Phosphorylated by PKC in vitro.
Receptor for netrin required for axon guidance (PubMed:9126742, PubMed:10399920). Functions in the netrin signaling pathway and promotes neurite outgrowth in response to NTN1 (PubMed:19755150). Mediates axon repulsion of neuronal growth cones in the developing nervous system in response to netrin (PubMed:10399920). Axon repulsion in growth cones may be mediated by its association with DCC that may trigger signaling for repulsion (PubMed:10399920). It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (PubMed:11387206, PubMed:12598531).
The ZU5 domain mediates the interaction with MAGED1, which participates in the induction of apoptosis.
Belongs to the complex I NDUFC2 subunit family.
Component of the BCR(KLHL12) E3 ubiquitin ligase complex, at least composed of CUL3 and KLHL12 and RBX1. This complex interacts with DVL3 upon activation of the Wnt signaling pathway by WNT3A. Interacts with DRD4, KLHL2 and SEC31A. 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).
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. 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). 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. 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. The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins.
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.
Belongs to the U1 small nuclear ribonucleoprotein C family.
Component of the U1 snRNP. 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 (By similarity). Interacts (via N-terminus) with TIA1 (via C-terminus); thereby promoting spliceosomal U1 snRNP recruitment to 5' splice sites (By similarity).
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.
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 (By similarity).
Belongs to the chloride channel (TC 2.A.49) family. ClC-7/CLCN7 subfamily.
Chloride channel 7 are heteromers of alpha (CLCN7) and beta (OSTM1) subunits.
Slowly voltage-gated channel mediating the exchange of chloride ions against protons (PubMed:18449189). Functions as antiporter and contributes to the acidification of the lysosome lumen and may be involved in maintaining lysosomal pH (By similarity). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (PubMed:18449189). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity).
Interacts with KHDRBS3. Interacts with HABP4. Interacts with NOL3/ARC/NOP30. Interacts with NSEP1/YB-1/YB1. Interacts with SAFB/SAFB1. Interacts with SRSF6/SFRS6. Interacts with TRA2B/SFRS10. Interacts with C1QBP. May also interact with DUSP11/PIR1.
Plays a role in constitutive splicing and can modulate the selection of alternative splice sites. Represses the splicing of MAPT/Tau exon 10 (By similarity).
Associates with pre-60S ribosomal particles.
Involved in the biogenesis of the 60S ribosomal subunit in the nucleus.
Histone chaperone that plays a role in the nuclear import of H2A-H2B and nucleosome assembly. Participates also in several important DNA repair mechanisms: greatly enhances ERCC6-mediated chromatin remodeling which is essential for transcription-coupled nucleotide excision DNA repair. Stimulates also homologous recombination (HR) by RAD51 and RAD54 which is essential in mitotic DNA double strand break (DSB) repair (By similarity). 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. The dimer binds strongly and sequentially to single and double H2A-H2B heterodimers. Interacts with ERCC6; this interaction increases ERCC6 processivity. Interacts with RAD54 (By similarity). Interacts with SETD1A (By similarity).
Polyglutamylated by TTLL4 on glutamate residues, resulting in polyglutamate chains on the gamma-carboxyl group. Both polyglutamylation and polyglycylation modifications can coexist on the same protein on adjacent residues, and lowering polyglycylation levels increases polyglutamylation, and reciprocally.
Polyglycylated by TTLL10 on glutamate residues, resulting in polyglycine chains on the gamma-carboxyl group. Both polyglutamylation and polyglycylation 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.
Belongs to the apolipoprotein A2 family.
May stabilize HDL (high density lipoprotein) structure by its association with lipids, and affect the HDL metabolism.
Monomer. Interacts with NAXE and NDRG1 (By similarity).
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) (By similarity).
Belongs to the ferredoxin--NADP reductase type 1 family.
Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylation in the kidney, and sterol C-27 hydroxylation in the liver.
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:9631240). Regulates angiogenesis by inhibiting the cAMP-dependent guanine nucleotide exchange factor RAPGEF3 and downstream phosphatidylinositol 3-kinase gamma-mediated signaling (By similarity). Controls cardiac contractility by reducing cAMP concentration in cardiocytes (By similarity).
Homodimer (By similarity). 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 (By similarity).
Phosphorylation at Ser-279 mediates insulin-induced activation of PDE3B.
Interacts with DDX39B/UAP56 and NXF1; interaction with DDX39B/UAP56 and NXF1 are mutually exclusive. Interacts with SSRP1; required for its recruitment to mRNAs. Interacts with CHTOP (By similarity).
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 (By similarity).
Highly expressed in most brain regions. Also expressed in other tissues such as lung, kidney, liver, stomach and spleen.
Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
Bifunctional mitochondrial folate-interconverting enzyme that has both NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities.
Has no NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase activity.
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 (By similarity).
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) (By similarity).
Monomer. Interacts with Armcx3 at the mitochondrial outer membrane surface. Interacts with PAX3 (By similarity).
Predominant expression in glial cells of the nervous system.
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 (By similarity). Transcriptional activator of MBP, via binding to the gene promoter (PubMed:26525805).
Belongs to the multi antimicrobial extrusion (MATE) (TC 2.A.66.1) family.
Highly expressed in kidney and placenta, moderately in stomach, colon, lung, spleen, skeletal muscle and prostate, and slightly in spleen. In the kidney, found in medulla and cortex, especially in the proximal convoluted and straight tubules. No expression was observed in heart, brain, small intestine and liver.
Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:17047166). 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:16850272, PubMed:16928787, PubMed:17047166, PubMed:17582384, PubMed:17327464).
Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits (By similarity).
Homodimer. Interacts with CDC42. 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. Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 (By similarity).
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 (By similarity).
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 (By similarity).
The UBA domain binds both poly- and mono-ubiquitin.
Homotrimer. Interacts with LTC4S and ALOX5 (By similarity).
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 (By similarity).
The C-terminal part after residue 140 is mostly disordered.
Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids (PUFAs) generating a spectrum of bioactive lipid mediators (PubMed:23382512). Inserts a peroxyl group at C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing (15S)-hydroperoxyeicosatetraenoate/(15S)-HPETE (PubMed:23382512). Also peroxidizes linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (PubMed:23382512). Oxygenates arachidonyl derivatives such as 2-arachidonoylglycerol (2-AG) leading to the production and extracellular release of 15-hydroxyeicosatetraenoyl glycerol (15-HETE-G) that acts as a peroxisome proliferator-activated receptor alpha agonist.Has the ability to efficiently class-switch ALOX5 pro-inflammatory mediators into anti-inflammatory intermediates. Participates in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs) resolvin D5 ((7S,17S)-diHPDHA), which can actively down-regulate the immune response and have anti-aggregation properties with platelets. In addition to free PUFAs hydrolyzed from phospholipids, it directly oxidizes PUFAs esterified to membrane-bound phospholipids. Has no detectable 8S-lipoxygenase activity on arachidonate but reacts with (8S)-HPETE to produce (8S,15S)-diHPETE. May regulate progression through the cell cycle and cell proliferation. May also regulate cytokine secretion by macrophages and therefore play a role in the immune response. May also regulate macrophage differentiation into proatherogenic foam cells (By similarity).
The PLAT domain can bind calcium ions; this promotes association with membranes.
Belongs to the dynactin 150 kDa subunit family.
Monomer and homodimer (PubMed:23648839). 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 MAPRE2 and MAPRE3. Interacts with FBXL5. Interacts with ECPAS and SNX6. Interacts with CLIP1. Interacts with CLN3 and DYNAP. Interacts with MISP; this interaction regulates its distribution at the cell cortex. Interacts with CEP131 (By similarity). Interacts (via CAP-Gly domain) with the C-terminus of MAPRE1, forming a heterotetramer (PubMed:23648839). Interacts with dynein intermediate chain and dynein heavy chain. Interacts with PLK1 (via POLO-box domain). Binds preferentially to tyrosinated microtubules than to detyrosinated microtubules. Interacts with TBCB, PARD6A, HPS6, KIF3A. Interacts with BICD2. Identified in a complex with MREG and RILP (By similarity). Interacts with BCCIP. Interacts with DCDC1 (By similarity). 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 and 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. 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. Plays a role in metaphase spindle orientation. 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. Plays a role in primary cilia formation.
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.
Ubiquitous with a high level expression observed in the brain (at protein level).
Testis, brain, and to much lower levels heart, skeletal muscle and fat cells. Expressed in the retina.
Interacts with SUPT6H; binds preferentially to the POLR2A-bound SUPT6H. Interacts with ALYREF/THOC4, SETD2 and PRMT5 (By similarity). Interacts with HDGFRP2 (By similarity). Interacts (via IBM motif) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (By similarity).
Transcription factor which plays a key role in defining the composition of the RNA polymerase II (RNAPII) elongation complex and in modulating the production of mature mRNA transcripts. Acts as an assembly factor to recruit various factors to the RNAPII elongation complex and is recruited to the complex via binding to the transcription elongation factor SUPT6H bound to the C-terminal domain (CTD) of the RNAPII subunit RPB1 (POLR2A). The SUPT6H:IWS1:CTD complex recruits mRNA export factors (ALYREF/THOC4, EXOSC10) as well as histone modifying enzymes (such as SETD2) to ensure proper mRNA splicing, efficient mRNA export and elongation-coupled H3K36 methylation, a signature chromatin mark of active transcription (By similarity).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A1 subfamily.
Inhibited by nipecotic acid, cis-3-aminocyclohexane carboxylic acid and 2,4-diaminobutyric acid.
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:1975955, PubMed:18054861). The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA (PubMed:18054861, PubMed:21775701). 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 (PubMed:18054861, PubMed:21775701). Also mediates sodium- and chloride-dependent transport of hypotaurine (By similarity).
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.
Found in all tissues tested. High expression found in brain, liver, kidney, colon, heart and lung.
Gstm7 is the putative ortholog of human GSTM2.
May play a role in the regulation of the cation channel TRPM8 activity.
Highly expressed in liver. Detected at lower levels in lung, kidney and testis.
Inhibited by warfarin (coumadin) (PubMed:15879509, PubMed:23772386, PubMed:23928358). Warfarin locks VKORC1 in both redox states into the closed conformation (By similarity).
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. VKOR becomes fully oxidized with an open conformation that releases reaction products, vitamin K quinone, or hydroquinone. Cys-132 and Cys-135 constitute the catalytic redox-active center. Cys-43 and Cys-51 are the cysteine pair that mediates transfer of reducing equivalents during catalysis.
Catalyzes the peptide bond hydrolysis in dipeptides, displaying a non-redundant activity toward threonyl dipeptides. Mediates threonyl dipeptide catabolism in a tissue-specific way (By similarity). Has high dipeptidase activity toward cysteinylglycine, an intermediate metabolite in glutathione metabolism. Metabolizes N-lactoyl-amino acids, both through hydrolysis to form lactic acid and amino acids, as well as through their formation by reverse proteolysis. Plays a role in the regulation of cell cycle arrest and apoptosis (By similarity).
Detected in neuronal cells in the dorsal part of the tuberomammilary nucleus of the posterior hypothalamus (at protein level). Expressed in the iris, ciliary body, trabecular meshwork, Schlemm's canal, sclera, retina, brain, kidney and lung.
Expressed in rat thymus, testis, and spleen. Is present predominantly in proliferative and differentiative organs.
Brain, lung, heart and islets. Moderate levels in the hippocampus, cortex and olfactory bulb.
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.
In contrast to UCHL3, does not hydrolyze a peptide bond at the C-terminal glycine of NEDD8.
Monomer. Homodimer. Interacts with COPS5 (By similarity). Interacts with SNCA.
The homodimer may have ATP-independent ubiquitin ligase activity. However, in another study, UCHL1 was shown to lack ubiquitin ligase activity.
Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins (By similarity). This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin (By similarity). Also binds to free monoubiquitin and may prevent its degradation in lysosomes (By similarity). The homodimer may have ATP-independent ubiquitin ligase activity (By similarity).
Actin-binding protein that contains 2 major actin binding sites (PubMed:8769857). Organizes filamentous actin into parallel bundles (PubMed:8769857). Plays a role in the organization of actin filament bundles and the formation of microspikes, membrane ruffles, and stress fibers. Important for the formation of a diverse set of cell protrusions, such as filopodia, and for cell motility and migration. Mediates reorganization of the actin cytoskeleton and axon growth cone collapse in response to NGF (By similarity).
Composed of four fascin beta-trefoil domains.
Detected in embryonic brain and brain from young rats (at protein level).
Interacts with RUFY3 (via N-terminus); the interaction induces neuron axon development (By similarity). Interacts with NGFR (PubMed:22155786). Associates with CTNNB1 (By similarity). Interacts with PLXNB3 (By similarity).
Phosphorylation at Ser-39 inhibits actin-binding. Phosphorylation is required for the reorganization of the actin cytoskeleton in response to NGF.
Homodimer (PubMed:8757804, PubMed:9533885, PubMed:11846560, PubMed:15522285). Interacts with RAN (GDP-bound form); the interaction is direct and regulates RAN nuclear import (PubMed:9822603, PubMed:8757804, PubMed:9368653, PubMed:9533885, PubMed:11846560, PubMed:15522285). 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:8707840, PubMed:9368653, PubMed:10543952, PubMed:11846560, PubMed:15522285). Interacts with CAPG; mediates its nuclear import (By similarity).
Mediates the import of GDP-bound RAN from the cytoplasm into the nucleus which is essential for the function of RAN in cargo receptor-mediated nucleocytoplasmic transport. Thereby, plays indirectly a more general role in cargo receptor-mediated nucleocytoplasmic transport. Interacts with GDP-bound RAN in the cytosol, recruits it to the nuclear pore complex via its interaction with nucleoporins and promotes its nuclear import.
Belongs to the DPH1/DPH2 family. DPH2 subfamily.
Binds 1 [4Fe-4S] cluster per subunit. The cluster facilitates the reduction of the catalytic iron-sulfur cluster in the DPH1 subunit.
Component of the 2-(3-amino-3-carboxypropyl)histidine synthase complex composed of DPH1, DPH2, DPH3 and a NADH-dependent reductase (By similarity). Interacts with DPH1 (By similarity).
Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (By similarity). 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).
Expressed in brain, heart, kidney, liver, lung, skeletal muscle, spleen and testis.
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 (By similarity).
Self-associates. May interact with CENPF, CNTRL, LIS1, dynactin, dynein, tubulin gamma, PCM1, PCNT, SLMAP and TCP1 (By similarity). Interacts with PAFAH1B1. Interacts with ZNF365 (By similarity).
Belongs to the universal ribosomal protein uL13 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. Interacts with DNAJC30; interaction is direct.
Trimethylated by ATPSCKMT at Lys-109. Methylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration.
Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cGMP subfamily.
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.
Localized within gonadotropes of the anterior pituitary of the brain. Broadly distributed throughout the cerebral cortex.
Overexpression of AVPR1A in the brain increases the duration of social memory.
Palmitoylated on three cysteine residues, of which only two are identified.
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Involved in social memory formation.
Expressed from day 16 dpc, but accumulation was primarily postnatal with maximal steady state levels reached at postnatal day 10.
Expressed in brain and weakly in eye. Not detected in liver, kidney, spleen, thymus, bladder, aorta, lung, intestine, esophagus, stomach, skeletal muscle, heart, diaphragm, uterus, tail skin, submaxillary gland, prostate, ear, epididymis, placenta, pancreas, ovary, testis, adrenal gland, parathyroid gland, thyroid gland, pineal gland, pituitary and sciatic nerve. In adult hippocampus, predominantly expressed in caudate nucleus, cortex, hypothalamus, olfactory bulb, and midbrain and faintly in pons, brainstem and spinal cord.
Has no detectable kinase activity in vitro.
Interacts with calmodulin, in the presence of calcium.
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.
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.
Leumorphin has a typical opiod activity and may have anti-apoptotic effect.
Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity.
In response to TGF-beta, phosphorylated on the C-terminal SXS motif by TGF-beta and activin type 1 receptor kinases, phosphorylation declines progressively in a KMT5A-dependent manner. Phosphorylation in this motif is required for interaction with a number of proteins including SMURF2, SNON and SMAD4 in response to TGF-beta. Dephosphorylated in this motif by PPM1A leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of the TGF-beta signaling. 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 (By similarity).
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 (By similarity). 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 (By similarity). Heterodimer; in the presence of TGF-beta (By similarity). Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4 (By similarity). Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity). Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD (By similarity). Interacts with TAZ/WWRT1 (By similarity). Interacts with FOXH1 (By similarity). Interacts with SNW1 (By similarity). Interacts with CREB-binding protein (CBP) and EP300 (By similarity). Interacts with SNON (By similarity). Interacts with ALK4/ACVR1B (By similarity). Interacts with SKOR1 (By similarity). Interacts with SKOR2 (By similarity). Interacts with PRDM16 (By similarity). Interacts (via MH2 domain) with LEMD3 (By similarity). Interacts with RBPMS (By similarity). 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 (By similarity). Interacts with PDPK1 (via PH domain) (By similarity). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (By similarity). Interacts with USP15 (By similarity). Interacts with PPP5C (By similarity). Interacts with LDLRAD4 (via the SMAD interaction motif) (By similarity). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif) (By similarity). Interacts with ZFHX3 (By similarity). Interacts with ZNF451 (By similarity). Interacts with SMURF2 when phosphorylated on Ser-465/467 (By similarity). Interacts with PPM1A (By similarity). Interacts with TGF-beta (By similarity). Interacts with TGFBR1 (By similarity). Interacts with TGIF (By similarity). Interacts with SMAD3 and TRIM33 (By similarity). Interacts with ZNF580 (By similarity). 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-112') (By similarity).
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 (By similarity).
Delivers copper to copper zinc superoxide dismutase (SOD1).
Homodimer, and heterodimer with SOD1. Interacts with COMMD1 (By similarity). Interacts with XIAP/BIRC4 (By similarity).
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.
Adapter protein, which negatively regulates T-cell receptor (TCR) signaling. Inhibits T-cell antigen-receptor induced activation of nuclear factor of activated T-cells. Involved in the negative regulation of positive selection and mitosis of T-cells. May act by linking signaling proteins such as ZAP70 with CBL, leading to a CBL dependent degradation of signaling proteins (By similarity).
Homodimer. Interacts with phosphorylated CBL, SYK and LAT. Homodimerization and interaction with phosphorylated CBL occurs via its C-terminal domain. Interacts with PDGFRB and EPHA2. Interacts with phosphorylated proteins ZAP70; CD3Z; VAV1 and LCP2 via its SH2 domain (By similarity).
The C-terminal domain is essential for the homodimerization and the interaction with CBL. While the interaction with CBL is apparently mediated via the hydrophobic region of this domain, the highly charged region is apparently required for the homodimerization (By similarity).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF: SWI/SNF-A (BAF), SWI/SNF-B (PBAF) and related complexes. The canonical complex contains a catalytic subunit (either SMARCA4/BRG1/BAF190A or SMARCA2/BRM/BAF190B), and at least SMARCE1, ACTL6A/BAF53, SMARCC1/BAF155, SMARCC2/BAF170, and SMARCB1/SNF5/BAF47. Other subunits specific to each of the complexes may also be present permitting several possible combinations developmentally and tissue specific. 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. 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). Interacts with UNKL. Interacts with CEBPE.
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. Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation.
Ubiquitinated through a signaling process involving RAC1 and the RING finger protein UNKL.
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.
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 CLEC5A. Forms an CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP (By similarity). Interacts with CD300H (By similarity).
Phosphorylated; PIK3R1 and GRB2 associate specifically with tyrosine-phosphorylated HCST.
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 (By similarity).
Heterodimer of a common alpha chain and a unique beta chain which confers biological specificity to thyrotropin, lutropin, follitropin and gonadotropin.
Indispensable for the control of thyroid structure and metabolism.
Component of a heterotrimeric complex containing IMP3, IMP4 and MPHOSPH10. Interacts with MPHOSPH10 (By similarity).
Component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP). Required for the early cleavages during pre-18S ribosomal RNA processing (By similarity).
Belongs to the Integrator subunit 2 family.
Divalent metal cation. Prefers Mn(2+) over Mg(2+).
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 (By similarity). 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 (By similarity).
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 (By similarity). 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 (By similarity).
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.
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.
Belongs to the complex I LYR family. LYRM9 subfamily.
High expression in brain, lower in other tissues.
Interacts with RHOH (By similarity). Interacts with the non-phosphorylated forms of RAB1A, RAB3A, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43 (By similarity).
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.
Heterodimer. The active follitropin is a heterodimer composed of an alpha chain/CGA shared with other hormones and a unique beta chain/FSHB shown here.
Together with the alpha chain CGA constitutes follitropin, the follicle-stimulating hormone, and provides its biological specificity to the hormone heterodimer. Binds FSHR, a G protein-coupled receptor, on target cells to activate downstream signaling pathways. Follitropin is involved in follicle development and spermatogenesis in reproductive organs.
Belongs to the Mediator complex subunit 4 family.
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. 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 (By similarity). Interacts with IFIH1/MDA5 (By similarity). Interacts with PML (By similarity). Interacts with PRDM1 (By similarity).
Expressed in spermatogonia and in primary spermatocytes up to late pachytene stage (at protein level).
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. The effects of this transcriptional coregulation, transactivation or silencing may vary depending upon the biological context and 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 (By similarity). Sumoylates PML at'Lys-65' and 'Lys-160' (By similarity).
The LXXLL motif is a transcriptional coregulator signature.
Belongs to the MsrA Met sulfoxide reductase family.
Has an important function as a repair enzyme for proteins that have been inactivated by oxidation. Catalyzes the reversible oxidation-reduction of methionine sulfoxide in proteins to methionine (By similarity).
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). Free secretory component interacts with bacterial antigens toxA of C. difficile and eae of E. coli.
Interacts (mainly via CDR1-like domain) with dimeric IgA. Interacts (mainly via CDR2-like domain) with pentameric IgM.
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. On its own (free form) may act as a non-specific microbial scavenger to prevent pathogen interaction with epithelial cells.
Expressed at high levels in brain, at moderate levels in heart, kidney and lung, and at low levels in skeletal muscle, stomach, spleen, colon and pancreas (PubMed:10970803). Not detected in the liver or small intestine (PubMed:10970803). In brain, highly expressed in white matter and detected in oligodendrocytes (PubMed:10970803, PubMed:11157071). Expressed in cerebellum as well as the anterior commissure (PubMed:11157071). Expressed mainly in the white matter but is also scattered in gray matter throughout the whole brain (PubMed:11157071). Expressed in myelinating cells of both ventral and dorsal restricted regions in newborn spinal cord (PubMed:12210128). Expressed in non-myelin-forming as well as in myelin-forming Schwann cells in the sciatic nerve (PubMed:17240058).
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:24201375). 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 (By similarity). 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). May play a role in myelin formation (PubMed:12210128).
Probable transporter, its natural substrate has not been found yet. May have a role in macrophage lipid metabolism and neural development. May play a role in myelination, perhaps as a transporter for certain kinds of myelin chemical components (PubMed:12210128). May play an important role in gamma-secretase processing of APP and thus in amyloid-beta peptide generation (PubMed:22086926). Regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism (PubMed:24201375).
Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis. 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. 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. 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. 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. 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. 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) (By similarity). 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. 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. At very high concentrations, calcium can however substitute for zinc at zinc-binding sites, leading to strongly reduced enzyme activity.
Phosphatase activity is specifically inhibited by 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425).
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 (By similarity). 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 (By similarity).
Important signaling molecule that activates signaling cascades downstream of NTRK2. Activates signaling cascades via the heterodimeric receptor formed by NGFR and SORCS2. 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.
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. Can be converted into mature BDNF by plasmin (PLG).
Monomers and homodimers (By similarity). Binds to NTRK2/TRKB. Can form heterodimers with other neurotrophin family members, such as NTF3 and NTF4 (in vitro), but the physiological relevance of this is not clear (By similarity). BDNF precursor form: interacts with the heterodimer formed by NGFR and SORCS2. Mature BDNF has much lower affinity for the heterodimer formed by NGFR and SORCS2 (By similarity).
Monomers and homodimers. Binds to NTRK2/TRKB.
N-glycosylated and glycosulfated, contrary to mature BDNF.
Contains G-L-F-G repeats. The FG repeat domains have a direct role in the transport (By similarity).
Isoform 1 is autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively. Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96.
Part of the nuclear pore complex (NPC). Interacts directly with NUP96. 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. Interacts with RAE1. Does not interact with TPR. Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC. 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.
Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. Involved in the bidirectional transport across the NPC. May anchor NUP153 and TPR to the NPC.
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. 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. Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body).
Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy. The zona pellucida is composed of 3 to 4 glycoproteins, ZP1, ZP2, ZP3, and ZP4. ZP1 ensures the structural integrity of the zona pellucida.
Polymers of ZP2 and ZP3 organized into long filaments cross-linked by ZP1 homodimers. Interacts with ZP3.
Interacts with SPIN1 (By similarity). Interacts with CHD3 and TDRD3. Interacts with ZDHHC17 (via ANK repeats) (By similarity).
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.
Interacts with FGFR1 and FGFR2. Interacts with FGFBP1 (By similarity).
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.
Preferentially expressed in the lung in adults.
Homodimer (By similarity). Can form oligomers with SYN2 (By similarity). Interacts with CAPON (PubMed:11867766). Forms a ternary complex with NOS1 (PubMed:11867766). 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:11685225). 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-oxide functions at a presynaptic level (PubMed:11867766).
Substrate of different protein kinases. 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 (PubMed:10571231, PubMed:11685225).
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.
Component of the U5 snRNP complex that is required for spliceosome assembly and for pre-mRNA splicing.
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1A subfamily.
Brain specific. Purkinje cells contain predominantly P-type VSCC, the Q-type being a prominent calcium current in cerebellar granule cells. Also found in heart, in kidney distal convoluted tubule (DCT), and in pituitary.
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 (By similarity). Interacts (via C-terminal CDB motif) with CABP1 in the pre- and postsynaptic membranes (PubMed:11865310). Interacts with the spider omega-agatoxin-IVA (AC P30288) (PubMed:1311418).
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 P30288) (PubMed:1311418). They are however insensitive to dihydropyridines (DHP).
Essentially expressed in liver and kidney and to a lesser extent in heart, adipose tissue, stomach and pancreas (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 (By similarity). 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) at carbon 13 to generate (11E,13Z)-octadecadienoate (also known as conjugated linoleic acid 11E,13Z-CLA) (PubMed:24070791).
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.
Two potential isoforms are detected in various tissues. A 75 kDa isoform is expressed in lung, spleen and thymus. A 37 kDa isoform is highly expressed in skeletal and abdominal muscles, brain and ovary and to a lesser extent in heart, lung, brown adipose tissue and eye.
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 (By similarity). Required for internalization of the GABA receptor GABRA1 from the cell membrane via endosomes and subsequent GABRA1 degradation (PubMed:25579817). Acts as a mediator of cell spreading and cytoskeletal responses to the extracellular matrix component THBS1 (By similarity).
Homodimer; may form higher oligomers (PubMed:25579817). 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. 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 (By similarity). Interacts with RANBP9 (By similarity). Part of a complex consisting of RANBP9, MKLN1 and GID8 (By similarity). Interacts with GABRA1 (PubMed:21482357). Interacts with the C-terminal tail of PTGER3 (PubMed:11006128).
The LisH mediates head to tail dimerization.
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.
Down-regulated in mammary adenocarcinomas.
Highly expressed in liver, kidney and heart.
Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+) (PubMed:9461611). Required for learming and memory by regulating neuronal Ca(2+), which is essential for the development of synaptic plasticity (By similarity).
Expressed abundantly in all regions of the brain and weakly in the eye, large intestine and adrenal tissue.
Associates with core 1 beta-3-galactosyltransferase (C1GALT1), probably not with the soluble active form.
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) (By similarity).
Component of the multiprotein chromatin-remodeling complexes SWI/SNF.
Detected in heart muscle (at protein level). Ubiquitous.
Has been suggested to play a role in the regulation of RYR2 channel activity and thereby contribute to the regulation of excitation-contraction coupling in cardiac muscle. According to PubMed:20431056, the amount of FKBP1B in rat heart is much lower than that of RYR2, suggesting that FKBP1B can play only a minor role in the regulation of RYR2 channel activity.
Has the potential to contribute to the immunosuppressive and toxic effects of FK506 and rapamycin. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1 (By similarity). Interacts directly with RYR2.
(Microbial infection) Interacts with C.botulinum neurotoxin type A (BoNT/A, botA).
(Microbial infection) Interacts with C.botulinum neurotoxin type F (BoNT/F) (PubMed:19650874). Interaction requires glycosylation of SV2 proteins (PubMed:19476346, PubMed:19650874).
(Microbial infection) Receptor for C.botulinum neurotoxin type A (BoNT/A, botA); the toxin binds Sv2c via extracellular loop 4 (PubMed:16543415). Restores uptake of BoNT/A in rat cells that are deleted for SV2 receptor (PubMed:16543415, PubMed:18815274).
(Microbial infection) Receptor for C.botulinum neurotoxin type F (BoNT/F); binding requires glycosylation of Asn-573 (PubMed:19476346, PubMed:19650874).
Expressed at high levels in very few brain areas including the striatum, midbrain and hindbrain, and in the olfactory bulb. Expressed at lower levels in cerebrum, hippocampus and cerebellum (at protein level). Mainly expressed in brain; also detected in lung, liver, kidney.
Interacts with SYT1 in a calcium-dependent manner.
Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint. The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies. The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner. In the complex, it is required for SKA1 localization. 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.
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 in vivo (By similarity).
Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF (By similarity). Interacts with SKP1 (By similarity). Interacts with CUL1 (By similarity). Interacts with CCNB1; interaction is required for nuclear localization of CCNB1 (By similarity). Interacts with CCP110; this interaction leads to CCP110 ubiquitination and degradation via the proteasome pathway (By similarity). Interacts (via the Cyclin N-terminal domain) with MYBL2/BMYB (By similarity). Interacts with FZR1/CDH1 (via N-terminus) (By similarity). Interacts with RRM2 (via Cy motif and when phosphorylated at 'Thr-33'); the interaction occurs exclusively in G2 and early M (By similarity). Interacts with CDC6 (via Cy motif); the interaction takes place during G2 and M phase (By similarity).
Degraded when the spindle assembly checkpoint is activated during the G2-M transition. Degradation is not dependent on the proteasome or ubiquitin and depends on the C-terminal PEST sequence.
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 (By similarity). 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 (By similarity). 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 (By similarity). Mediates the ubiquitination and subsequent proteasomal degradation of CP110 during G2 phase, thereby acting as an inhibitor of centrosome reduplication (By similarity). In G2, mediates the ubiquitination and proteasomal degradation of CDC6, thereby suppressing DNA re-replication and preventing genome instability (By similarity). 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 (By similarity). May play a role in the G2 cell cycle checkpoint control after DNA damage, possibly by promoting the ubiquitination of MYBL2/BMYB (By similarity).
The D box motifs 1-4 (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.
Phosphorylation is accompanied by a decrease in enzyme activity.
Olfactory receptor specific for 2-phenylethylamine, a trace amine present at high concentration in the urine of carnivore species, playing a key role in fear and avoidance responses. 2-phenylethylamine acts as a kairomone in the chemical detection of carnivore odor and triggers fear in mice. This receptor is probably mediated by the G(s)-class of G-proteins which activate adenylate cyclase (By similarity).
May be involved in transcriptional regulation. Modulates various viral and cellular promoters in a promoter context-dependent manner. Does not bind DNA directly (By similarity).
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 (By similarity).
Endoplasmic reticulum disulfide reductase involved both in the correct folding of proteins and degradation of misfolded proteins. Required for efficient folding of proteins in the endoplasmic reticulum by catalyzing the removal of non-native disulfide bonds formed during the folding of proteins, such as LDLR. Also involved in endoplasmic reticulum-associated degradation (ERAD) by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1. Interaction with HSPA5 is required its activity, not for the disulfide reductase activity, but to facilitate the release of DNAJC10 from its substrate. Promotes apoptotic signaling pathway in response to endoplasmic reticulum stress (By similarity).
Interacts with HSPA5 (via its J domain). Interacts with EDEM1 (By similarity).
The thioredoxin-like regions Trxb 1 and 2 lack a redox-active CXXC motif.
Thioredoxin domains 3 and 4 are the primary reductase domains.
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 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. 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 (ANDR)-dependent transcription, by being recruited to ANDR 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. 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. 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.
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) (By similarity).
Interacts with PDK1. Interacts in vitro with PRKCBP1. Interacts with PHLPP1 and PHLPP2; both proteins mediate its dephosphorylation. Interacts with KDM1A/LSD1, PKN1 and ANDR (By similarity).
Phosphorylation on Thr-500 of isoform beta-I, 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. Similarly, isoform beta-II is autophosphorylated on 'Thr-641' and 'Ser-660', subsequent to phosphorylation on Thr-500. Autophosphorylated 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.
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 (By similarity).
ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals. Uses ATP as an energy source to transport cytosolic Ca(2+) ions across the plasma membrane to the extracellular compartment (PubMed:25014339, PubMed:9880546). May counter-transport protons, but the mechanism and the stoichiometry of this Ca(2+)/H(+) exchange remains to be established (PubMed:25014339, PubMed:9880546).
Expressed predominantly in brain and skeletal muscle (PubMed:2530223). Expressed in the molecular layer of the cerebellar cortex, in particular in granule cells (at protein level) (PubMed:27035656, PubMed:17183553, PubMed:9880546). Expressed in aldosterone producing glomerulosa cells of adrenal glands (at protein level) (PubMed:27035656). Detected at low levels in various tissues including testis, stomach, small intestine, and large intestine (PubMed:2530223).
Interacts with PDZD11. Interacts (via N-terminus) with YWHAE.
Most abundant form in brain and most other tissues.
Most abundant form in skeletal muscle and is also found in brain and at low levels in testis and kidney.
Up-regulated upon activation of glutamate-operated calcium channels.
A soluble short form may be released by proteolytic cleavage from the long membrane-anchored form.
Chemokine that acts as a ligand for both CX3CR1 and integrins ITGAV:ITGB3 and ITGA4:ITGB1. The CX3CR1-CX3CL1 signaling exerts distinct functions in different tissue compartments, such as immune response, inflammation, cell adhesion and chemotaxis. Regulates leukocyte adhesion and migration processes at the endothelium. Can activate integrins in both a CX3CR1-dependent and CX3CR1-independent manner. In the presence of CX3CR1, activates integrins by binding to the classical ligand-binding site (site 1) in integrins. 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.
Highest levels in brain (neurons). Significant levels in kidney, heart, lung and adrenal gland.
Monomer. Forms a ternary complex with CX3CR1 and ITGAV:ITGB3 or ITGA4:ITGB1.
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.
Amidase that catalyzes the last step of diphthamide biosynthesis using ammonium and ATP. Diphthamide biosynthesis consists in the conversion of an L-histidine residue in the translation elongation factor eEF-2 (EEF2) to diphthamide (By similarity).
Belongs to the Diphthine--ammonia ligase 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).
Binding to PtdIns(3,5)P2 is not required for localization.
Expressed in brain with no expression detected in non-neuronal tissues (at protein level).
Forms a complex with clathrin heavy chain and gamma-adaptin.
Required for normal morphology of late endosomes and/or lysosomes in neurons. 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.
Has a negative effect on cell proliferation.
Interacts with FGF2 with a low affinity.
Highest expression in pregnant ovary. Also found in a low extent in the kidney. In the brain, expressed in astrocytes and oligodendrocytes, and meningeal fibroblasts, but not in migroglia cells.
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.
Belongs to the G-protein coupled receptor 1 family. 5-hydroxytryptamine receptor subfamily. HTR1A sub-subfamily.
Detected in hypothalamus, mesencephalon, amygdala, medulla, thalamus, septum and hippocampus.
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 (By similarity). Interacts with YIF1B (PubMed:18685031).
Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components. Interacts with NR1I3. Interacts with PAAF1. Interacts with TRIM5. Interacts with ZFAND1 (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. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.
Belongs to the bZIP family. CNC subfamily.
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 (By similarity).
Homodimer; can bind DNA as a homodimer (By similarity). 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. 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.
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.
Belongs to the ubiquitin-conjugating enzyme family. FTS subfamily.
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. The FHF complex associates with the homotypic vesicular sorting complex (the HOPS complex). Also interacts with AKT1. May interact with FHIP1A.
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). 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.
Lacks the conserved Cys residue necessary for ubiquitin-conjugating enzyme E2 activity.
Expressed in kidney proximal tubules and outer medulla (at protein level) (PubMed:20584908).
Forms multimers (By similarity). Forms heteromultimers with AHCYL2 (via the C-terminal region). Interacts (when phosphorylated) with ITPR1 (when not phosphorylated); the interaction suppresses inositol 1,4,5-trisphosphate binding to ITPR1 (By similarity). Interacts with BCL2L10; this strengthens the interaction of AHCYL1 with ITPR1 (By similarity). 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. Interacts (when phosphorylated) with SLC9A3; the interaction is required for SLC9A3 apical location and activity (PubMed:20584908). Interacts (when phosphorylated) with FIP1L1; the interaction is direct and associates AHCYL1 with the CPSF complex and RNA. Interacts with PAPOLA (By similarity). Interacts with ZCCHC4 (By similarity).
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 (By similarity). 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 (By similarity). In the pancreatic and salivary ducts, at resting state, attenuates inositol 1,4,5-trisphosphate-induced calcium release by interacting with ITPR1 (By similarity). 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 (By similarity). 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. 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. Acts as a (dATP)-dependent inhibitor of ribonucleotide reductase large subunit RRM1, controlling the endogenous dNTP pool and ensuring normal cell cycle progression (By similarity). In vitro does not exhibit any S-adenosyl-L-homocysteine hydrolase activity (By similarity).
Phosphorylated at Ser/Thr residues between Ser-21 and Thr-25 in the PEST region: required for interaction with dATP-bound RRM1 and ITPR1. Phosphorylation at Ser-21 by PRKD1 and CAMK4 is required for further phosphorylations by CSNK1A1. Phosphorylation is induced by oxidative stress. Probably phosphorylated by CAMK2A; phosphorylation at Ser-21 may be required for interaction with SLC9A3. Dephosphorylated in response to apoptotic stress conditions which causes translocation of both AHCYL1 and BCL2L10 from mitochondria-associated endoplasmic reticulum membranes and promotes apoptosis.
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).
Detected in osteoblastic cells (at protein level). Detected in brain, and at lower levels in kidney, heart and lung.
Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake (PubMed:2211693). Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses (By similarity). 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 (By similarity). In association with BSG and NXNL1, promotes retinal cone survival by increasing glucose uptake into photoreceptors (By similarity).
Found in a complex with ADD2, DMTN and SLC2A1. Interacts (via C-terminus cytoplasmic region) with DMTN. Interacts with SNX27; the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane. Interacts with STOM (By similarity). Interacts with GIPC (via PDZ domain) (PubMed:10198040). Interacts with SGTA (via Gln-rich region) (PubMed:15708368). Interacts with isoform 1 of BSG (By similarity).
Phosphorylation at Ser-226 by PKC promotes glucose uptake by increasing cell membrane localization.
The uptake of glucose is inhibited by cytochalasin B. 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.
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 (By similarity). Facilitates surface trafficking and the 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 (By similarity). Also regulates many processes through PTK2 (By similarity). Regulates blood vessel endothelial cell migration and angiogenesis by regulating VEGF protein expression through PTK2 activation (By similarity). Regulates cell migration and cell contraction through PTK2 and SRC activation (By similarity). Regulates focal adhesion density, F-actin conformation and cell adhesion capacity through interaction with PTK2 (By similarity). Positively regulates cell proliferation (By similarity). Plays a role during cell death and cell blebbing. Promotes angiogenesis and vasculogenesis through induction of VEGFA via a HIF1A-dependent pathway (By similarity). Also plays a role in embryo implantation by regulating surface trafficking of integrin heterodimer ITGA5-ITGB3 (By similarity). 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 (By similarity). Interacts with ITGB3; regulates the levels of the heterodimer ITGA5-ITGB3 integrin surface expression (By similarity). Interacts with P2RX7 (via C-terminus) (By similarity). Interacts with ITGB1; the interaction may be direct or indirect and ITGB1 has a heterodimer form (By similarity).
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, SLCO6C1, 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). 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 (By similarity). Interacts with Ca(v)3.3/CACNA1I, leading to suppression of T-type calcium channel activity (By similarity).
Voltage-gated calcium channel that plays a central role in sperm cell hyperactivation. Controls calcium entry to mediate the hyperactivated motility, a step needed for sperm motility which is essential late in the preparation of sperm for fertilization. Activated by intracellular alkalinization.
Belongs to the dienelactone hydrolase family.
Interacts with FYB1, which is required for SKAP2 protein stability. Interacts with PTPNS1. Part of a complex consisting of SKAP2, FYB1 and PTPNS1. Part of a complex consisting of SKAP2, FYB1 and LILRB3. Interacts with LAT, GRB2, PTK2B, and PRAM1. May interact with actin. May interact with FYN, HCK and LYN. Interacts with FASLG (By similarity).
May be involved in B-cell and macrophage adhesion processes. In B-cells, may act by coupling the B-cell receptor (BCR) to integrin activation. May play a role in src signaling pathway (By similarity).
The SH3 domain interacts with FYB1 and PTK2B.
Expressed in all tissues examined with the highest expression in brain.
Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family (PubMed:9020086). Converts GDP-bound inactive form of RAB27A and RAB27B to the GTP-bound active forms (By similarity). 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 (PubMed:9020086). 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 (By similarity). May link TNFRSF1A with MAP kinase activation (By similarity). May be involved in the regulation of TNFA-induced apoptosis (By similarity).
Interacts (via death domain) with TNFRSF1A (via death domain) (By similarity). Interacts with PIDD1 (By similarity). Interacts with YWHAZ (By similarity). 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).
RNAi-mediated knockdown in hippocampal cells leads to neuronal cell death.
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 (By similarity).
Expressed in brain. Localized primarily to the neuropil and enriched in synaptic areas (at protein level).
May link the scaffolding protein CASK to downstream intracellular effectors.
Polymerizes, via the tandem SAM domains, to form long, 8 nM wide fibers, upon which other proteins can assemble (By similarity). Binds the CaM kinase domain of CASK. Forms a ternary complex with CASK and LIN7A, LIN7B or LIN7C. Competes with APBA1 that forms a similar complex with CASK and LIN7 proteins. The tripartite complex CASKIN1/CASK/LIN7(A/B/C) binds the cytoplasmic tail of NRXN1.
Receptor for MSH (alpha, beta and gamma) and ACTH. This receptor is mediated by G proteins which activate adenylate cyclase. Required for expression of anticipatory patterns of activity and wakefulness during periods of limited nutrient availability and for the normal regulation of circadian clock activity in the brain.
Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. This complex may also include HSP70.
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.
Expressed in basal forebrain, brain stem, spinal chord, and striatum. Specific for cholinergic neurons.
Homooligomerizes at cell surface (By similarity). 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 to the neuron with high affinity. Choline uptake is the rate-limiting step in acetylcholine synthesis. Sodium ion- and chloride ion-dependent.
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:1371282, PubMed:8020496). 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:1371282, PubMed:8020496). NADPH, however, is the probable reactant in biological systems (PubMed:8020496).
Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor.
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. Functions as a linker component that maintains centrosome cohesion. Associates with CROCC and regulates its stability and localization to the centrosome.
Interacts with CROCC. Interacts with POC1B; the interaction is direct and recruits POC1B to centriolar microtubules. Binds to centriolar microtubules.
Interacts with PPIF; the interaction is impaired by CsA.
Belongs to the nuclear transition protein 2 family.
Expressed during stages 12-15 of spermiogenesis.
Plays a key role in the replacement of histones to protamine in the elongating spermatids of mammals (PubMed:11772016). In condensing spermatids, loaded onto the nucleosomes, where it promotes the recruitment and processing of protamines, which are responsible for histone eviction (By similarity).
In response to the presence of allergens, this protein directly promotes the accumulation of eosinophils (a prominent feature of allergic inflammatory reactions), but not lymphocytes, macrophages or neutrophils (PubMed:9458816). Binds to CCR3 (By similarity).
Homodimer; disulfide-linked, upon oxidation (PubMed:10535922). 5 homodimers assemble to form a ring-like decamer (PubMed:17974571). Interacts with GDPD5; forms a mixed-disulfide with GDPD5 (By similarity). Interacts with SESN1 and SESN2 (By similarity). Interacts with FAM107A (By similarity).
Phosphorylated on Thr-90 during the M-phase, which leads to a 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) (By similarity). Reduces an intramolecular disulfide bond in GDPD5 that gates the ability to GDPD5 to drive postmitotic motor neuron differentiation (By similarity).
NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction.
Interacts with SGSM1, SGSM2 and SGSM3 (By similarity). Interacts with RAB11FIP1, RABEP1, ZFYVE20 and RUFY1. Interacts (membrane-bound form) with NDRG1; the interaction involves NDRG1 in vesicular recycling of E-cadherin. Interacts (in GTP-bound form) with GRIPAP1 (via N-terminus) (PubMed:20098723). Interacts with RABEP1 and RBSN (By similarity). Does not interact with HPS4 (By similarity). Interacts with RABEP2; this interaction may mediate VEGFR2 cell surface expression (By similarity).
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 (By similarity). Involved in protein transport. Plays a role in vesicular traffic. Mediates VEGFR2 endosomal trafficking to enhance VEGFR2 signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).
Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases. Involved in coordinating actin remodeling, which is necessary for cell migration and growth (By similarity). Plays a key role in the regulation of neurite outgrowth and lamellipodia formation (By similarity). 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 (PubMed:26721934). May act as a regulator of adipogenesis (By similarity).
Highly expressed during the early postnatal period (P1 to P7) in the hippocampus. At P11, levels start to decrease rapidly until p19 and then more progressively until adulthood (at protein level).
Interacts with CARMIL1 (By similarity). Interacts with PTPRF/LAR (By similarity). Interacts with ANKRD26 (By similarity). Interacts with Bassoon/BSN and Piccolo/PCLO (PubMed:27907191). Interacts with the cytoplasmic region of the heterodimer formed by NGFR and SORCS2. ProNGF binding mediates dissociation of TRIO from the receptor complex (By similarity).
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.
Expressed in embryo at 14 dpc and in skeletal muscle at 18 dpc.
Expressed in kidney, spleen, lung, liver, testis and muscle.
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 mu E3 enhancer sequence. Binds to mu E3 DNA sequence of the immunoglobulin heavy-chain gene enhancer. 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.
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Involved in the extracellular metabolism of lung surfactant (By similarity).
Catalyzes the cleavage of 5-oxo-L-proline to form L-glutamate coupled to the hydrolysis of ATP to ADP and inorganic phosphate.
Well expressed in testis, kidney and liver.
Transcriptional factor involved in the regulation of MAG (Myelin-associated glycoprotein) expression. Acts as a regulator of Schwann cell differentiation and myelination.
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:28209804, PubMed:19737935, PubMed:15683247). ACSL3 is required for the incorporation of fatty acids into phosphatidylcholine, the major phospholipid located on the surface of VLDL (very low density lipoproteins) (By similarity). Has mainly an anabolic role in energy metabolism. Mediates hepatic lipogenesis (PubMed:19737935). Preferentially uses myristate, laurate, arachidonate and eicosapentaenoate as substrates (PubMed:9276691, PubMed:8663269). Both isoforms exhibit the same level of activity (PubMed:9276691).
Detected 5 days after birth, increased to a maximal level at 15 days, and then decreased gradually to 10% of its maximum level in adult.
Predominantly expressed in the brain, and to a much lesser extent, in lung, adrenal gland, kidney, small intestine, and adipose tissue but not detected in heart or liver.
Can form homo- and heteropolymers with other CLDN. Homopolymers interact with CLDN3, but not CLDN2, homopolymers. Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3. Interacts with MPDZ and PATJ. Interacts with OCLN, CD81, CLDN4, CLDN6 and CLDN9.
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 (By similarity).
Detected in epididymis (at protein level). Detected in testis and epididymis.
Belongs to the SOS response-associated peptidase family.
Glu-127 is involved in sensing abasic sites in single-stranded DNA (ssDNA). His-209 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. 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. The HMCES DNA-protein cross-link is then degraded by the proteasome. 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. Has preference for ssDNA, but can also accommodate double-stranded DNA with 3' or 5' overhang (dsDNA), and dsDNA-ssDNA 3' junction (By similarity). 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. 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.
Belongs to the SRP receptor beta subunit family.
Component of the signal recognition particle (SRP) complex receptor (SR) (By similarity). Ensures, in conjunction with the SRP complex, the correct targeting of the nascent secretory proteins to the endoplasmic reticulum membrane system (By similarity). May mediate the membrane association of SR (By similarity).
Downstream regulator in the Wnt/Frizzled-signaling pathway (By similarity). Associated with cell survival. Adheres to skin and melanoma fibroblasts (By similarity). In vitro binding to skin fibroblasts occurs through the proteoglycans, decorin and biglycan (By similarity).
Channel activity is inhibited by mercury ions and phloretin.
Detected in testis and liver. Detected in immature spermatocytes and in interstitial Leydig cells.
Forms a water channel with a broad specificity. Also permeable glycerol and urea. Mediates passage of a wide variety of small, non-charged solutes including carbamides, polyols, purines, and pyrimidines.
By sleep deprivation. By acute nicotine in adolescent brain (at protein level).
Forms a ternary complex with MAGI2 and SH3KBP1; recruits DDN to the cytoplasm. Interacts with MAGI1. Interacts with ACTN1 and may interact with WWC1 (By similarity). Interacts with the podocyte slit diaphragm proteins CD2AP, NPHS1 and NPHS2; the interaction with CD2AP and NPHS1 is direct.
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.
Specifically expressed in forebrain structures, particularly in neocortex, olfactory bulb, hippocampus, caudate-putamen, and limbic system (at protein level). Also detected in spleen, liver, kidney and placenta (at protein level).
There are 2 forms of 81 kDa and 89 kDa detected in brain by an antibody raised against a C-terminal peptide arguing for alternative N-terminal sequences.
ADP-ribosylated; when cells are exposed to brefeldin A.
Cofactor binding induces a conformational change.
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 ELK3 (via its PXDLS motif). Interacts with RBBP8 (via its PXDLS motif); the interaction is disrupted by binding to adenovirus E1A. Interacts with PNN, MECOM and ZFHX1B. Interacts with ZNF366 (via PXDLS motif) (By similarity). Interaction with SATB1 (non-acetylated form); the interaction stabilizes its attachment to DNA and promotes transcription repression. Interacts with PRDM16; the interaction represses white adipose tissue (WAT)-specific genes expression. Interacts with GLIS2, HIPK2, FOXP1, FOXP2, HDAC4, HDAC5, HDAC9, NRIP1 and WIZ. Interacts with ZNF217. 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 (By similarity). Interacts with Bassoon/BSN; this interaction targets and anchors CTBP1 to presynapses (PubMed:25652077). Interacts with SIMC1 (By similarity).
Sumoylation on Lys-418 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-412 induces proteasomal degradation (By similarity).
Highest expression in lung and tongue. Also expressed in brain, colon, heart and liver. Isoform 1 is the predominant form in tongue whereas both isoforms are expressed in similar amounts in lung. At the cellular level, expression is confined to epithelial cells within the cleft of the circumvallate papillae extending into the ducts of the minor salivary glands, the respiratory epithelium of the nasal cavity and tear gland ducts.
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.
Detected in intestine and liver (at protein level).
Interacts with PCSK9. Interacts with MTTP. Interacts with AUP1.
Palmitoylated; structural requirement for proper assembly of the hydrophobic core of the lipoprotein particle.
The stop codon (UAA) at position 2147 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.
Component of the elastin-associated microfibrils.
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. 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. Binds to m7GpppG and strongly to m7GDP. Plays a role in first intron splicing of pre-mRNAs. Inhibits activation-induced cell death.
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.
Transcription factor that may function in dorsoventral specification of the forebrain. Regulates the expression of Wnt signaling antagonists including the expression of a truncated TCF7L2 isoform that cannot bind CTNNB1 and acts therefore as a potent dominant-negative Wnt antagonist. Plays a crucial role in eye development and, in particular, in the specification of the ventral optic vesicle (By similarity). May be a regulator of axial polarization in the retina.
Function as phospholipase selective for phosphatidylcholine (By similarity). 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).
It is uncertain whether palmitoylation is on Cys-240 and/or Cys-241. Palmitoylation is required prior to phosphorylation.
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.
Cleaved by FURIN to yield two fragments that remain associated via a disulfide bond.
Has been proposed to act as a receptor for neuronostatin, a peptide derived from the somatostatin/SST precursor (PubMed:22933024, PubMed:26561648). Involved in blood sugar regulation through the induction of glucagon in response to low glucose (PubMed:26561648).
Widely expressed (PubMed:22933024, PubMed:26561648). Not detected in the duodenum, nor in the exocrine pancreas (PubMed:22933024).
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.
Mediates apoptosis and actin stress fiber dissolution.
Cleaved into a 85 kDa membrane-spanning subunit (LRP-85) and a 515 kDa large extracellular domain (LRP-515) that remains non-covalently associated. Gamma-secretase-dependent cleavage of LRP-85 releases the intracellular domain from the membrane.
Endocytic receptor involved in endocytosis and in phagocytosis of apoptotic cells (By similarity). Required for early embryonic development (By similarity). Involved in cellular lipid homeostasis. Involved in the plasma clearance of chylomicron remnants and activated LRPAP1 (alpha 2-macroglobulin), as well as the local metabolism of complexes between plasminogen activators and their endogenous inhibitors. Acts as an LRPAP1 alpha-2-macroglobulin receptor. Acts as TAU/MAPT receptor and controls the endocytosis of TAU/MAPT as well as its subsequent spread. May modulate cellular events, such as APP metabolism, kinase-dependent intracellular signaling, neuronal calcium signaling as well as neurotransmission (By similarity).
Heterodimer of an 85-kDa membrane-bound carboxyl subunit and a non-covalently attached 515-kDa N-terminal subunit. Intracellular domain interacts with MAFB (By similarity). Found in a complex with PID1/PCLI1, LRP1 and CUBNI. Interacts with SNX17, PID1/PCLI1, PDGF and CUBN. The intracellular domain interacts with SHC1, GULP1 and DAB1. Can weakly interact (via NPXY motif) with DAB2 (via PID domain); the interaction is enhanced by tyrosine phosphorylation of the NPXY motif. Interacts with MDK; promotes neuronal survival. Interacts with LRPAP1; this interaction is followed by rapid internalization. Interacts with uPA/PLAU and PAI1/SERPINE1, either individually or in complex with each other, leading to rapid endocytosis; this interaction is abolished in the presence of LRPAP1/RAP. Also interacts with tPA/PLAT alone or in complex with SERPINE1. Interacts with the urokinase receptor PLAUR; this interaction leads to PLAUR internalization and is impaired in the presence of SORL1. Interacts with PDGFB. Interacts with TAU/MAPT, leading to endocytosis; this interaction is reduced in the presence of LRPAP1/RAP (By similarity).
Phosphorylated on tyrosine residues upon stimulation with PDGF. Tyrosine phosphorylation promotes interaction with SHC1.
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 pre-mRNAs. Associates with chromatin. Associates with nascent mRNAs transcribed by RNA polymerase II. Component of the supraspliceosome complex that regulates pre-mRNA alternative splice site selection. Binds non-specifically to pre-mRNAs (By similarity).
Binds and deliver cytosolic copper to the copper ATPase proteins. May be important in cellular antioxidant defense (By similarity).
Interacts with ATP7B (By similarity). Interacts with ATP7A (By similarity).
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.
A membrane-associated isoform interacts with STX3 and STXBP1.
A membrane-associated isoform is expressed in acini of the pancreas (at protein level). Ubiquitous.
A membrane-associated isoform may be involved in the exocytosis of zymogens by pancreatic acini. May regulate calcium-dependent activities in the endoplasmic reticulum lumen or post-ER compartment.
Down-regulated by ethanol. Down-regulated during the progression of cerebellum differentiation.
Belongs to the helicase family. Dicer subfamily.
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.
Myosin-binding protein which plays a role in cardiac function. Seems to regulate conduction in the atria and ventricular conduction systems.
Belongs to the sodium channel auxiliary subunit SCN2B (TC 8.A.17) family.
Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-2 causes an increase in the plasma membrane surface area and in its folding into microvilli. Interacts with TNR may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier.
Detected in the earliest phase of neurogenesis in brain, and expression is greatly increased concomitant with axon extension and synaptogenesis.
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:26894959). Interacts with SCN10A and TNR.
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. 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. Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with SHMT2 and the other subunits of the BRISC complex. In the BRISC complex, interacts directly with ABRAXAS2. Identified in a complex with ABRAXAS2 and NUMA1. 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 (By similarity). Interacts with PWWP2B (By similarity). Interacts with HDAC1; this interaction is enhanced in the presence of PWWP2B (By similarity).
Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. 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). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates. 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. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1. 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. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (By similarity). Deubiquitinates HDAC1 and PWWP2B leading to their stabilization (By similarity).
Interacts with CABP1 and CALR (By similarity). Interacts with INCA1 (PubMed:18756329).
Testis-specific. Expressed in round spermatids.
Expressed in oligodendroglial lineage cells.
Interacts with BAX (By similarity). Interacts with BCL2, BCL2L1/BCLX (By similarity). Interacts with APAF1 (By similarity). Interacts with ITPR1, ITPR2 and ITPR3; the interaction with ITPR1 is increased in the presence of AHCLY1 (By similarity). Interacts with AHCYL1 (By similarity). Interacts with HIP1R (via ENTH and I/LWEQ domains) (By similarity). Interacts with CASP9 (By similarity). Interacts with BCL2L11/BIM (By similarity). Interacts with BIK (By similarity). Interacts with UBQLN4 (By similarity). Interacts with NME2/NM23-H2 (PubMed:17532299). Interacts with and PMAIP1/NOXA (By similarity). Interacts with TPX2 (By similarity). Interacts with UBQLN1; in the cytoplasm (By similarity). Interacts (via BH1 domain) with BECN1 (By similarity).
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 (By similarity). Increases binding of AHCYL1/IRBIT to ITPR1 (By similarity). Reduces ITPR1-mediated calcium release from the endoplasmic reticulum cooperatively with AHCYL1/IRBIT under normal cellular conditions (By similarity). 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 (By similarity). 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).
Able to bind hyaluronan. However, its intracellular localization suggests that this interaction may not be relevant in vivo.
Associates with polysomes. Interacts with FMR1. Interacts with FXR1 and FXR2. Interacts with CHD3 (via C-terminus). Interacts (via C-terminus) with RACK1. Interacts with p53/TP53. Interacts (via N-terminus) with SRSF9; this interaction is direct. Interacts with SYNCRIP; this interaction is direct (By similarity). 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). Interacts with SPIN1 (By similarity).
Methylated. Methylation is decreased by phorbol 12-myristate 13-acetate (PMA)-activated PKC, in vitro.
Phosphorylated by phorbol 12-myristate 13-acetate (PMA)-activated PKC isoforms at Thr-352 and Thr-373.
RNA-binding protein that plays a role in the regulation of transcription, pre-mRNA splicing and mRNA translation (PubMed:15862299). Negatively regulates DNA-binding activity of the transcription factor MEF2C in myocardial cells in response to mechanical stress (PubMed:15862299). Plays a role in pre-mRNA splicing regulation. Binds (via C-terminus) to poly(U) RNA. Involved in mRNA translation regulation, probably at the initiation step (By similarity). Seems to play a role in PML-nuclear bodies formation (By similarity).
The C-terminal region is necessary for nucleus and cytoplasmic localization. The N-terminal region is necessary for nucleus and nuclear bodies localization. Regions containing Arg-Gly-Gly repeats (RGG/RXR-box) may be preferentially methylated by PRMT1.
Up-regulated in response to mechanical stimuli in cardiac myocytes (at protein level) (PubMed:15862299).
Expressed in the brain (at protein level), with highest levels in olfactory bulb, piriform cortex and hippocampus.
Highly expressed during the first week after birth.
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 (By similarity). May be involved in NOS1 regulation and targeting to the synaptic membrane (PubMed:15105416).
Expressed in both the inner and outer renal medulla of the kidney.
Expressed in the inner medulla of the kidney.
Inhibited by phloretin (PubMed:8958221). Activated by vasopressin, forskolin, 3-isobutyl-1-methylxanthine (IBMX) and cAMP (PubMed:16959825).
Inhibited by phloretin and activated by forskolin.
Inhibited by urea analogs and phloretin and activated by forskolin.
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.
Acetylated. Deacetylated by SIRT1, resulting in decreased protein stability. Deacetylated by SIRT6, preventing its degradation by the proteasome, resulting in increased protein stability.
Expressed in all tissues examined including eye, brain, heart, lung, spleen, liver, pancreas and kidney. In the CNS, highly expressed in the SCN, internal granular layer of granular cells of the olfactory bulb, tuberculum olfactorium, piriform cortex, gyrus dentatus of the hippocampus, cerebellum, pars tuberalis/median eminence, and pituitary, and moderately in the tenia tecta, caudate putamen, accumbens nucleus, superior and inferior colliculus and pineal gland.
Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with CLOCK-BMAL1 (off DNA). Interacts directly with PER1 and PER3, and through a C-terminal domain, with CRY1 and CRY2. Interacts, via its second PAS domain, with TIMELESS in vitro. Interacts with NFIL3. Different large complexes have been identified with different repressive functions. The core of PER complexes is composed of at least PER1, PER2, PER3, CRY1, CRY2, CSNK1D and/or CSNK1E. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with SETX; the interaction inhibits termination of circadian target genes. Interacts with the nuclear receptors HNF4A, NR1D1, NR4A2, RORA, PPARA, PPARG and THRA; the interaction with at least PPARG is ligand dependent. Interacts with PML. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Interacts with NONO and SFPQ. Interacts with CAVIN3 (By similarity). Interacts with MAGEL2 (By similarity). Interacts with MAP1LC3B (By similarity). Interacts with HNF4A (By similarity).
In eye, brain, heart, lung, spleen, liver, pancreas and kidney, expression exhibits a circadian rhythm in the presence of light/dark cycles.
Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. May be dephosphorylated by PP1 (By similarity).
Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndrome and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like BMAL1 or G6PC1. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.
Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibited by CRY1.
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. Responsible for the synthesis of short- and branched-chain acylcarnitines. Active towards some branched-chain amino acid oxidation pathway (BCAAO) intermediates. Trans-2-enoyl-CoAs and 2-methylacyl-CoAs are poor substrates.
Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. 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. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. 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. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
Expressed in bile ducts and other epithelial brush borders (small intestine, kidney, colon, pancreatic duct); acinar structures in salivary glands; endothelial structures and T cell areas in thymus, spleen and lymph node.
Monomer. Homodimer. Heterodimer with Seprase (FAP). 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. Associates with collagen. Interacts with PTPRC; the interaction is enhanced in an interleukin-12-dependent manner in activated lymphocytes. Interacts (via extracellular domain) with ADA; does not inhibit its dipeptidyl peptidase activity. Interacts with CAV1 (via the N-terminus); the interaction is direct. Interacts (via cytoplasmic tail) with CARD11 (via PDZ domain); its homodimerization is necessary for interaction with CARD11. Interacts with IGF2R; the interaction is direct. Interacts with GPC3.
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 (By similarity).
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.
Expressed in neurons (at protein level). Present in growth cones and abundant in developing neurons.
In the developing cerebellum, maximal levels occur at postnatal day 7 and correlate with the onset of neuronal differentiation.
Interacts with ITM2C (By similarity). Interacts with MAPK8. Interacts with KIFBP (By similarity). Interacts (via the N-terminal region) with CIB1 (via C-terminal region); the interaction is direct, occurs in a calcium-dependent manner and attenuates the neurite outgrowth inhibition of STMN2 (By similarity).
Pphosphorylated by MAPK9 and MAPK10 in the developing brain cortex (By similarity). Phosphorylated mostly by MAPK8.
Regulator of microtubule stability. When phosphorylated by MAPK8, stabilizes microtubules and consequently controls neurite length in cortical neurons. In the developing brain, negatively regulates the rate of exit from multipolar stage and retards radial migration from the ventricular zone.
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 (By similarity). Interacts with ZNF768 (By similarity).
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).
Belongs to the complex I NDUFC1 subunit family.
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.
In the C-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.
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 (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. Interacts with DYNC1I1 and DYNC1I2. Self-associates. Interacts with DYNLRB2. Interacts with RAB6A; the interaction is direct. Interacts with RAB6B (GDP-bound) (By similarity).
Belongs to the Mediator complex subunit 30 family.
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 (By similarity).
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 (By similarity).
Has intrinsic E3 ubiquitin ligase activity and promotes ubiquitination.
Parathymosin may mediate immune function by blocking the effect of prothymosin alpha which confers resistance to certain opportunistic infections.
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.
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.
Bound potassium ions stabilize the protein structure.
Heterotetramer of alpha and beta chains.
At 15 dpc highly expressed in developing skeletal muscles, tongue, sternocephalic and tail. Weaker expression is seen in the heart atrium and ventricle. Expressed in a circular pattern in the intestine.
Highly expressed in skeletal muscle and at low levels in the heart.
Interacts with ACTN2 (PubMed:9334352). Forms a heterodimer with PDLIM4 (via LIM domain) (By similarity).
May play a role in the organization of actin filament arrays within muscle cells.
Transaminase involved in tyrosine breakdown. Converts tyrosine to p-hydroxyphenylpyruvate. Can catalyze the reverse reaction, using glutamic acid, with 2-oxoglutarate as cosubstrate (in vitro). Has much lower affinity and transaminase activity towards phenylalanine.
Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins.
Intestine and in low abundance in adrenal gland, kidney, and uterus/oviduct.
Microtubule-dependent motor protein required for mitochondrion morphology and transport of mitochondria in neuronal cells.
Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity.
Glycosylated. Glycosylation is essential for its activity.
Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. Activated by detection of double stranded RNA (dsRNA): polymerizes higher oligomers of 2'-5'-oligoadenylates (2-5A) from ATP which then bind to the inactive monomeric form of ribonuclease L (RNASEL) leading to its dimerization and subsequent activation. Activation of RNASEL 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 RNASEL-dependent pathway or an alternative antiviral pathway independent of RNASEL. In addition, it may also play a role in other cellular processes such as apoptosis, cell growth, differentiation and gene regulation (By similarity). May act as a negative regulator of lactation, stopping lactation in virally infected mammary gland lobules, thereby preventing transmission of viruses to neonates (By similarity). Non-infected lobules would not be affected, allowing efficient pup feeding during infection (By similarity).
Myristoylation is not essential for its activity.
Produced as a latent enzyme which is activated by double stranded RNA (dsRNA) generated during the course of viral infection. The dsRNA activator must be at least 15 nucleotides long, and no modification of the 2'-hydroxyl group is tolerated. ssRNA or dsDNA do not act as activators. Strongly inhibited by copper, iron and zinc ions. Partially inhibited by cobalt and nickel ions.
Binds DNA as a dimer; homodimer and heterodimer with RXRB. Interacts with NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes. Probably interacts with SFPQ. Interacts with C1D. Interacts with AKAP13. Interacts with TP53INP2. Interacts with PER2 (By similarity). Isoform alpha-2 and isoform alpha-1 interact with TACC1, but the interaction with alpha-1 is weaker. The interaction with isoform alpha-1, but not alpha-2, is decreased in the presence of thyroid hormone T3 (By similarity).
Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.
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 (By similarity).
High levels detected in developing central and peripheral nervous systems with little expression elsewhere. In brain, highest levels in cerebral cortex and hindbrain at E15. At postnatal day 1, highest levels in basilar pons and superficial layers of the neocortex. In the developing spinal cord, restricted to a subpopulation of neurons in the dorsal and spinal ventral cord, probably D1 interneurons. Expressed in brain.
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.
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.
Has both L-asparaginase and beta-aspartyl peptidase activity. 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 (By similarity). May be involved in the production of L-aspartate, which can act as an excitatory neurotransmitter in some brain regions.
Heterodimer of an alpha and beta chain produced by autocleavage. This heterodimer may then dimerize in turn, giving rise to a heterotetramer (By similarity).
In vasectomized rats, autoantibodies against Asrgl1 are present.
Present in testis, brain, liver, kidney, heart and skeletal muscle. In brain, specifically present in the astrocytic lineage. Present in sperm (at protein level).
Acts both as a regulator of telomere function and as a transcription regulator. Involved in the regulation of telomere length and protection as a component of the shelterin complex (telosome). In contrast to other components of the shelterin complex, it is dispensible for telomere capping and does not participate in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair. Instead, it is required to negatively regulate telomere recombination and is essential for repressing homology-directed repair (HDR), which can affect telomere length. Does not bind DNA directly: recruited to telomeric double-stranded 5'-TTAGGG-3' repeats via its interaction with TERF2. Independently of its function in telomeres, also acts as a transcription regulator: recruited to extratelomeric 5'-TTAGGG-3' sites via its association with TERF2 or other factors, and regulates gene expression. When cytoplasmic, associates with the I-kappa-B-kinase (IKK) complex and acts as a regulator of the NF-kappa-B signaling by promoting IKK-mediated phosphorylation of RELA/p65, leading to activate expression of NF-kappa-B target genes (By similarity).
Associates with the I-kappa-B-kinase (IKK) core complex, composed of CHUK, IKBKB and IKBKG (By similarity). Homodimer. Component of the shelterin complex (telosome) composed of TERF1, TERF2, TINF2, TERF2IP ACD and POT1. Interacts with TERF2 (but not TERF1) with its C-terminus. Interacts with SLX4/BTBD12. Interacts with TERF2; the interaction is direct (By similarity).
Belongs to the complex I NDUFA8 subunit family.
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. May be involved in regulation of integrin-mediated cell motility (By similarity).
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.
Phosphorylated on tyrosine residues upon stimulation with pervanadate and concanavalin-A (ConA). Phosphorylation at Tyr-242 and Tyr-264 is required for interaction with PTPN11/SHP-2. Dephosphorylated by PTPN11/SHP-2 (in vitro) (By similarity).
Both CARD and transmembrane domains are essential for antiviral function. The CARD domain is responsible for interaction with RIGI and IFIH1/MDA5 (By similarity).
Following activation, phosphorylated by TBK1 at Ser-422 in the pLxIS motif. The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines.
Proteolytically cleaved by apoptotic caspases during apoptosis, leading to its inactivation. Cleavage by CASP3 during virus-induced apoptosis inactivates it, preventing cytokine overproduction.
Required for innate immune defense against viruses. Acts downstream of DHX33, RIGI and IFIH1/MDA5, which detect intracellular dsRNA produced during viral replication, to coordinate pathways leading to the activation of NF-kappa-B, IRF3 and IRF7, and to the subsequent induction of antiviral cytokines such as IFN-beta and RANTES (CCL5). Peroxisomal and mitochondrial MAVS act sequentially to create an antiviral cellular state. Upon viral infection, peroxisomal MAVS induces the rapid interferon-independent expression of defense factors that provide short-term protection, whereas mitochondrial MAVS activates an interferon-dependent signaling pathway with delayed kinetics, which amplifies and stabilizes the antiviral response. May activate the same pathways following detection of extracellular dsRNA by TLR3. May protect cells from apoptosis.
Self-associates and polymerizes (via CARD domains) to form 400 nM long three-stranded helical filaments on mitochondria, filament nucleation requires interaction with RIGI whose CARD domains act as a template for filament assembly. Interacts with RIGI, IFIH1/MDA5, TRAF2, TRAF6 and C1QBP. May interact with FADD, RIPK1, CHUK and IKBKB. Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3. Interacts with NLRX1. Interaction with NLRX1 requires the CARD domain. Interacts with PSMA7 (By similarity). Interacts with TRAFD1 (By similarity). Interacts (via C-terminus) with PCBP2 in a complex containing MAVS/IPS1, PCBP2 and ITCH. Interacts with CYLD. Interacts with SRC. Interacts with DHX58/LGP2 and IKBKE. Interacts with STING1. Interacts with IFIT3 (via N-terminus). Interacts with TBK1 only in the presence of IFIT3. Interacts with TTLL12; the interaction prevents MAVS binding to TBK1 and IKBKE (By similarity). Interacts with MUL1. Interacts with ANKRD17. Interacts with NDFIP1. Interacts with SMURF1; the interaction is mediated by NDFIP1 and leads to MAVS ubiquitination and degradation. Interacts with UBXN1; this interaction inhibits MAVS-mediated antiviral pathway. Interacts (via C-terminus) with GPATCH3; the interaction is markedly increased upon viral infection. Directly interacts (via CARD domain) with ATG5 and ATG12, either as ATG5 and ATG12 monomers or as ATG12-ATG5 conjugates (By similarity). Interacts with DHX33 (via the helicase C-terminal domain) (By similarity). Interacts with DDX3X (via C-terminus); this interaction may occur rapidly, but transiently after viral infection (By similarity). The interaction with DDX3X potentiates MAVS-mediated IFNB induction (By similarity). Conversely inhibition of this interaction prevents MAVS-mediated IFNB induction (By similarity). Transiently interacts with TRAF3 early during viral infection (By similarity). Interacts with CLPB (By similarity). Interacts with TRAF3IP3 (By similarity). Interacts with TOMM70; the interaction is enhanced by virus infection (By similarity). Interacts with ZNFX1 (By similarity). Interacts with DHX15 (By similarity). Interacts with N4BP3; this interaction promotes the polyubiquitination of MAVS (By similarity). Interacts with TAX1BP1; this interaction induces MAVS polyubiquitination (By similarity).
The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of MAVS recruits IRF3. IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines.
The transmembrane domain and residues 288-424 are essential for its interaction with DHX58/LGP2.
Ubiquitinated. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH; ITCH-dependent polyubiquitination is mediated by the interaction with PCBP2 and leads to MAVS/IPS1 proteasomal degradation. Ubiquitinated by RNF125, leading to its degradation by the proteasome. Undergoes 'Lys-48'-linked ubiquitination catalyzed by SMURF1. Undergoes 'Lys-63'-linked ubiquitination leading to enhanced interaction between MAVS and TRAF2.
Cargo transport protein that is required for apical transport from the trans-Golgi network (TGN). 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 (By similarity).
Homodimer. 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).
Belongs to the reverse transcriptase family. Telomerase subfamily.
Catalytic component of the telomerase holoenzyme complex composed of one molecule of TERT, one molecule of WRAP53/TCAB1, two molecules of H/ACA ribonucleoprotein complex subunits DKC1, NOP10, NHP2 and GAR1, and a telomerase RNA template component (TERC). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1. The molecular chaperone HSP90/P23 complex is required for correct assembly and stabilization of the active telomerase. Interacts directly with HSP90A and PTGES3. Interacts with HSPA1A; the interaction occurs in the absence of TERC and dissociates once the complex has formed. Interacts with RAN; the interaction promotes nuclear export of TERT. Interacts with XPO1. Interacts with PTPN11; the interaction retains TERT in the nucleus. Interacts with NCL (via RRM1 and C-terminal RRM4/Arg/Gly-rich domains); the interaction is important for nucleolar localization of TERT (By similarity). Interacts with SMARCA4 (via the bromodomain); the interaction regulates Wnt-mediated signaling (By similarity). Interacts with MCRS1 (isoform MCRS2); the interaction inhibits in vitro telomerase activity (By similarity). Interacts with PIF1; the interaction has no effect on the elongation activity of TERT (By similarity). Interacts with PML; the interaction recruits TERT to PML bodies and inhibits telomerase activity (By similarity). Interacts with GNL3L (By similarity). Interacts with isoform 1 and isoform 2 of NVL (By similarity). Interacts with DHX36 (By similarity). Interacts with ATF7 (By similarity).
Down-regulated by TGFbeta in fibroblasts. This inhibition is mediated by SMAD3.
High activity in cortex at embryonic stage 16 and postnatal day 2. Low activity in cortex from postnatal day 5.
Isoform 1 and isoform 2 expressed in thymus, liver, spleen, lung, kidney and testis. High level of inactive isoform 3 in adult hippocampus, low level in heart, cortex and cerebellum.
Phosphorylation at Tyr-697 under oxidative stress leads to translocation of TERT to the cytoplasm and reduces its antiapoptotic activity. Dephosphorylated by SHP2/PTPN11 leading to nuclear retention. Phosphorylation at the G2/M phase at Ser-447 by DYRK2 promotes ubiquitination by the EDVP complex and degradation (By similarity).
Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes. Active in progenitor and cancer cells. Inactive, or very low activity, in normal somatic cells. Catalytic component of the teleromerase holoenzyme complex whose main activity is the elongation of telomeres by acting as a reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide telomeric repeat unit, 5'-TTAGGG-3'. The catalytic cycle involves primer binding, primer extension and release of product once the template boundary has been reached or nascent product translocation followed by further extension. More active on substrates containing 2 or 3 telomeric repeats. Telomerase activity is regulated by a number of factors including telomerase complex-associated proteins, chaperones and polypeptide modifiers. Modulates Wnt signaling. Plays important roles in aging and antiapoptosis (By similarity).
The RNA-interacting domain 1 (RD1)/N-terminal extension (NTE) is required for interaction with the pseudoknot-template domain of each of TERC dimers. It contains anchor sites that bind primer nucleotides upstream of the RNA-DNA hybrid and is thus an essential determinant of repeat addition processivity (By similarity).
The RNA-interacting domain 2 (RD2) is essential for both interaction with the CR4-CR5 domain of TERC and for DNA synthesis.
The primer grip sequence in the RT domain is required for telomerase activity and for stable association with short telomeric primers.
Ubiquitinated by the EDVP complex, a E3 ligase complex following phosphorylation at Ser-447 by DYRK2. Ubiquitinated leads to proteasomal degradation (By similarity).
Binds DNA via bZIP domain; DNA-binding is under control of cellular redox homeostasis (in vitro) (By similarity). 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) (By similarity). The bZIP domain is able to form homomeric oligomers via formation of interchain disulfide bonds under non-reducing conditions (in vitro) (By similarity). Under reducing conditions, the disulfide-bonded homomeric species dissociates into monomers (in vitro) (By similarity).
Expressed in brain (PubMed:16687504). Expressed in pyramidal cells in CA1 and CA3, in the dentate gyrus and the nucleus accumbens (at protein level) (PubMed:26446228).
Heterodimer; binds to DNA as heterodimer (By similarity). 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 (By similarity).
Heterodimerizes with proteins of the JUN family to form an AP-1 transcription factor complex, thereby enhancing their DNA binding activity to an AP-1 consensus sequence 5'-TGA[GC]TCA-3' and enhancing their transcriptional activity (By similarity). Exhibits transactivation activity in vitro (By similarity). 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 (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).
Induced by chronic electroconvulsive seizure (ECS) treatment (PubMed:16687504). Induced in the hippocampus by novelty exposure and spatial learning (PubMed:26446228).
Phosphorylated; phosphorylation is induced by chronic electroconvulsive seizure (ECS) treatment.
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. 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) direct ubiquitination of BCL2.
Interacts with KDM2B, forming heterodimers (By similarity). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (By similarity). 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. Interacts with CEP68 (By similarity). Interacts with NOTCH2 and FBXW15 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (By similarity).
Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.
L-aspartate and 3-sulfino-L-alanine uptake are both inhibited by glisoxepide.
Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle (PubMed:4436323). Also mediates the uptake of L-cysteinesulfinate by mitochondria in exchange of L-glutamate and proton. Can also exchange L-cysteinesulfinate with aspartate in their anionic form without any proton translocation (PubMed:486467).
The EF-hand 2 domain within the regulatory N-terminal domain binds one calcium in the mitochondrial intermembrane space. Calcium triggers the binding of the regulatory N-terminal domain to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain (By similarity). In the absence of calcium, the linker loop domain may close the vestibule and prevent substrates from entering the carrier domain (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 (By similarity).
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.
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 (By similarity).
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 (By similarity).
Stabilizes the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex.
Homodimer; disulfide-linked, upon oxidation. 5 homodimers assemble to form a ring-like decamer.
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. Regulates the activation of NF-kappa-B in the cytosol by a modulation of I-kappa-B-alpha phosphorylation.
Expressed in brain, retina, lung, cerebellum, liver, kidney, hippocampus, spleen, cortex and heart (at protein level).
Found in a complex with ARL2, ARL2BP and SLC25A6. Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD. Interacts with ELMOD2. The GTP-bound form interacts with ARL2BP. The GDP-bound form interacts preferentially with TBCD. Interacts with UNC119. Found in a complex with ARL2, ARL2BP and SLC25A4. The GTP-bound form interacts with PDE6D (By similarity).
Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Regulates formation of new microtubules and centrosome integrity. Prevents the TBCD-induced microtubule destruction. Participates in association with TBCD, in the disassembly of the apical junction complexes. Antagonizes the effect of TBCD on epithelial cell detachment and tight and adherens junctions disassembly. Together with ARL2, plays a role in the nuclear translocation, retention and transcriptional activity of STAT3. Component of a regulated secretory pathway involved in Ca(2+)-dependent release of acetylcholine. Required for normal progress through the cell cycle (By similarity).
Expression is higher in 2 and 3 week old rats and lower in adults.
Intestine. Shows an apical localization in intestinal epithelial cells.
Expressed preferentially in brain, and its neuronal expression is relegated to limbic brain regions, particularly in forebrain.
G-protein coupled receptor for PEN, a neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N). Acts through a G(i)- and G(q)-alpha-alpha-mediated pathway in response to PEN. Plays a role in food intake and body weight regulation. May contribute to the regulation of anxiety-related behaviors.
Increased in the prefrontal cortex of rat chronically treated with amphetamines.
NPY has been reported to be a ligand for GPR83 (PubMed:17240481). However, a more recent study found that radiolabeled PEN binding to GPR83 is not affected by NPY concentrations below 1 mM, only very high, non-physiological concentrations causes a partial, displacement of PEN binding (By similarity).
May be involved in photoreceptor outer segment disk morphogenesis (By similarity).
May be involved in photoreceptor outer segment disk morphogenesis.
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. Plays a key role in NHEJ by promoting the ligation of various mismatched and non-cohesive ends. Together with PAXX, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends. 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. 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. 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. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors. Binds DNA in a length-dependent manner.
Homodimer; mainly exists as a homodimer when not associated with XRCC4. Interacts with XRCC4; the interaction is direct and is mediated via a head-to-head interaction between N-terminal head regions. 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. Additional component of the NHEJ complex includes PAXX. 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. Interacts with POLL (DNA polymerase lambda); promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL.
Phosphorylated by PRKDC at the C-terminus in response to DNA damage. Phosphorylation 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. Phosphorylation does not prevent interaction with XRCC4 but disrupts ability to bridge DNA and promotes detachment from DNA.
The Leu-lock (Leu-120) site inserts into a hydrophobic pocket in XRCC4.
The coiled-coil region mediates homodimerization.
Reversible hydration of carbon dioxide. Its role in saliva is unknown.
Interacts with FKBP6. 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. Interacts with MOV10L1 (By similarity).
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. 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. Plays a role in spermatogenesis. In association with SHCBP1L may participate in the maintenance of spindle integrity during meiosis in male germ cells.
Expressed in liver, kidney, adrenal gland and heart.
Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis (By similarity). Maintains mitochondrial 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 also essential for catalytic activity (By similarity).
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.
Belongs to the 5'-AMP-activated protein kinase gamma subunit family.
Highly expressed in heart and brain, also found in kidney, white adipose tissue, lung and spleen.
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. There is some ambiguity for a phosphosite: Ser-260/Thr-262.
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 (By similarity).
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 (By similarity).
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.
Binds 'Lys-48'-linked polyubiquitin chains of ubiquitinated proteins. Associates with the proteasome complex; upon exposure to arsenite. Interacts (via VIM motif) with VCP; the interaction is direct. Interacts with BAG6. Interacts with IGF1R (nascent precursor form). Interacts with DERL1, FAF2, NPLOC4 and UFD1; probably through VCP.
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 controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway.
The UIM domains specifically bind 'Lys-48'-linked ubiquitin polymers. The UIM domains mediate interaction with polyubiquitinated proteins.
Component of the mitochondrial ribosome large subunit (39S) which comprises a 16S rRNA and about 50 distinct proteins. Interacts with BCL2 (By similarity). Was also identified in the 28S mitochondrial ribosome (PubMed:9857009).
Component of the mitochondrial ribosome large subunit. Also involved in apoptosis and cell cycle. Enhances p53/TP53 stability, thereby contributing to p53/TP53-induced apoptosis in response to growth-inhibitory condition. Enhances p53/TP53 translocation to the mitochondria. Has the ability to arrest the cell cycle at the G1 phase, possibly by stabilizing the CDKN1A and CDKN1B (p27Kip1) proteins.
Seems to play a negative regulatory role in 5-phosphoribose 1-diphosphate synthesis.
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. 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. 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. 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.
Interacts with PKN2 (By similarity). Interacts with TIAM1 and TIAM2 (By similarity). Interacts with HA, as well as other glycosaminoglycans, collagen, laminin, and fibronectin via its N-terminal segment. Interacts with UNC119. 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 (By similarity). Interacts with RDX, EZR and MSN (By similarity). Interacts with EGFR (By similarity). Interacts with CD74; this complex is essential for the MIF-induced signaling cascade that results in B cell survival (By similarity).
O-glycosylated; contains chondroitin sulfate glycans which can be more or less sulfated.
Phosphorylated; activation of PKC results in the dephosphorylation of Ser-467 (constitutive phosphorylation site), and the phosphorylation of Ser-433.
The lectin-like LINK domain is responsible for hyaluronan binding.
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). Mediates transport of adenine, adenosine and uridine (By similarity).
Widely expressed. Highest levels in heart and liver (at protein level).
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 (By similarity). Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (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. 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 (By similarity). Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (By similarity).
Catalyzes the covalent attachment of ubiquitin to other proteins. Specific substrate for UBA6, not charged with ubiquitin by UBE1. May be involved in apoptosis regulation.
Homooligomer. Does not interact MYO18; differs from GOLPH3 by its inability to interact with MYO18. May interact with ARF1 (By similarity).
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.
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).
Has a role in ciliogenesis and is required for proper cephalic and left/right axis development.
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.
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. Interacts with DGKZ. 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.
Isoform 1 is predominantly expressed in the testis, whereas isoform 2 is predominant in various brain regions, including, neocortex, paleocortex, striatum, hippocampus, cerebellum and brain stem. Expressed in cells of hematopoietic origin.
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 (PubMed:17828261, PubMed:21422294). The PDZ domain also mediates binding to the retromer complex via direct interaction with VPS26 (VPS26A or VPS26B).
The PX domain mediates binding to phosphatidylinositol 3-phosphate (PtdIns(3P)) and localization to early endosome membranes.
Up-regulated by methamphetamine and cocaine in the neocortex, but not by pentobarbital nor by D1 antagonist.
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 (By similarity).
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 (By similarity). Interacts with CDC6 and KAT7/HBO1 (By similarity). Interacts with LRWD1 predominantly during the G1 phase and with less affinity during mitosis, when phosphorylated (By similarity).
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 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 (By similarity).
The BAH domain mediates binding to dimethylated histone H4 'Lys-20' (H4K20me2), which is enriched at replication origins.
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. Inhibitor of protein phosphatase 1.
Fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl-4'-phosphopantetheine and adenosine 3',5'-bisphosphate (By similarity). Mediates the hydrolysis of a wide range of CoA esters, including choloyl-CoA and branched-chain fatty-acyl-CoA esters and at low substrate concentrations medium and long-chain fatty-acyl-CoA esters are the primary substrates (By similarity). Highest activity seen with medium-chain acyl-CoA esters and higher rates of activity seen with the unsaturated acyl-CoA esters compared with the saturated esters (By similarity). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
Belongs to the eukaryotic ribosomal protein eL19 family.
Detected in brain, brain stem and brain cortex.
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.
May form homooligomers. Forms a heterodimer with OPRM1. Interacts with GPRASP1. Interacts with RTP4; the interaction promotes cell surface localization of the OPRD1-OPRM1 heterodimer.
Detected in the cytoplasmic lobe of elongated spermatids, in residual bodies, and in the acrosomal cap of round spermatids.
The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Interacts with NCOA2 and NCOA3 (By similarity).
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 interferon gamma (at protein level). Up-regulated by theophylline (THP), a reprotoxic agent thought to induce infertility.
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 (By similarity). 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 (By similarity). 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 (By similarity). Post-transcriptional inactivation of REST by SRRM4-dependent alternative splicing into isoform 6 is required in mechanosensory hair cells in the inner ear for derepression of neuronal genes and hearing (By similarity).
Expressed in the hippocampus including the granule cell layer of the dentate gyrus, the pyramidal cell layers of CA1 and CA3, the apical and basilar dendrite layers of the stratum radiatum and stratum oriens of CA1, the stratum lucidum and stratum oriens of CA3 and in astroglia (at protein level) (PubMed:22960932, PubMed:22371606, PubMed:12657670). Expressed in the brain, with the highest levels in the neurons of hippocampus, pons/medulla and midbrain (PubMed:9454838, PubMed:25108103).
Isoform 1 and isoform 6 form heterodimers (By similarity). Isoform 6: Forms homodimers and homooligomers; binds to the neuron-restrictive silencer element (NRSE) as monomer (By similarity). Interacts with SIN3A, SIN3B and RCOR1 (By similarity). Interacts with CDYL (By similarity). Interacts with EHMT1 and EHMT2 only in the presence of CDYL (By similarity). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2 (By similarity). Interacts (via zinc-finger DNA-binding domain) with ZFP90 (via N- and C-termini); the interaction inhibits REST repressor activity (By similarity). Interacts (via C2H2-type zinc finger 5) with PRICKLE1 (By similarity). Interacts with FBXW11 and BTRC (By similarity). Interacts with USP7 (By similarity).
Isoform 6: Controversial data exists concerning the repressor activity of isoform 6. In human, a study showed that human isoform 3 exhibits weak repressor activity of a NRSE motif-containing reporter construct (By similarity). Another report, however, does not observe any isoform 3 repressor activity of a NRSE motif-containing reporter construct (By similarity). Isoform 6: Controversial data also exists regarding the function of isoform 6 on the negative regulation of isoform 1. In mouse, it was shown that isoform 2 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 (By similarity). Another study in human, however, did not observe any inhibitory activity of human isoform 3 on the isoform 1 transcriptional repressor activity (By similarity).
Levels decrease during embryonic brain development (PubMed:9454838). Expressed during postnatal days P3 to P60, with an increase in expression at postnatal day P14-P15 (PubMed:22960932). Increased abundance in the nucleus at P14-P15 relative to P9 (PubMed:22960932).
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 (By similarity).
The C2H2-type zinc finger 5 is required for nuclear localization.
Transcriptional repressor which binds neuron-restrictive silencer element (NRSE) and represses neuronal gene transcription in non-neuronal cells (By similarity). 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 (By similarity). 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 (PubMed:9454838). Transcriptional repression by REST-CDYL via the recruitment of histone methyltransferase EHMT2 may be important in transformation suppression (By similarity). 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 6 (By similarity). Repressor activity may be inhibited by forming heterodimers with isoform 6, thereby preventing binding to NRSE or binding to corepressors and leading to derepression of target genes (By similarity). 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 hippocampal neural stem cells and preventing premature differentiation into mature neurons (By similarity). 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 (PubMed:22960932). 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 (By similarity). 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 (By similarity). 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 (PubMed:22371606, PubMed:12657670). After ischemia, might play a role in repression of miR-132 expression in hippocampal neurons, thereby leading to neuronal cell death (PubMed:25108103).
Ubiquitinated; ubiquitination is mediated by BTRC and leads to proteasomal degradation in G2 phase (By similarity). Ubiquitination increases during neuronal differentiation (By similarity). Deubiquitinated by USP7; leading to its stabilization and promoting the maintenance of neural progenitor cells (By similarity).
Up-regulated by kainic acid (PubMed:9454838). Up-regulated in the pyramidal cell layer of CA1 in the hippocampus by global ischemia (PubMed:25108103, PubMed:22371606, PubMed:12657670). Down-regulated in the hippocampus by maternal deprivation (PubMed:22960932).
Expressed in liver in hepatocytes and weakly in Kupffer's cells. Expression detected in testes in primary and secondary spermatocytes and interstitial cells. High expression levels detected in the inner cortex of kidney, with lower levels detected in the tubules of the outer cortex, medulla, renal pelvis and glomeruli (at protein level). Expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.
Oxidized purine nucleoside triphosphate hydrolase which is a prominent sanitizer of the oxidized nucleotide pool (PubMed:7586133). Catalyzes the hydrolysis of 2-oxo-dATP (2-hydroxy-dATP) into 2-oxo-dAMP (PubMed:7586133). Has also a significant hydrolase activity toward 2-oxo-ATP, 8-oxo-dGTP and 8-oxo-dATP (By similarity). 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:7586133). 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:7586133, PubMed:30304478, PubMed:32144205).
Autophosphorylation on Thr-674 appears to regulate motor functions of junctophilins, JPH3 and JPH4.
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors and neuronal functions related to sensitivity to opiates, pain and alcohol, mediation of synaptic function and cell survival after ischemia, and inhibition of gap junction activity after oxidative stress. Binds and phosphorylates GRIA4/GLUR4 glutamate receptor and regulates its function by increasing plasma membrane-associated GRIA4 expression. In primary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropic glutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptor which plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. May be involved in the regulation of hippocampal long-term potentiation (LTP), but may be not necessary for the process of synaptic plasticity. May be involved in desensitization of mu-type opioid receptor-mediated G-protein activation in the spinal cord, and may be critical for the development and/or maintenance of morphine-induced reinforcing effects in the limbic forebrain. May modulate the functionality of mu-type-opioid receptors by participating in a signaling pathway which leads to the phosphorylation and degradation of opioid receptors. May also contributes to chronic morphine-induced changes in nociceptive processing. Plays a role in neuropathic pain mechanisms and contributes to the maintenance of the allodynia pain produced by peripheral inflammation. Plays an important role in initial sensitivity and tolerance to ethanol, by mediating the behavioral effects of ethanol as well as the effects of this drug on the GABA(A) receptors. During and after cerebral ischemia modulate neurotransmission and cell survival in synaptic membranes, and is involved in insulin-induced inhibition of necrosis, an important mechanism for minimizing ischemic injury. Required for the elimination of multiple climbing fibers during innervation of Purkinje cells in developing cerebellum. Is activated in lens epithelial cells upon hydrogen peroxide treatment, and phosphorylates connexin-43 (GJA1/CX43), resulting in disassembly of GJA1 gap junction plaques and inhibition of gap junction activity which could provide a protective effect against oxidative stress. Phosphorylates p53/TP53 and promotes p53/TP53-dependent apoptosis in response to DNA damage. Involved in the phase resetting of the cerebral cortex circadian clock during temporally restricted feeding. Stabilizes the core clock component BMAL1 by interfering with its ubiquitination, thus suppressing its degradation, resulting in phase resetting of the cerebral cortex clock (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-514 (activation loop of the kinase domain), Thr-655 (turn motif) and Thr-674 (hydrophobic region), need to be phosphorylated for its full activation.
Interacts with GRIA4. Interacts with CDCP1, TP53INP1 and p53/TP53 (By similarity). Interacts with BMAL1 (By similarity).
Putative GTPase which is required for IFNG-mediated 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).
Belongs to the glycosyl hydrolase 37 family.
Has antimicrobial activity against Gram-positive bacteria, including Staphylococcus aureus and Actinomyces spec., and Mycoplasma hominis and lentivirus.
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). May be a tumor suppressor; together with SUSD2 has a growth inhibitory effect on colon cancer cells which includes G1 cell cycle arrest. May regulate keratinocyte proliferation. 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 (By similarity).
Interacts with SUSD2; the interaction is direct.
Peroxisomal protease that mediates both the removal of the leader peptide from proteins containing a PTS2 target sequence and processes several PTS1-containing proteins. Catalyzes the processing of PTS1-proteins involved in the peroxisomal beta-oxidation of fatty acids.
The full-lengh TYSND1 is the active the proteolytic processing of PTS1- and PTS2-proteins and in self-cleavage, and intermolecular self-cleavage of TYSND1 down-regulates its protease activity.
Activated by autophosphorylation; phosphorylated predominantly on serine and threonine residues, but also on tyrosine residues. Autophosphorylation at Thr-486 is required for kinase activation. The active autophosphorylated form apparently is largely refractory to cellular heme fluctuations.
In normal conditions, the protein kinase activity is inhibited; inhibition is relieved by various stress conditions (By similarity). Inhibited by heme: in presence of heme, forms a disulfide-linked inactive homodimer (By similarity). Heme depletion relieves inhibition and stimulates kinase activity by autophosphorylation. Inhibited by the heme metabolites biliverdin and bilirubin. Induced by oxidative stress generated by arsenite treatment. Binding of nitric oxide (NO) to the heme iron in the N-terminal heme-binding domain activates the kinase activity, while binding of carbon monoxide (CO) suppresses kinase activity (By similarity). Protein kinase activity is also activated upon binding to the processed form of DELE1 (S-DELE1): interaction with S-DELE1 takes place in response to mitochondrial stress and triggers the integrated stress response (ISR) (By similarity).
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 heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock. 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 activator ATF4, and hence allowing ATF4-mediated reprogramming. Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. It thereby plays an essential protective role for RBC survival in anemias of iron deficiency. Also activates the ISR in response to mitochondrial dysfunction: HRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming (By similarity).
Synthesized in an inactive form that binds to the N-terminal domain of CDC37. Has to be associated with a multiprotein complex containing Hsp90, CDC37 and PPP5C for maturation and activation by autophosphorylation. The phosphatase PPP5C modulates this activation (By similarity). Homodimer; homodimerizes in presence of heme, forming a disulfide-linked inactive homodimer (By similarity). Interacts with DELE1; binds to the processed form of DELE1 (S-DELE1) in response to mitochondrial stress, leading to activate its protein kinase activity and trigger the integrated stress response (ISR) (By similarity).
Was reported to be induced by various cytochrome P450 inducers, including phenobarbital, dexamethasone, rifampicin and barbituric acid in its autophosphorylated state, and that carbamazepine has no effect. Was also reported to be expressed predominantly in erythroid cells, and at much lower levels, expressed in hepatocytes (at protein level). However, this paper has been retracted because of improper data manipulation, reuse, and analyses.
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).
Predominantly expressed in brain, pituitary and stomach. In adult brain, it is restricted to the choroid plexus, the striatal proliferative subventricular zone and the cerebellum where it colocalizes with the D(3)R in the Purkinje cells of the lobules IX and X.
Catalyzes the conversion of 17-oxosteroids to 17beta-hydroxysteroids. Favors the reduction of androstenedione to testosterone. Testosterone is the key androgen driving male development and function (By similarity). Uses NADPH while the two other EDH17B enzymes use NADH. Androgens such as epiandrosterone, dehydroepiandrosterone, androsterone and androstanedione are accepted as substrates and reduced at C-17. Can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms (By similarity). Plays a role in the rate-limiting-step for the maximum level of testosterone production by the testis but does not affect basal testosterone production (By similarity).
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.
Belongs to the G-protein coupled receptor 1 family. Adrenergic receptor subfamily. ADRA2C sub-subfamily.
Interacts with distinct SNARE complexes that contain either STX5 or STX6 (By similarity). Interacts with NAPA and, to a lesser extent, with NAPG (By similarity). Identified in a complex containing STX6, STX12, VAMP4 and VTI1A.
Specifically expressed in the neuronal tissues cerebellum, cortex and hippocampus. Isoform 1/VTI1A is expressed in the same neuronal tissues but also in lung, liver, kidney and spleen.
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 (By similarity). May be concerned with increased secretion of cytokines associated with cellular senescence.
Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:19122147). 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. Plays a key role for peroxisome movement through a direct interaction with tubulin (By similarity).
Interacts with PEX13; forming the PEX13-PEX14 docking complex (By similarity). Interacts with PEX5 (via WxxxF/Y motifs) (PubMed:19122147). Interacts with PEX19 (By similarity). Interacts with tubulin (By similarity).
Interacts with SEC61B. May interact with Derlin-1/DERL1.
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. Regulates the exposure of nascent secretory protein chain to the cytosol during translocation into the ER. May affect the phospholipid bilayer in the vicinity of the lateral gate of the SEC61 channel, thereby facilitating ER protein transport. Intimately associates with transmembrane (TM) domain of nascent membrane proteins during the entire integration process into the ER membrane. 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. 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.
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.
Forms a complex with CDH1 and CTNNB1; interacts directly with CTNNB1 (By similarity). Interacts with AP1M2 and with isoform 2 of BSG/CD147 (By similarity).
Plays a role in cell adhesion and cell migration.
By FSH in Sertoli cells but not in peritubular cells; by cAMP in both type of cells.
Expressed in brain, heart, vas deferens, kidney, skeletal muscle, thymus, lung and spleen. Weak expression in liver.
In the nervous system, could hydrolyze ATP and other nucleotides to regulate purinergic neurotransmission. Hydrolyzes ADP only to a marginal extent.
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.
Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1 and CAMK4. Phosphorylates CAMK1D (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). 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. May play a role in neurite growth. Isoform 2 may promote neurite elongation, while isoform 1 may promoter neurite branching.
Mainly expressed in brain, but detected in all tissues tested (at protein level). In the brain, isoform 1 may be predominant. with high levels in the cerebellum and hippocampus, although isoform 3 is detectable. Isoform 3 is also expressed in lung.
Phosphorylated by PKA (By similarity). Each isoform may show a different pattern of phosphorylation (By similarity). Autophosphorylated.
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.
Belongs to the queuosine salvage protein family.
Activated by Ca(2+)/calmodulin. Binding of calmodulin may relieve intrasteric autoinhibition. Partially inhibited upon phosphorylation by PRCAKA/PKA. May be regulated through phosphorylation by CAMK1 and CAMK4.
Appears to be autophosphorylated. Phosphorylated at multiple sites by PRCAKA/PKA. Phosphorylation of Ser-458 is blocked upon binding to Ca(2+)/calmodulin. May be phosphorylated by CAMK1 and CAMK4.
Calcium/calmodulin-dependent protein kinase that belongs to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4. Involved in regulating cell apoptosis. Promotes cell survival by phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-antagonist of cell death.
Mostly expressed in the brain with higher levels in cortex and hippocampus. Lower expression levels were detected in striatum, nucleus accumbens and cerebellum (at protein level). Abundant in forebrain, weaker in cerebellum and also detected in thymus and spleen.
Belongs to the chibby family. SPERT subfamily.
Homodimer. Binds to NEK1 (By similarity).
Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. 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 (By similarity). By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes. May be involved in Mg(2+) transport (By similarity).
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.
Atria (at protein level) (PubMed:2673236). Cardiocytes (at protein level) (PubMed:9252368).
Cardiac hormone that plays a key role in mediating cardio-renal homeostasis (PubMed:2525380, PubMed:9252368). May also function as a paracrine antifibrotic factor in the heart (By similarity). Acts by specifically binding and stimulating NPR1 to produce cGMP, which in turn activates effector proteins that drive various biological responses (By similarity). Likely involved in regulating the extracellular fluid volume and maintaining the fluid-electrolyte balance through natriuresis, diuresis, kaluresis and chloruresis (PubMed:2525380, PubMed:9252368).
Expressed in the atria and ventricles throughout postnatal development and in adults.
Expressed in the atria and ventricles, but at much lower levels than NPPA (PubMed:1837590). Expression levels in the ventricles are slightly higher than in the atria (PubMed:1837590). Very low levels of expression detected in the brain, hypothalamaus, lung and aorta (PubMed:1837590).
The precursor molecule is proteolytically cleaved by the endoprotease Furin to produce brain natriuretic peptide 45 (PubMed:9252368). May undergo further proteolytic cleavage by various proteases such as DPP4, MME and possibly FAP, to give rise to a variety of shorter peptides (By similarity). May be cleaved at Ser-91 by the prolyl endopeptidase FAP (seprase) activity (in vitro) (By similarity). May be degraded by IDE (By similarity). During IDE degradation, the resulting products initially increase the activation of NPR1 and can also stimulate NPR2 to produce cGMP before the fragments are completely degraded and inactivated by IDE (in vitro) (By similarity).
Up-regulated in cardiocytes in response to stretching for 48hr.
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.
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.
Highly expressed in heart, lung, spleen and adrenal gland. Moderately expressed in skeletal muscle, testis and small intestine.
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:15020217). Steroid sulfate hormones are commonly considered to be biologically inactive metabolites, that may be activated by steroid sulfatases into free steroids (By similarity). 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 (By similarity). Can also transport other sulfoconjugated molecules such as taurolithocholic acid-3-sulfate and sulfoconjugated pyrenes (By similarity).
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 874.
Down-regulated by angiotensin II and iron overload (at protein level). Down-regulated by acute inflammatory stress, and in models for long-term hypertension, diabetes mellitus and chronic renal failure.
Expressed faintly from 18 dpc in the kidney. Expression increases in the kidney after 4 days of age.
Homodimer. Interacts with FGF23 and FGFR1.
May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 241 and 874, 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).
Present in cortical renal tubules and the parathyroid (at protein level). Strongly expressed in kidney. Expressed at low levels in brain, lung, intestine and ovaries.
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.
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 (By similarity).
Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. 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). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. 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 (By similarity). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (By similarity). 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 (By similarity).
Expressed in brain, kidney, lung, spleen, ovary and testis.
Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function (By similarity). 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 (By similarity). Interacts with EPHA2 (By similarity). 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 (By similarity). Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions (By similarity). Interacts with NGF in a divalent cation-dependent manner (By similarity). Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression (By similarity). Interacts with TSPAN5, TSPAN10, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity (By similarity). Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (By similarity). Interacts (via extracellular domain) with BACE1 (via extracellular domain) (By similarity). Interacts with FAM171A1 (By similarity).
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. Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33. Stalk region is sufficient for interaction with TSPAN15.
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.
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. However, the CST complex has been shown to be involved in several aspects of telomere replication.
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. 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. 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. Required for efficicient replication of the duplex region of the telomere. Promotes efficient replication of lagging-strand telomeres. Promotes general replication start following replication-fork stalling implicating new origin firing. May be in involved in C-strand fill-in during late S/G2 phase independent of its role in telomere duplex replication (By similarity).
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.
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. 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 C18 to C26 acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA. May participate to 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. Indirectly inhibits RPE65 via production of VLCFAs.
Interacts with LASS2, TECR and HSD17B12.
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).
Widely expressed. Highest level in ovary, testis, uterus and prostate. Protein found in plasma.
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. Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. Acts as a 2-carboxybenzaldehyde reductase.
With 4-nitrobenzaldehyde as substrate, it exhibits a substantially greater specific activity with NADPH than with NADH. Conversely, it has a 1.8-fold higher activity towards succinic semialdehyde with NADH than with NADPH.
Interacts with vasopressin receptors V1bR/AVPR1B (Ki=85 pM), V1aR/AVPR1A (Ki=0.6 nM) and V2R/AVPR2 (Ki=4.9 nM) (By similarity). Interacts with oxytocin receptor (OXTR) (Ki=110 nM) (By similarity).
Neurophysin 2 specifically binds vasopressin.
Vasopressin 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) (By similarity).
Expression is significantly decreased in renal failure.
Mediates the transport of organic anions such as estrone 3-sulfate and thyroid hormones 3,3',5'-triiodo-L-thyronine (T3) and L-thyroxine (T4) (PubMed:14993604). Capable of transporting pharmacological substances such as digoxin, ouabain, methotrexate and cAMP (PubMed:14993604). Shows a pH-sensitive substrate specificity estrone 3-sulfate 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 (By similarity). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (By similarity). May participate in the regulation of membrane transport of ouabain (PubMed:14993604). Involved in the uptake of the dipeptidyl peptidase-4 inhibitor sitagliptin and hence may play a role in its transport into and out of renal proximal tubule cells (By similarity). May be involved in the first step of the transport pathway of digoxin and various compounds into the urine in the kidney (PubMed:14993604). May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells (By similarity). This ion-transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation (By similarity). May have a role in secretory functions since seminal vesicle epithelial cells are assumed to secrete proteins involved in decapacitation by modifying surface proteins to facilitate the acquisition of the ability to fertilize the egg (By similarity).
Predominantly expressed in kidney and lung but also weakly expressed in brain.
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 PRKACA and PRKACB (By similarity). PRKAR1A also interacts with RFC2; the complex may be involved in cell survival. Interacts with AKAP4. Interacts with RARA; the interaction occurs in the presence of cAMP or FSH and regulates RARA transcriptional activity. Interacts with the phosphorylated form of PJA2. Interacts with CBFA2T3. Interacts with PRKX; regulates this cAMP-dependent protein kinase (By similarity). Interacts with smAKAP; this interaction may target PRKAR1A to the plasma membrane. Interacts with AICDA (By similarity).
The pseudophosphorylation site binds to the substrate-binding region of the catalytic chain, resulting in the inhibition of its activity.
Two types of regulatory chains are found: type I, which predominates in skeletal muscle, and type II, which predominates in cardiac muscle.
Brain. Greater expression found in the cerebral cortex than the cerebellum.
Homodimer (PubMed:9804790). Interacts with SAR1A (PubMed:19181664).
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.
Adds the first Dol-P-Man derived mannose in an alpha-1,3 linkage to Man(5)GlcNAc(2)-PP-Dol.
Belongs to the glycosyltransferase 58 family.
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).
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 (By similarity). 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. Preferentially protects single-stranded overhangs at break sites by inhibiting classical NHEJ, thereby creating a local environment that favors homologous recombination. Acts via interaction with XRCC5/Ku80 and XRCC6/Ku70 (By similarity). 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).
Interacts (via KBM motif) with XRCC5/Ku80 and XRCC6/Ku70 heterodimer. Interacts (via XLF motif) with TRIM28/KAP1, ATM, MRE11, NBN and RAD50.
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).
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12. 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. The PeBoW complex also associates with DDX27, PES1 interacts directly with DDX27. Interacts with IRS1 and UBTF. May interact with MAP1B.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RMT2 methyltransferase family.
Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.
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.
Interacts with POLR2A (via the C-terminal domain).
Heterotetramer of two type I and two type II keratins (By similarity). Heterodimer with KRT10 (By similarity). Two heterodimers of KRT1 and KRT10 form a heterotetramer (By similarity). Forms a heterodimer with KRT14; the interaction is more abundant in the absence of KRT5 (By similarity). Interacts with ITGB1 in the presence of RACK1 and SRC, and with RACK1 (By similarity). Interacts with C1QBP; the association represents a cell surface kininogen receptor (By similarity). Interacts with EPPK1; interaction is dependent of higher-order structure of intermediate filament (By similarity).
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 (By similarity).
Undergoes deimination of some arginine residues (citrullination).
Forms heterodimers with IL17RE; the heterodimer binds IL17C.
Specific functional receptor for IL17C, signaling through the NF-kappa-B and MAPK pathways. Requires TRAF3IP2 /ACT1 for signaling. Crucial regulator in innate immunity to bacterial pathogens (By similarity).
By nutritional state, up-regulated by fasting.
Highly expressed in the brain in the prefrontal cortex, hippocampus, paraventricular thalamus, ventromedial hypothalamus, arcuate nucleus, dorsal raphe nucleus, and locus coeruleus. Not detected in the spleen, lung, liver, skeletal muscle, kidney and testis. Orexin receptor mRNA expression has also been reported in the adrenal gland, enteric nervous system, and pancreas.
Moderately selective excitatory receptor for orexin-A and, with a lower affinity, for orexin-B neuropeptide. Triggers an increase in cytoplasmic Ca(2+) levels in response to orexin-A binding.
Interacts with INSC/inscuteable and GPSM2.
Receptor for activated thrombin coupled to G proteins that stimulate phosphoinositide hydrolysis.
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.
Expressed in leukocytes and pinealocytes. Expression in the pineal gland does not undergo circadian variations.
IgE Fc receptor is a tetramer of an alpha chain, a beta chain, and two disulfide linked gamma chains. Associates with FCGR1A to form a functional receptor complex (By similarity). 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:1825220). Associates with CLEC6A. Interacts with CLEC4E (PubMed:23921530). Interacts (via ITAM domain) with SYK (via SH2 domains); activates SYK, enabling integrin-mediated activation of neutrophils and macrophages (By similarity). Interacts with common beta chain of interleukin 3 receptor CSF2RB and recruits SYK in response to IL3 stimulation; this interaction is direct (By similarity). Interacts with CD300LH; the interaction may be indirect. Interacts with CD300LD (By similarity). Interacts with TARM1 (By similarity).
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 (By similarity).
Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. 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 (By similarity).
Phosphorylation at Ser-180 mediated by FAM20C slows down glycosylation at Thr-178 notably.
Regulator of phosphate homeostasis (By similarity). Inhibits renal tubular phosphate transport by reducing SLC34A1 levels (By similarity). Regulator of vitamin-D metabolism (By similarity). Negatively regulates osteoblasts differentiation and matrix mineralization (By similarity). Acts directly on the parathyroid to decrease PTH secretion (PubMed:17992255). Up-regulates EGR1 expression in the presence of KL (PubMed:17086194).
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 (By similarity). 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).
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 (By similarity).
Down-regulated in a number of tumor cell lines in response to methylation of the CpG island in exon 1.
Expressed in spleen, liver and lung. Not detected in kidney, colon, stomach or brain.
Heterodimer with CDK4 or CDK6. Predominamt 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 (By similarity).
Phosphorylation seems to increase interaction with CDK4.
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 Q8QZZ9) which is encoded by the same gene.
Belongs to the glycosyl hydrolase 2 family.
Plays an important role in the degradation of dermatan and keratan sulfates.
Undergoes a post-transcriptional proteolytic cleavage near its C-terminal end, which reduces its size by approximately 3 kDa. The site of this cleavage has as yet not been determined.
Catalyzes a dehydrogenation to introduce C5-6 double bond into lathosterol in cholesterol biosynthesis.
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 (By similarity).
Monomer. Homodimer and homotetramer; disulfide-linked.
Widely distributed throughout the adult brain, including cerebral cortex, hippocampus, thalamus, hypothalamus, olfactory bulb, and cerebellum.
Homodimer; disulfide-linked. Interacts with TXNIP through the redox-active site. Interacts with MAP3K5 and CASP3. Interacts with APEX1; the interaction stimulates the FOS/JUN AP-1 DNA-binding activity in a redox-dependent manner (By similarity).
In the fully reduced protein, both Cys-69 and Cys-73 are nitrosylated in response to nitric oxide (NO). When two disulfide bonds are present in the protein, only Cys-73 is nitrosylated. Cys-73 can serve as donor for nitrosylation of target proteins (By similarity).
Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (By similarity). Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity. Induces the FOS/JUN AP-1 DNA binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity (By similarity).
Binds and activates TIE2 receptor by inducing its tyrosine phosphorylation. 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. Mediates blood vessel maturation/stability. It may play an important role in the heart early development.
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. Binds to the trophoblast-specific element 2 (TSE2) of the aromatase gene enhancer. Binds to the SYDE1 promoter. Has a central role in mediating the differentiation of trophoblast cells along both the villous and extravillous pathways in placental development.
By inflammatory stimulus in liver. The level of this protein increases during acute phase, then decreases again.
Highest constitutive expression in ovary. Low level in testis, uterus and non-acute phase liver. Protein found in plasma.
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.
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.
Increased calcium sensitivity of myofilaments relative to isoform 1.
Can be regulated by protein kinase C-dependent phosphorylation.
Forms high-molecular-mass aggregates with elongation factor 1.
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 potassium channel family. S (TC 1.A.1.2) subfamily. Kv9.2/KCNS2 sub-subfamily.
Detected in brain, lung and in pulmonary arteries (PubMed:11891605).
Heterotetramer with KCNB1 and KCNB2. Does not form homomultimers.
Interacts with PCM1. Interacts with TTLL1, TPGS1, TPGS2 and LRRC49; the interactions link CSTPP1 to the complex TPGC. Binds to alpha-tubulin.
Regulator of the tubulin polyglutamylase complex (TPGC) that controls cytoskeletal organization, nuclear shape, and cilium disassembly by balancing microtubule and actin assembly. Regulates the assembly and stability of the TPGC and thereby modulates polyglutamylation of the microtubule, which antagonizes MAP4 binding.
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.
Most abundant in stomach, followed by colon. Lesser amounts were found in kidney, liver, brain, uterus and skeletal muscle. Predominantly expressed in the inner segments of inner medullary collecting ducts (IMCD) in kidney. Highly expressed in the cavi amnoni fields of hippocampus. Expressed in pancreas. Expressed in multiple nephron segments including proximla tubules, medullar thick ascending limbs (MTAL), cortical thick ascending limbs (CTAL), distal covoluted tubules and cortical and medullary collecting ducts. Expressed in submandibular gland.
Cleaved by CASP3 and CASP7. The potential C-terminal product released by CASP3 cleavage may inhibit the ERK signaling pathway through MAP2K2 (By similarity).
Defects in Atcay are the cause of primary generalized dystonia. The dt (SD-dt:JFL) rat is a spontaneous mutant that develops a dystonic motor syndrome by P12. Dystonic rats exhibit both axial and appendicular dystonia that progresses in severity with increasing postnatal age. There are no gross differences between normal and dt rats in terms of brain morphology.
Detected at 15 dpc, P1, P7, P14, P36 and in adult cerebellum in all neuronal populations. Peakes at P7 in hippocampus, increases linearly from P1 to P36 in cerebellum, and shows minimal developmental regulation in cerebral cortex. At 15 dpc, also detected in dorsal root and peripheral ganglia. In cerebellum, the transcript is present in the molecular, Purkinje and granular layers with higher expression in the molecular layer at P14.
Functions in the development of neural tissues, particularly the postnatal maturation of the cerebellar cortex. May play a role in neurotransmission through regulation of glutaminase/GLS, an enzyme responsible for the production in neurons of the glutamate neurotransmitter. Alternatively, may regulate the localization of mitochondria within axons and dendrites.
Interacts with KLC1; may link mitochondria to KLC1 and regulate mitochondria localization into neuron projections. Interacts with GLS; the interaction is direct and may control GLS localization, negatively regulating its activity. Interacts with PIN1; upon NGF stimulation (By similarity). The interaction with PIN1 (via WW domain) and GLS is competitive (By similarity).
Specifically expressed in brain. Detected in cerebellum (at protein level).
The CRAL-TRIO domain is known to bind small hydrophobic molecules.
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:1350383, PubMed:1834949, PubMed:1388270, PubMed:8428958, PubMed:18177891, PubMed:28384476, PubMed:15996549, PubMed:24876489, PubMed:27135925, PubMed:27618671, PubMed:28468946). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:28384476).
Detected throughout the brain, in brain cortex, cerebellum, thalamus and olfactory bulb.
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:18177891, PubMed:28384476, PubMed:16281028, PubMed:15996549, PubMed:21389213, PubMed:24876489, PubMed:27135925, PubMed:28468946, Ref.32). Can also form heterotetrameric channels that contain at least one zeta subunit (GRIN1), an epsilon subunit, plus GRIN3A or GRIN3B (in vitro) (PubMed:11160393, PubMed:11929923, PubMed:12391275). In vivo, the subunit composition may vary in function of the expression levels of the different subunits (Probable). Found in a complex with GRIN2A or GRIN2B, GRIN3A and PPP2CB (PubMed:11588171). 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 (PubMed:15312654). Interacts with LRFN1 and LRFN2 (PubMed:16495444, PubMed:16630835). Interacts with MYZAP (PubMed:18849881). Found in a complex with DLG4 and PRR7 (PubMed:27458189). 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.
Expressed in liver (in bile canalicular membrane vesicles (CMV) but not in sinusoidal vesicles), jejunum, spleen and heart (PubMed:7775409). Also expressed in brain and skeletal muscle (PubMed:7775409). Not expressed in kidney, muscle and lung (PubMed:7775409).
Inhibited by formycin B, partially inhibited by purine analog ara-A.
Sodium-dependent and purine-selective (PubMed:7775409, PubMed:8967974, PubMed:1315767). Exhibits the transport characteristics of the nucleoside transport system cif or N1 subtype (N1/cif) (selective for purine nucleosides and uridine) (PubMed:7775409, PubMed:8967974, PubMed:1315767). Accepts purine, analogs of purine nucleosides and uridine, and exhibits high affinity for adenosine (PubMed:7775409).
Belongs to the complex I NDUFA12 subunit family.
Essential for sperm motility and is involved in the regulation of the beating frequency of motile cilia on the epithelial cells of the respiratory tract (By similarity). Required for the establishment of radial spokes in sperm flagella (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity).
Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
Phosphorylation by ATM following gamma-irradiation results in its stabilization.
Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response. Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Increases IL-8 transcription. 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, induces IL1B release through NLRP3 inflammasome activation (By similarity). 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).
Homodimer. Also forms heterodimers with TIRAP. Binds to TLR2, TLR4, 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. Interacts with OTUD4 deubiquitinase; the interaction is direct.
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.
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).
Expressed at embryonic day 20, postnatal days 1, 7, 14, 36, six months and one and a half years. Highest level at 20 dpc. In muscle, expression is over 10 times higher at 20 dpc and during the early postnatal period than in adults. In adults, expression levels are several-fold higher in brain, particularly in the cerebellar cortex, than in muscle.
In both neural tissues including cerebellar cortex, striatum, cerebral cortex, thalamus and hippocampus, and non-neural tissues including quadriceps muscle, liver, kidney, spleen, lung, testis and heart. Widely distributed in the brain, with a robust signal obtained from regions with dense neuronal packing such as the pyramidal cell layer of the hippocampus, cerebellar molecular layer, and cerebral cortex. Levels are highest in kidney, moderate in brain and lung, and low in skeletal muscle, liver, spleen and testis.
Expressed predominantly in gastric mucosa and at much lower levels in the intestine. Also expressed in testis.
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 ZNF260. Interacts with TBX18.
Methylation at Lys-299 attenuates transcriptional activity.
Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key role in cardiac development (By similarity). In cooperation with TBX5, it binds to cardiac super-enhancers and promotes cardiomyocyte gene expression, while it down-regulates endocardial and endothelial gene expression (By similarity). Acts as a transcriptional activator of ANF in cooperation with NKX2-5 (By similarity). Promotes cardiac myocyte enlargement (By similarity). Required during testicular development (By similarity). Involved in bone morphogenetic protein (BMP)-mediated induction of cardiac-specific gene expression (PubMed:15329343). Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (PubMed:15329343). May play a role in sphingolipid signaling by regulating the expression of sphingosine-1-phosphate degrading enzyme, sphingosine-1-phosphate lyase (By similarity).
Interacts with AURKA, AURKB, BIRC5 and INCENP. May be a component of the CPC at least composed of BIRC5/survivin, CDCA8/borealin, INCENP and AURKB/Aurora-B (By similarity).
Required for normal cytokinesis during mitosis. Plays a role in the regulation of cell proliferation. May be a component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Increases AURKB activity. Inhibits apoptosis induced by TGFB1. Overexpression induces swelling of mitochondria and reduces mitochondrial membrane potential (By similarity).
Allosterically regulated by ATP (activator) and ADP (inhibitor) (PubMed:11322891). Cold labile, it dissociates into inactive monomers at low temperature (PubMed:6136404).
By 2-(p-chlorophenoxy)isobutyric acid (CPIB).
Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Preferentially hydrolyzes acetyl-CoA.
Expressed at 8 dpc. In brain, expression increases between 14 dpc and 16 dpc, reaches a plateau at 18 dpc, and subsequently decreases.
Expressed at high levels in heart, and at lower levels in skeletal muscle, spleen and lung. Expressed at low levels in brain regions where nascent and immature neurons are present.
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 (By similarity). 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 (By similarity).
Despite its name, it does not contain any EF-hand domains.
Expressed in the developmental stages from spermatocyte to spermatozoon.
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 (By similarity).
Chemotactic factor that attracts monocytes and eosinophils, but not neutrophils. Augments monocyte anti-tumor activity (By similarity).
Monomer. Interacts with TNFAIP6 (via Link domain).
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 on Tyr-87 enhances proteolytic processing, and blocks peptide degradation. Levels of sulfation differ between proteolytically-cleaved gastrins and between tissues (By similarity).
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. INTS9 subfamily.
Component of the CatSper complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with CHCHD3, DNAJC7, IRAK1BP1, PPP5C and TSC2. Interacts with TERT; the interaction occurs in the absence of the RNA component, TERC, and dissociates once the TERT complex has formed. Interacts with METTL21A. Interacts with DNAAF2. Interacts with TRIM5 (via B30.2/SPRY domain). Interacts with PRKN. Interacts with FOXP3. Interacts with NOD2; the interaction enhances NOD2 stability. Interacts with DNAJC9 (via J domain). Interacts with ATF5; the interaction protects ATF5 from degradation via proteasome-dependent and caspase-dependent processes. Interacts with RNF207 (via the C-terminus); this interaction additively increases KCNH2 expression. 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. Interacts with NAA10, HSP40, HSP90 and HDAC4. The acetylated form and the non-acetylated form interact with HOPX and STUB1 respectively. Interacts with NEDD1 and SMAD3. Interacts (via NBD) with BAG1, BAG2, BAG3 and HSPH1/HSP105. Interacts with DNAJC8. Interacts with NLRP12. Interacts with PGLYRP.
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. 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. 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. Enhances STUB1-mediated SMAD3 ubiquitination and degradation and facilitates STUB1-mediated inhibition of TGF-beta signaling. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation. Negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response.
Expressed in neuronal tissues. Widely distributed in neuropil regions in discrete puncta throughout the brain (at protein level). Detected in cortex, thalamus, striatum, olfactory bulb, cerebellum and all hippocampal subfields (at protein level). More abundant in deep than in superficial layers of neocortex (at protein level).
Involved in the development and maintenance of excitatory synapse in the 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.
Synaptogenic effects are mediated by the extracellular LRR region.
Expressed at low level in most tissues, except in adult testis, where it is highly expressed. Expressed in both spermatocytes and spermatids.
Has strong transforming capabilities on a variety of cell lines including NIH 3T3 fibroblasts and on athymic nude mice. Overexpressed in animals suffering from pituitary adenomas. The transforming capability may be due to its interaction and regulation of p53/TP53 pathway.
Interacts with the caspase-like ESPL1, and prevents its protease activity by covering its active site. Interacts with p53/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 (By similarity). Interacts with RPS10 and DNAJA1.
Phosphorylated at Ser-162 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 p53/TP53. The negative regulation of p53/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 (By similarity).
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 (By similarity).
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 (By similarity).
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. Mediates also the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4). The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4. Mediates the cotransport of bile acids with reduced glutathione (GSH). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules.
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.
Dopamine- and cyclic AMP-regulated neuronal phosphoprotein.
Phosphorylation of Thr-34 is required for activity.
Interacts with MYD88, IRAK1, IRAK4, and TRAF6 (By similarity). 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 (By similarity). Interacts with TMED1 (By similarity).
Isoform A is detected in spleen, lung, bone marrow and lymh node. Isoform B is predominant in fibroblasts.
Receptor for interleukin-33 (IL-33), 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 (By similarity).
Expressed in most sensory neurons but not in autonomic neurons. Also expressed in the dorsal horn of the spinal cord.
First detected at 12.5 dpc in the nervous system and in the dorsal root ganglia of the trunk region. By 15.5 dpc, strong expression in trunk and dorsal spinal cord and at 17.5 dpc expression increases in the dorsal horns.
Transcription factor required for the formation of correct projections from nociceptive sensory neurons to the dorsal horn of the spinal cord and normal perception of pain.
Activated by ascorbate. Inhibited by N-oxalylglycine, fumarate and succinate.
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. Specifically demethylates N(6)-methyladenosine (m6A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. M6A demethylation by FTO affects mRNA expression and stability. Also able to demethylate m6A in U6 small nuclear RNA (snRNA). 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. Demethylation of m6A(m) in the 5'-cap by FTO affects mRNA stability by promoting susceptibility to decapping. Also acts as a tRNA demethylase by removing N(1)-methyladenine from various tRNAs. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. 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. Ability to repair alkylated DNA and RNA is however unsure in vivo. Involved in the regulation of fat mass, adipogenesis and body weight, thereby contributing to the regulation of body size and body fat accumulation. Involved in the regulation of thermogenesis and the control of adipocyte differentiation into brown or white fat cells (By similarity). Regulates activity of the dopaminergic midbrain circuitry via its ability to demethylate m6A in mRNAs (By similarity).
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.
Ubiquitous (PubMed:17143547, PubMed:18218688). Highly expressed in teeth and weakly in bone (PubMed:17143547).
Up-regulated in the hypothalamus after 48 hours fasting.
Expression restricted to the placenta in trophoblast cells within the labyrinth zone.
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-947 is important for interaction with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin cytoskeleton. Phosphorylation at Tyr-1171 is important for interaction with PLCG1 and SHB. Phosphorylation at Tyr-1210 is important for interaction with NCK1 and FYN. Dephosphorylated by PTPRB. Dephosphorylated by PTPRJ at Tyr-797, Tyr-947, Tyr-992, Tyr-1050, Tyr-1055, Tyr-1171 and Tyr-1210 (By similarity).
Expressed in the post-pubertal mammary glands.
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- and vascular endothelial growth factor (VEGF)-dependent manner in endothelial cells (By similarity). 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 (By similarity). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the KDR/VEGFR2 C-terminal region (By similarity). Interacts with isoform 2 of BSG (By similarity).
Increases during pregnancy (1.6-fold at 4 days) and lactation (3.8-fold at 7 days). Decreases in the early phases of involution (45%, 50% and 34% on days 1, 2, and 3 respectively).
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. May be regulated by hydrogen sulfide (H(2)S) levels via a sensitive intracellular disulfide bond (By similarity).
The inhibitory disulfide bond between Cys-1020 and Cys-1041 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 may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. 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 (By similarity).
Ubiquitinated. Tyrosine phosphorylation of the receptor promotes its poly-ubiquitination, leading to its degradation via the proteasome or lysosomal proteases (By similarity).
Interacts with SH3GL2. Interaction appears to regulate MAP4K3-mediated JNK activation.
May play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway (By similarity).
Forms homodimers (in vitro) (PubMed:9388258). Forms heterodimers with NEFH or NEFM; which can further hetero-oligomerize (in vitro) (PubMed:9388258). Forms heterodimers with INA (in vitro) (PubMed:9388258). 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.
O-glycosylated; contains three N-acetylglucosamine side chains.
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.
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. Has a preference for sulfating keratan sulfate, but it also transfers sulfate to the unsulfated polymer (By similarity). 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 (By similarity). Catalyzes sulfation of N-acetyllactosamine (LacNAc) oligosaccharides with highest efficiency for sialylated LacNAc structures (By similarity).
May have a potential role in hypercalcemia of malignancy.
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 (By similarity). Interacts with JAK1 and TYK2 (By similarity). Forms a complex with GABBR1 and KIF5B/kinesin-1.
Specifically expressed in brain and testis by spermatogonia, spermatocytes, spermatozoa and Sertoli cells (at protein level).
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.
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. Also able, with less efficiently, to methylate the 5' monophosphate of a subset of pre-miRNAs, acting as a negative regulator of miRNA processing. 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. 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.
Central nervous system-specific myelin protein that increase myelin genes expression during oligodendrocyte differentiation. Promotes oligodendrocyte terminal differentiation.
After birth, expression in the organ of Corti increases about 10-fold by postnatal day 5 (P5) and remains at constant levels thereafter.
Expressed in brain, retina, testis, heart and lung. Not detected in liver, kidney or intestine. In brain, highly abundant in CNS neurons of the hippocampus and cerebellum. Strongly expressed in cochlea and vestibular sensory epithelia. In both the organ of Corti and the vestibular organ, expression is restricted to hair cells.
May play a role in spermatogenesis (By similarity). May be involved in synaptic processes.
Can form linear homooligomers in the membrane, giving rise to tight junction strand-like structures.
Claudins function as major constituents of the tight junction complexes that regulate the permeability of epithelia. While some claudin family members function as 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. CLDN15 forms tight junctions that mediate the paracellular transport of small monovalent cations along a concentration gradient, due to selective permeability for Na(+), Li(+) and K(+) ions, but selects against Cl(-) ions. Plays an important role in paracellular Na(+) transport in the intestine and in Na(+) homeostasis. Required for normal Na(+)-dependent intestinal nutrient uptake (By similarity).
Detected in kidney, jejunum and colon (at protein level).
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. 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).
Does not display channel activity in response to noxious chemical compounds, such as capsaicin and the vanilloid resiniferatoxin. Channel activity is not elicited by mildly acidic extracellular pH, and only slight channel activity is observed in response to noxiuos heat stimuli.
Interacts with PIRT (By similarity). Homotetramer (PubMed:15190102, PubMed:24305160, PubMed:24305161, PubMed:27281200). May also form a heteromeric channel with TRPV3 (By similarity). Interacts with CALM, PRKCM and CSK (PubMed:12808128, PubMed:15084474, PubMed:15471852, PubMed:17582331). Interacts with PRKCG and NTRK1, probably by forming a trimeric complex (PubMed:11418861). Interacts with the Scolopendra mutilans RhTx toxin (By similarity). Interacts with the spider Tau-theraphotoxin-Hs1a (PubMed:27281200). Interacts with TMEM100 (By similarity). Interacts with PACS2 (By similarity).
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-116 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.
Predominantly expressed in trigeminal and dorsal root sensory ganglia. Expressed also in hippocampus, cortex, cerebellum, olfactory bulb, mesencephalon and hindbrain. High expression in the cell bodies and dendrites of neurons in the hippocampus and in the cortex. In the brain detected also in astrocytes and pericytes (at protein level) (PubMed:15857679). Isoform 1 and isoform 3 are expressed in brain and peripheral blood mononuclear cells.
Responses evoked by capsaicin, but not by low pH and heat, can be antagonized by capsazepine.
The association domain (AD) is necessary for self-association.
Arginine methyltransferase involved in the assembly or stability of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). Acts by mediating symmetric dimethylation of 'Arg-118' of NDUFS2 after it assembles into the complex I, stabilizing the early intermediate complex.
Brain, pituitary, islet, jejunum, stomach, heart, spleen.
Receptor for somatostatin with higher affinity for somatostatin-14 than -28. This receptor is coupled to phosphotyrosine phosphatase and Na(+)/H(+) exchanger via pertussis toxin insensitive G proteins.
Accepts electrons from ETF and reduces ubiquinone.
Expressed in embryo and adult. Embryonic expression is detected from 12 dpc.
Interacts with CBFA2T3, ZBTB4 and 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. 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 (By similarity). Acts as a transcriptional activator. May be involved in the differentiation and/or survival of late postmitotic neurons (PubMed:15713629).
Ubiquitinated by RBBP6; leading to its degradation by the proteasome.
Widely expressed throughout the adult brain where it is found mainly in neurons. Also expressed in the adrenal medulla. Not detected in non-neural tissues including heart, spleen, liver and muscle. In the embryo, expressed in the developing brain and spinal cord but not in the migratory neural crest. Also expressed in the limbs, transiently in somites, and in the embryonic liver. In the embryonic neural tube, expression is restricted to late postmitotic neurons.
Expressed in the striatum; predominantly in the caudate putamen. Expressed in hippocampus; particularly strong in the CA1 area. Expressed in the spinal dorsal horn with especially strong expression in lamina IIi; found in excitory synaptic boutons (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.
Cell adhesion leukocyte receptor expressed by mucosal venules, helps to direct lymphocyte traffic into mucosal tissues including the Peyer patches and the intestinal lamina propria. It can bind both the integrin alpha-4/beta-7 and L-selectin, regulating both the passage and retention of leukocytes (By similarity).
Detected in Peyer patches and mesenteric lymph nodes but not in spleen.
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:17179049). In contrast, Ca(2+) acts as a cofactor by inducing conformational change to the active open form. In absence of Ca(2+), Mg(2+) may bind Ca(2+)-binding sites, promoting GTP-binding and subsequent inhibition of the acyltransferase activity (By similarity).
Auto-transglutaminated: Forms covalent cross-links mediated by transglutaminase between Gln-632 and the epsilon-amino group of a lysine residue of itself or HMGB1, forming homopolymers and heteropolymers, respectively.
By retinoic acid (PubMed:11073883). Up-regulated during pregnancy (PubMed:14970202).
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 (By similarity). Involved in many biological processes, such as bone development, angiogenesis, wound healing, cellular differentiation, chromatin modification and apoptosis (By similarity). 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:16341586, PubMed:29622788). Under physiological conditions, the protein cross-linking activity is inhibited by GTP; inhibition is relieved by Ca(2+) in response to various stresses (By similarity). When secreted, catalyzes cross-linking of proteins of the extracellular matrix, such as FN1 and SPP1 resulting in the formation of scaffolds (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Catalyzes serotonylation of 'Gln-5' of histone H3 (H3Q5ser) during serotonergic neuron differentiation, thereby facilitating transcription (By similarity). 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 (By similarity). 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 (By similarity). Catalyzes specific deamidation of protein gliadin, a component of wheat gluten in the diet (By similarity). May also act as an isopeptidase cleaving the previously formed cross-links (By similarity). 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:7911253, PubMed:12054611, PubMed:14970202). Activates alpha-1 adrenergic receptor signaling during pregnancy, promoting smooth muscle cell proliferation (PubMed:14970202).
Disulfide bond formation inactivates the calcium-dependent acyltransferase activity. 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 Cy-370 and Cys-371, which promotes inactivation of the acyltransferase activity. May also form interchain disulfids between Cys-230 and Cys-370. Ca(2+) protects against disulfide bond formation and inactivation.
Monomer (By similarity). Interacts with phospholipase C; promoting alpha-1 adrenergic receptor signaling (By similarity). Interacts with PLCD1 (PubMed:12054611).
S-nitrosylated, leading to its inactivate the acyltransferase activity.
Acetylated by p300/CBP, acetylation increases stability. Deacetylated by HDAC1 (By similarity).
Binds DNA as a monomer (PubMed:10331876). Interacts with GADD45GIP1. Interacts with STK11 (By similarity). Interacts with IFI27 (By similarity). Heterodimer (via DNA-binding domain) with RXRA (via C-terminus); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (By similarity). Competes for the RXRA interaction with EP300 and thereby attenuates EP300 mediated acetylation of RXRA (By similarity).
By nerve growth factor and during liver regeneration.
Expressed in lung, brain and superior cervical ganglia. High levels are seen in the adrenal tissue.
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'. 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 (By similarity). Plays a role in the vascular response to injury (By similarity).
Phosphorylated at Ser-350 by RPS6KA1 and RPS6KA3 in response to mitogenic or stress stimuli (By similarity). Phosphorylation of Ser-350 results in decrease in NBRE binding while phosphorylation of Ser-340 has little effect on it.
Down-regulated in cultured insuloma cells after dexamethasone treatment.
Highly expressed in pancreas, in particular in pancreatic islets and pancreatic beta-cells. Detected in prostate, adrenal gland, small intestine, stomach and thyroid (at protein level).
Acetylated on Lys-425 by CREBBP. Acetylated by EP300. Deacetylated by SIRT1 and HDAC3 (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 (By similarity). Forms a heterodimer with MEF2A (By similarity). Interacts with MAPK7; the interaction phosphorylates but does not activate MEF2D (PubMed:9753748). Interacts with MYOG (By similarity). Interacts with CCAR2 and HDAC3 (By similarity).
Phosphorylated on Ser-430 by CDK5 is required for Lys-425 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 (By similarity).
Sumoylated on Lys-425 with SUMO2 but not SUMO1; which inhibits transcriptional activity and myogenic activity. Desumoylated by SENP3 (By similarity).
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).
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 (By similarity).
Testis-specific. Strongly expressed in the testicular seminiferous tubules, mostly in the round spermatids.
Transiently expressed in spermiogenesis, being mostly concentrated in the periaxonemal compartment of the tail of the elongating spermatid, where it transiently associates with the longitudinal column of the FS. In the very last steps (steps 17-19), when periaxonemal expression disappears, it is still weakly present in the shrinking cytoplasmic lobe (at protein level).
Expressed in the hippocampus. Expression is rapidly up-regulated in granule cells of the dentate gyrus after LTP induction.
May play a role in prolonged long term-potentiation (LTP) maintenance.
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). Interacts with the proteasomal scaffolding protein PSMD1. Interacts with deubiquitinase UCHL5; this interaction activates the auto-inhibited UCHL5 by deoligomerizing it. Interacts with UBQLN2 and ubiquitin.
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. Within the complex, functions as a proteasomal ubiquitin receptor. Engages and activates 19S-associated deubiquitinases UCHL5 and PSMD14 during protein degradation. UCHL5 reversibly associate with the 19S regulatory particle whereas PSMD14 is an intrinsic subunit of the proteasome lid subcomplex.
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.
Forms two exclusive ternary complexes with CASK and CASKIN1 (PubMed:12040031). The brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, 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:9753324, PubMed:14960569). 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:10341223, PubMed:14960569). 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 (By similarity). Associates with KIF17 via APBA1 (PubMed:14960569). Interacts with ASIC3 (By similarity). Interacts with TOPK. Interacts with RTKN (By similarity). Interacts with APBA1 (PubMed:9753324, PubMed:14960569). Interacts with MPP7 (By similarity). 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).
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).
Highly expressed in presecretory ameloblasts with very high expression in secretory ameloblasts. Expression decreases in the maturation stage and is very low in the late maturation stage.
Highly expressed in the ameloblast layer of mandibular incisors, moderately expressed in submandibular gland, calvaria, kidney and lung, and expressed at low levels in brain and thymus.
Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface.
Inhibited by the not secondly cleaved propeptide (By similarity). 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) (By similarity). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK) (PubMed:9252368). Inhibited by heparin/heparan sulfate-binding (By similarity).
Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:9695949).
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:9252368). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (By similarity). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-45) (PubMed:9252368). 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).
Monomer. Interacts with TBC1D32 and MAK.
Required for high-level Shh responses in the developing neural tube. Together with TBC1D32, 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. Involved in cell growth. Activates CDK2, a kinase involved in the control of the cell cycle, by phosphorylating residue 'Thr-160' (By similarity).
Plays an important role in the degradation of some oligopeptides.
Predominantly expressed in kidney, but also expressed in a variety of tissues.
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.
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. Interacts with GRB2; the interaction is enhanced by EGF and NT-3 stimulation. Interacts (via NPXY motif) with DAB2 (via PID domain).
Phosphorylated. Phosphorylation during mitosis is leading to membrane displacement. There is some ambiguity for the mitotic phosphosite Ser-326/328.
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.
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.
Component of the oligosaccharyltransferase (OST) complex (By similarity). 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 (By similarity). 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.
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 (By similarity). 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.
Has glycerol-3-phosphate dehydrogenase activity.
According to some reports, mediates transmembrane transport of glucose and fructose (By similarity). However, another group coud not confirm transporter activity for glucose or fructose (By similarity).
Probable sugar transporter. Even if its physiological substrate is subject to discussion, it is able to transport glucose and fructose. Does not transport galactose, 2-deoxy-d-glucose and xylose.
This enzyme catalyzes the hydrolysis of the N-terminal peptide bond of an N-acetylated peptide to generate an N-acetylated amino acid and a peptide with a free N-terminus. It preferentially cleaves off Ac-Ala, Ac-Met and Ac-Ser.
Monomer as well as in a tight complex with SELENOF (PubMed:11278576). Interacts with METTL23 (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 (PubMed:12475965).
N-terminal non-catalytic domain is assumed to mediate recognition of proteins with partial folding defects.
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.
Centrosomal protein which may be required for microtubule attachment to centrosomes.
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. 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 (By similarity). 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.
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. Isoforms Beta 4b bind alpha-dystroglycan and neuroligins NLGN1, NLGN2 and NLGN3. Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity).
The laminin G-like domain 1 binds to NXPH1 (PubMed:9856994). Interacts with PATJ (PubMed:9647694). Interacts with CBLN1, CBLN2 and, less avidly, with CBLN4 (By similarity). Isoforms alpha 2C bind to alpha-dystroglycan (PubMed:11470830). Interacts (via Laminin G-like 1 domain) with IGSF21 (Ig-like 1 domain) in a trans-interaction manner (By similarity).
Essential for retina photoreceptor outer segment disk morphogenesis, may also play a role with ROM1 in the maintenance of outer segment disk structure (By similarity). Required for the maintenance of retinal outer nuclear layer thickness (By similarity). Required for the correct development and organization of the photoreceptor inner segment (By similarity).
Homodimer; disulfide-linked (By similarity). Forms a homotetramer (By similarity). Forms a heterotetramer with ROM1 (By similarity). Homotetramer and heterotetramer core complexes go on to form higher order complexes by formation of intermolecular disulfide bonds (By similarity). Interacts with MREG (By similarity). Interacts with STX3 (By similarity). Interacts with SNAP25 (By similarity).
Retina (photoreceptor). In rim region of ROS (rod outer segment) disks.
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.
Differs at a number of positions and in the total number of residues.
Prolactin acts primarily on the mammary gland by promoting lactation.
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 (By similarity).
Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. May be involved in iron metabolism, hepatocyte function and erythrocyte differentiation (By similarity).
Binds 2 Zn(2+) ions per subunit. One is catalytic, whereas the other seems to have a structural role.
The protein has been described as presenting a second isoform with a missign Lys in position 309 (PubMed:15972818). However, the paper has been retracted.
Abundantly expressed in brain, arterial and cardiac endothelium. Found as well in sperm, in the head of the epididymis. Lower expression is found in vascular smooth muscle, exocrine pancreas, testis and placenta.
This is a specific receptor for parathyroid hormone. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. PTH2R may be responsible for PTH effects in a number of physiological systems. It may play a significant role in pancreatic function. PTH2R presence in neurons indicates that it may function as a neurotransmitter receptor.
Acts as a ligand for FGFR1, FGFR2, FGFR3 and FGFR4 (By similarity). Also acts as an integrin ligand which is required for FGF2 signaling (By similarity). Binds to integrin ITGAV:ITGB3 (By similarity). Plays an important role in the regulation of cell survival, cell division, cell differentiation and cell migration (By similarity). Functions as a potent mitogen in vitro (By similarity). Can induce angiogenesis (By similarity). Mediates phosphorylation of ERK1/2 and thereby promotes retinal lens fiber differentiation (By similarity).
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. Interacts with integrin ITGAV:ITGB3; the interaction is required for FGF2 signaling. Interacts with SNORC (via the extracellular domain). Interacts with GPC3 (PubMed:9065409).
Phosphorylation at Tyr-81 regulates FGF2 unconventional secretion.
Acetylated. Deacetylation at Lys-780 by SIRT6 stimulates its ability to coactivate PPARA.
Contains 2 C-terminal transcription activation domains (AD1 and AD2) that can function independently.
Contains four Leu-Xaa-Xaa-Leu-Leu (LXXLL) motifs. The LXXLL motifs are essential for the association with nuclear receptors and are, at least in part, functionally redundant.
Present in a complex containing NCOA3, IKKA, IKKB, IKBKG and CREBBP. Interacts (via C-terminus) with CREBBP. Interacts with ESR1, HIF1A, NCOA1, APEX1, NR3C1, NR3C2, CARM1, RARA, and RXRA. Present in a complex containing CARM1 and EP300/P300. Interacts with CASP8AP2 and TTLL5/STAMP. Interacts with PSMB9 and DDX5. Interacts (via LXXLL 1, 2 and 3 motifs) with RORA and RORC (via AF-2 motif). Interacts with RWDD3. Interacts with CLOCK and BMAL1. Interacts with NR4A3; potentiates the activity of the NR4A3 (By similarity). Interacts with NR1H3 (By similarity).
The LLXXLXXXL motif is involved in transcriptional coactivation and CREBBP/CBP binding.
Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues. Critical regulator of glucose metabolism regulation, acts as RORA coactivator to specifically modulate G6PC1 expression. Involved in the positive regulation of the transcriptional activity of the glucocorticoid receptor NR3C1 by sumoylation enhancer RWDD3. Positively regulates the circadian clock by acting as a transcriptional coactivator for the CLOCK-BMAL1 heterodimer.
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 (By similarity).
Widely expressed in peripheral tissues with the highest level in the spleen and moderate levels in the adipose tissues, thymus, lung, kidney, testis, uterus and small intestine.
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. 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. Interacts with IMMT/MIC60.
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. This protein may be involved in the regulation of renal function.
Heterodimer of a light chain and heavy chain linked by a disulfide bond.
Kidney and submandibular gland, where it is found in the granular convoluted tubule and striated duct cells. It is likely that the enzyme is mainly synthesized in the granular convoluted tubules and then transferred to other tissues by release into the vasculature or interstitial space.
First detected at embryonic day 15. At postnatal day 14 detected in skin, spleen, liver, kidney, heart, testicle, lung and brain. At adulthood is most abundant in brain.
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. 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 (By similarity).
Palmitoylated by ZDHHC5. Palmitoylation is required for targeting to plasma membrane, enabling G(i) coupling.
Seems to act as an inhibitor of cellular proliferation.
Regulates the composition and fluidity of the plasma membrane (By similarity). Inhibits the incorporation of membrane-fluidizing phospholipids containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA) and thereby promotes membrane rigidity (By similarity). Does not appear to have any effect on LCPUFA synthesis (By similarity).
Was originally proposed to be a calcium channel facilitator (By similarity). However, a more recent study shows that this protein regulates membrane phospholipid homeostasis (By similarity). Therefore, any effects on calcium flux are most likely a secondary consequence of defects in membrane composition or fluidity (By similarity).
Acetylated by KAT5 at Lys-243 following phosphorylation by AMPK, leading to monomerization and conversion into a tyrosine-protein kinase.
Belongs to the choline/ethanolamine kinase family.
Heterodimer with CHKB (By similarity). Homodimer (By similarity).
Monomer; acetylation by KAT5 promotes dissociation of the homodimer and monomerization.
Phosphorylated at Ser-275 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. Also phosphorylates ethanolamine, thereby contributing to phosphatidylethanolamine biosynthesis. Has higher activity with choline. May contribute to tumor cell growth.
This isoform plays a key role in lipolysis of lipid droplets following glucose deprivation (By similarity). In response to glucose deprivation, phosphorylated by AMPK, promoting localization to lipid droplets (By similarity). Phosphorylation is followed by acetylation by KAT5, leading to dissociation of the homodimer into a monomer (By similarity). 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 (By similarity).
Cell surface receptor that transfers passive humoral immunity from the mother to the newborn. Binds to the Fc region of monomeric immunoglobulin gamma and mediates its selective uptake from milk (PubMed:18818657, PubMed:7969498). IgG in the milk is bound at the apical surface of the intestinal epithelium. The resultant FcRn-IgG complexes are transcytosed across the intestinal epithelium and IgG is released from FcRn into blood or tissue fluids (PubMed:7298722, PubMed:18818657). Throughout life, contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation. Mechanistically, monomeric IgG binding to FcRn in acidic endosomes of endothelial and hematopoietic cells recycles IgG to the cell surface where it is released into the circulation. In addition of IgG, regulates homeostasis of the other most abundant circulating protein albumin/ALB (By similarity).
FcRn complex consists of two subunits: p51, and p14 which is equivalent to beta-2-microglobulin. It forms an MHC class I-like heterodimer (PubMed:2911353, PubMed:7969498, PubMed:9493268). Interacts with albumin/ALB; this interaction regulates ALB homeostasis (By similarity).
AMP deaminase plays a critical role in energy metabolism. Catalyzes the deamination of AMP to IMP and plays an important role in the purine nucleotide cycle (By similarity).
During spermatogenesis, it is mainly expressed postmeiotically.
Interacts with BCL2. Interacts with BCL2L1.
Suppressor of apoptosis. Modulates unfolded protein response signaling. Modulates ER calcium homeostasis by acting as a calcium-leak channel. Negatively regulates autophagy and autophagosome formation, especially during periods of nutrient deprivation, and reduces cell survival during starvation.
The intra-membrane loop at the C-terminus acts as a calcium pore, mediating calcium leak from the ER into the cytosol.
Actin-depolymerizing protein. Severs actin filaments (F-actin) and binds to actin monomers (G-actin). Acts in a pH-independent manner.
Can be converted from the dehydrogenase form (D) to the oxidase form (O) irreversibly by proteolysis or reversibly through the oxidation of sulfhydryl groups.
Contains sulfhydryl groups that are easily oxidized (in vitro); this alters the enzyme from the dehydrogenase form (D) to the oxidase form (O).
Homodimer. Interacts with BTN1A1 (By similarity).
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species.
Subject to partial proteolysis; this alters the enzyme from the dehydrogenase form (D) to the oxidase form (O).
Highly expressed at sites of inflammation.
Homodimer. Preferentially exists as a heterodimer or heterotetramer with S100A8 known as calprotectin (S100A8/A9) (By similarity). 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. S100A9 binds quinoline-3-carboxamides in the presence of calcium and/or zinc ions. S100A9 interacts with amyloid-beta protein 40. Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes. Calprotectin (S100A8/9) interacts with NCF2/P67PHOX, RAC1, RAC2, CYBA and CYBB. Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox) (By similarity).
Methylation at His-107 by METTL9 reduces zinc-binding without affecting heterodimerization with S100A8.
Phosphorylated. Phosphorylation inhibits activation of tubulin polymerization.
S100A9 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response (PubMed:15153104, PubMed:21487906). 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 (By similarity). Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions (By similarity). 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 (By similarity). 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 (By similarity). The extracellular functions involve pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities (PubMed:21487906). Its pro-inflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration (By similarity). 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) (By similarity). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the pro-inflammatory cascade (By similarity). Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth (By similarity). 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 (By similarity). 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 (By similarity). Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants (By similarity). The iNOS-S100A8/A9 transnitrosylase complex is proposed to direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as GAPDH, NXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif (By similarity).
By angiotensin-II or its agonist CGP42112A, via MTUS1 and PTPN6 (at protein level).
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.
Heterodimer with UBE2N. Binds CHFR (By similarity).
Highly expressed in embryonic cerebral cortex, hippocampus and cerebellum between day 18 and up to birth. Levels are distictly lower 10 days after birth, and not detectable in adults (at protein level).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. NCD subfamily.
Binds NUBP1 and NUBP2. Interacts with PPP1R42 (By similarity).
Minus end-directed microtubule-dependent motor required for bipolar spindle formation. May contribute to movement of early endocytic vesicles. Regulates cilium formation and structure.
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. Together with GOPC/CAL mediates the ubiquitination and lysosomal degradation of CFTR (By similarity). Ubiquitinates and therefore mediates the degradation of DLG1 (By similarity). Regulates the intracellular trafficking and secretion of alpha1-antitrypsin/SERPINA1 and HP/haptoglobin via ubiquitination and degradation of the cargo receptor ERGIC3 (By similarity). 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 (By similarity). May be involved in endosomal trafficking through interaction with STX6.
Interacts with STX6; the interaction promotes MARCHF2-mediated ubiquitination and degradation of CFTR (PubMed:15689499). Interacts with MARCHF3 (PubMed:16428329). Interacts with GOPC/CAL; the interaction leads to CFTR ubiquitination and degradation (By similarity). Interacts with CFTR; the interaction leads to CFTR ubiqtuitination and degradation (By similarity). Interacts (via PDZ domain) with DLG1 (via PDZ domains); the interaction leads to DLG1 ubiqtuitination and degradation (By similarity). Interacts with ERGIC3 (By similarity). Interacts with ADRB2 (By similarity). Interacts with IKBKG/NEMO; during the late stages of macrophage viral and bacterial infection; the interaction leads to ubiquitination and degradation of IKBKG/NEMO (By similarity).
Ubiquitously expressed. Present in liver (at protein level).
Expressed transiently in developing spinal cord and selectively in the postnatal cerebellum.
Homotetramer, and heterotetramer with CRMP1, DPYSL2, DPYSL3 or DPYSL5. Interacts with PLEXA1 (By similarity). Interacts with FLNA (By similarity).
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 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 uncleaved transit peptide is required for mitochondrial targeting and proper membrane integration.
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:9822604). InsP6 (inositol hexakisphosphate) is not a substrate (By similarity). 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 (By similarity). The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A (By similarity). Also able to hydrolyze 5- phosphoribose 1-diphosphate (By similarity). Acts as a decapping enzyme that modulates the stability of a subset of mRNAs implicated in cell motility (By similarity).
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.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (PubMed:12954101). Interacts with CNTRL (By similarity). Interacts with RAB11A in a GTP-dependent manner (By similarity).
Belongs to the HAD-like hydrolase superfamily. CbbY/CbbZ/Gph/YieH family.
Expression was confirmed in liver, adipose tissue, testis and pancreatic islet.
Glycerol-3-phosphate phosphatase hydrolyzing glycerol-3-phosphate into glycerol (PubMed:26755581). 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 (By similarity). In vitro, has also a phosphatase activity toward ADP, ATP, GDP and GTP (By similarity).
Broadly expressed, with highest levels in heart, liver, skeletal muscle and aorta.
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 (By similarity). May be involved in dendritic cell and neuron differentiation.
Contributes to the regulation of the Wnt signaling pathway. Down-regulates CTNNB1-mediated transcriptional activation of target genes. May be involved in neuron differentiation.
Up-regulated by aldosterone in kidney and colon, but not in heart. Down-regulated in cortex by antidepressant treatments.
Expressed during development in embryonic stages 8.5 dpc, 9.5 dpc, 12.5 dpc and 19 dpc.
Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL. Plays a role in cell growth and maintenance of cell morphology. Plays a role in the proteolytic processing of ACE2. Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization.
Widely expressed. Present in brain, heart, kidney, liver, stomach, muscle, lung, testis, skin and eye. Not expressed in ovary and thynus. In inner ear tissues, expressed in stria vascularis, modiolus, organ of Corti and spiral ganglion.
Detected in liver (at protein level) (PubMed:7682971, PubMed:10518020). Not detected in muscle, brain, heart, testis, intestine or spleen (PubMed:10518020).
Fructose 1-phosphate and fructose 6-phosphate compete for the same binding site.
Interacts (fructose 6-phosphate bound form) with GCK.
Regulates glucokinase (GCK) by forming an inactive complex with this enzyme (PubMed:23957911). Acts by promoting GCK recruitment to the nucleus, possibly to provide a reserve of GCK that can be quickly released in the cytoplasm after a meal (PubMed:10456334). The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6-phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity (PubMed:23957911).
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 (By similarity).
Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42.
Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites (By similarity).
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 (By similarity).
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. Interacts with COA3 and MT-CO1/COX1.
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.
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.
Component of the Golgi to ER traffic (GET) complex, which is composed of GET1/WRB, CAMLG/GET2 and GET3/TRC40 (PubMed:23041287). Within the complex, GET1 and CAMLG form a heterotetramer which is stabilized by phosphatidylinositol binding and which binds to the GET3 homodimer (By similarity). Interacts (via C-terminus) with GET1 (PubMed:23041287). Interacts (via N-terminus) with GET3 (PubMed:23041287). GET3 shows a higher affinity for CAMLG than for GET1 (By similarity). Interacts (via N-terminus) with TNFRSF13B/TACI (via C-terminus) (By similarity).
In the central nervous system, expressed in astrocytes, microglia and neurons (at protein level).
Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (PubMed:23041287). 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). Required for the stability of GET1 (By similarity). Stimulates calcium signaling in T cells through its involvement in elevation of intracellular calcium (By similarity). Essential for the survival of peripheral follicular B cells (By similarity).
Required for the function of coenzyme Q in the respiratory chain. May serve as a chaperone or may be involved in the transport of Q6 from its site of synthesis to the catalytic sites of the respiratory complexes (By similarity).
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.
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. Interacts with LCK in a zinc-dependent manner.
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.
Enzyme with a broad specificity. 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 (By similarity).
Isgylation negatively regulates its activity.
Monomer. Interacts with PAK6. Interacts with the phosphorylated form of IKBKB/IKKB.
Important role in determination of the surface properties of the casein micelles.
Belongs to the adenylate kinase family. AK1 subfamily.
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP (By similarity). 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 (By similarity). Also catalyzes at a very low rate the synthesis of thiamine triphosphate (ThTP) from thiamine diphosphate (ThDP) and ADP (By similarity).
Detected in prostate, mammary gland and erythrocytes (at protein level). Detected in testis, brain, prostate, heart, kidney, liver, mammary gland and lung.
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 (By similarity). Plays a role in targeting the monocarboxylate transporters SLC16A1 and SLC16A7 to the cell membrane.
Regulated by muscle activity. Strongly up-regulated after muscle denervation, including that of soleus muscle. Expression is significantly increased 3 days after denervation and reaches a maximum, about 130-fold increase, after 5 days.
Aminopeptidase which catalyzes the hydrolysis of amino acid residues from the N-terminus of peptide or protein substrates.
Belongs to the chemokine-like factor family.
Both isoforms have highest expression levels in testis with relatively lower expression level in liver, spleen, lung, brain and heart and barely detectable levels in skeletal muscle and kidney were barely detected. In most tissues, isoform CKLF2 has higher expression levels than isoform CKLF1.
Has chemotactic response in monocytes, neutrophils and lymphocytes (PubMed:12706894). Binds CCR4 (By similarity).
May play an important role in inflammation and regeneration of skeletal muscle (By similarity). Essential for embryonic development (By similarity).
N-glycosylation is necessary for assembly and functional expression of the pump at the plasma membrane.
The ATPase pump is composed of two subunits: alpha (catalytic) and beta (regulatory). Interacts with alpha subunit ATP12A; this interaction is required for the formation of a functionally active pump and targeting at the plasma membrane (By similarity). Interacts (via N-terminus) with alpha subunit ATP4A (via the P-domain) (By similarity).
The C-terminal lobe folds into an immunoglobulin-like domain and mediates cell adhesion properties.
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 the epidermis (at protein level) and testis (within pachytene spermatocytes).
Heterodimer of a type I and a type II keratin. Heterodimer with type I keratin KRT25 leading to the formation of keratin intermediate filament (KIF) network (By similarity). Forms a heterodimer (via 2B domains) with KRT14 (via 2B domains) (By similarity). Interacts with TCHP (By similarity). Interacts with EPPK1 (By similarity). Interacts with AMELX (By similarity). Interacts with PKP1 (via N-terminus) and PKP2 (By similarity).
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).
Acetylated by EP300; acetylation positively regulates the transcriptional activity of XBP1. Deacetylated by SIRT1; deacetylation negatively regulates the transcriptional activity of XBP1.
Acts as a weak transcriptional factor. Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress. Binds to the ER stress response element (ERSE) upon ER stress. Binds to the consensus 5'-GATGACGTG[TG]N(3)[AT]T-3' sequence related to cAMP responsive element (CRE)-like sequences. Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner. Binds to the CDH5/VE-cadherin gene promoter region.
Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland. Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins. Modulates the cellular response to ER stress in a PIK3R-dependent manner. Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes. Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Functions also as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention.
Isoform 1 N-terminus domain is necessary for nuclear localization targeting. Isoform 1 C-terminus domain confers localization to the cytoplasm and is sufficient to impose rapid degradation. Isoform 1 N-terminus and C-terminus regions are necessary for DNA-binding and weak transcriptional activity, respectively.
Isoform 1 interacts with HM13. Isoform 1 interacts with RNF139; the interaction induces ubiquitination and degradation of isoform 1. Isoform 1 interacts (via luminal domain) with DERL1; the interaction obviates the need for ectodomain shedding prior HM13/SPP-mediated XBP1 isoform 1 cleavage. Isoform 1 interacts with HDAC3 and AKT1; the interactions occur in endothelial cell (EC) under disturbed flow. Isoform 1 interacts with the oncoprotein FOS. Interacts with SIRT1.
Isoform 1 is ubiquitinated, leading to proteasome-mediated degradation in response to ER stress.
X-box-binding protein 1, cytoplasmic form and luminal form are produced by intramembrane proteolytic cleavage of ER membrane-anchored isoform 1 triggered by HM13/SPP in a DERL1-RNF139-dependent and VCP/p97-independent manner. X-box-binding protein 1, luminal form is ubiquitinated leading to proteasomal degradation.
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:11786535). 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:11786535). Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes (By similarity). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia (By similarity). Promotes monoubiquitination of SNCA (By similarity). 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:11786535). It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes (By similarity). Has some overlapping function with SIAH1 (By similarity). Triggers the ubiquitin-mediated degradation of TRAF2, whereas SIAH1 does not (By similarity). Regulates cellular clock function via ubiquitination of circadian transcriptional repressors NR1D1 and NR1D2 leading to their proteasomal degradation. Plays an important role in mediating the rhythmic degradation/clearance of NR1D1 and NR1D2 contributing to their circadian profile of protein abundance (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 (By similarity).
Homodimer (By similarity). Interacts with VAV1, without mediating its ubiquitin-mediated degradation (By similarity). Probable component of some large E3 complex possibly composed of UBE2D1, SIAH2, CACYBP/SIP, SKP1, APC and TBL1X (By similarity). Interacts with UBE2I (By similarity). Interacts with UBE2E2 (PubMed:11786535). Interacts with PEG10, which may inhibit its activity (By similarity). Interacts with PEG3 and EGLN2 (By similarity). Interacts with DYRK2 (By similarity). Interacts with SNCAIP (PubMed:15064394, PubMed:19224863). Interacts with NR1D1 and NR1D2 (By similarity). Interacts with DCC (By similarity). Interacts with AXIN1.
Phosphorylated at Thr-24 and Ser-29 by MAPK14, which mediates the degradation by the proteasome of EGLN3. Phosphorylated at Ser-29 by DYRK2; this increases the ubiquitin ligase activity and promotes degradation of EGLN3 (By similarity).
Corepressor targeting diverse transcription regulators. Functions in brown adipose tissue (BAT) differentiation. Isoform 2 probably acts as a scaffold for specialized synapses (By similarity).
Interacts with HIPK2, ZNF217 and PNN (By similarity). Interacts with the transcription factors BKLF, delta EF1/AREB6/ZEB, EVI-1 and Friend of GATA (FOG) via the consensus motif P-X-[DNS]-L-[STVA]. Can form a complex with BKLF on a CACCC-box oligonucleotide. Can form homodimers or heterodimers of CTBP1 and CTBP2. Interacts with NRIP1 and WIZ. Interacts with PRDM16; represses white adipose tissue (WAT)-specific genes expression (By similarity). Interacts with MCRIP1 (By similarity).
Isoform 2 is specifically localized in synaptic ribbon (at protein level).
Phosphorylation by HIPK2 on Ser-428 induces proteasomal degradation.
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 (By similarity).
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, and, but is not observed by. 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. Interacts with METTL3. Interacts with ZFC3H1 in a RNase-insensitive manner (By similarity). Interacts with MTREX (By similarity). Interacts with TASOR (By similarity). Interacts with DHX34; the interaction is RNA-dependent (By similarity).
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. 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.
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.
Endogenous activator of intestinal guanylate cyclase. It stimulates this enzyme through the same receptor binding region as the heat-stable enterotoxins. May be a potent physiological regulator of intestinal fluid and electrolyte transport. May be an autocrine/paracrine regulator of intestinal salt and water transport.
Expressed not only in the gastrointestinal tract but also in the lung, pancreas and kidney.
Required for the processing of the 27S pre-rRNA.
Belongs to the RING-Cys relay (RCR) family.
ADP-ribosylated on Ser-104 in response to DNA damage.
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.
Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. 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. IL17A-IL17F is primarily involved in host defense against extracellular bacteria and fungi by inducing neutrophilic inflammation. As signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites. Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers. IL17F homodimer can signal via IL17RC homodimeric receptor complex, triggering downstream activation of TRAF6 and NF-kappa-B signaling pathway. 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. Regulates the composition of intestinal microbiota and immune tolerance by inducing antimicrobial proteins that specifically control the growth of commensal Firmicutes and Bacteroidetes.
Homodimer; disulfide-linked (By similarity). Heterodimer with IL17A (IL17A-IL17F) (By similarity). 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. IL17RA and IL17RC chains cannot distinguish between IL17A and IL17F molecules, potentially enabling the formation of topologically distinct complexes (By similarity).
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.
Found in the basement membranes (major component). S-laminin is concentrated in the synaptic cleft of the neuromuscular junction.
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).
The alpha-helical domains I and II are thought to interact with other laminin chains to form a coiled coil structure.
Belongs to the ubiquitin-activating E1 family. UBA5 subfamily.
E1-like enzyme which specifically catalyzes the first step in ufmylation. Activates UFM1 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 UFM1-E1 thioester and free AMP. Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer. Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding. Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism. Ufmylation is involved in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (By similarity). Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes (By similarity).
Homodimer; homodimerization is required for UFM1 activation. Interacts (via UIS motif) with UFM1; binds UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer. Interacts (via UIS motif) with GABARAPL2 and, with lower affinity, with GABARAP and GABARAPL1. Interacts (via C-terminus) with UFC1.
The UFM1-interacting sequence (UIS) motif mediates interaction with both UFM1 and LC3/GABARAP proteins (GABARAP, GABARAPL1 and GABARAPL2).
Binds specifically to phosphatidylinositol 3-phosphate (PtdIns3P), but not to other phosphoinositides.
Forms a complex with GRIP1, GRIA2 and STX12; controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. Interacts with GRIP1 (PubMed:16037816). Interacts with STX12 (PubMed:12070131). Interacts with APP; could regulate APP processing (By similarity). Interacts with FAM171A1 (By similarity).
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 (PubMed:18299352, PubMed:15911354). 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 (PubMed:15911354). Is required for faithful sorting of L1CAM to axons by facilitating trafficking from somatodendritic early endosome or the recycling endosome (PubMed:18299352). In an other hand, induces apoptosis via the activation of CASP3 in response to DNA damage (By similarity).
Widely expressed in brain and spinal cord (PubMed:6347394, PubMed:9013775, PubMed:9461575). Expressed in neurons during maturation and synapse formation (PubMed:12070131).
Associates with GIRK1 to form a G-protein-activated heteromultimer pore-forming unit (By similarity). 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.
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 (PubMed:17828261, PubMed:21422294).
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).
Cell cycle associated protein capable of promoting cell proliferation through the activation of CDK2 at the G1/S phase transition.
Abundantly expressed in testes and moderately in spleen, thymus, and lung. In mouse seminiferous tubules, is specifically localized in germ cells from late pachytene spermatocytes to round spermatids.
Forms homohexameric rings. 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. 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 (By similarity). 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. 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. Interacts with PIH1D1. Interacts with ITFG1. 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 (By similarity). 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 (By similarity). Interacts with NOPCHAP1; the interaction is direct and disrupted upon ATP binding (By similarity). Interacts with SMG1 (By similarity).
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 (By similarity). 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 (By similarity). This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (By similarity). 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 (By similarity). The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400 (By similarity). NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (By similarity). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (By similarity). Proposed core component of the chromatin remodeling INO80 complex which exhibits DNA- and nucleosome-activated ATPase activity and catalyzes ATP-dependent nucleosome sliding (By similarity). Plays an essential role in oncogenic transformation by MYC and also modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex (By similarity). Essential for cell proliferation (By similarity). May be able to bind plasminogen at cell surface and enhance plasminogen activation (By similarity).
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. The olfactory GST may be crucial for the acuity of the olfactory process (PubMed:8110735, PubMed:8664265). Participates in the formation of novel hepoxilin regioisomers (By similarity).
Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated. The complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and may be directly involved in trafficking to lysosomes. In concert with the BLOC-1 complex, AP-3 is required to target cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals.
A Rab11 effector protein involved in the endosomal recycling process. Also involved in controlling membrane trafficking along the phagocytic pathway and phagocytosis (By similarity).
Homooligomer. Interacts with RAB4A, RAB11A, RAB11B and RAB25 (By similarity).
Expression in liver (at protein level). Also detected in heart, lung, spleen and kidney.
Inhibited by menadione and isovanillin. Not inhibited by allopurinol, a xanthine dehydrogenase potent inhibitor. Inhibited by the flavonoids quercetin, myricetin and genistein. Nitric oxide generation is inhibited by raloxifene and competitively inhibited by an increase in oxygen levels.
Male and female rats possess kinetically distinct forms which may be due to differences in redox states.
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide, N-methylphthalazinium and phthalazine, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir, which is a potent antiviral agent. Is probably involved in the regulation of reactive oxygen species homeostasis. Is a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. Also catalyzes nitric oxide (NO) production; under anaerobic conditions, reduces nitrite to NO with NADH or aldehyde as electron donor, but under aerobic conditions, NADH is the preferred substrate. These reactions may be catalyzed by several isozymes. May play a role in adipogenesis.
The experimental design does not allow to distinguish AOX1 from AOX3 in rat liver as the effector of the superoxide and nitric oxide production (PubMed:17353002 and PubMed:19801639).
The sequence variants between males and females could be due to differences between individual animals, reflect gender differences or arise from technical problems (PubMed:9920943). The sequence shown here is that of a Sprague-Dawley female.
Might play a role in cell proliferation.
Interacts with STX3 (By similarity). Interacts with clathrin (By similarity).
Required for correct function and survival of retinal photoreceptors (By similarity). 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).
Interacts with CPNE3; this interaction may mediate the binding of CPNE3 with ERBB2 (By similarity). 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 APS. Interacts with phosphorylated LRP1 and IRS4. Interacts with INPP5D/SHIP1 and INPPL1/SHIP2. Interacts with ALK, GAB2, GRB7 and KIT. Interacts with PTPN6/SHP (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2A, SRC, SHC1, GAP43 and CTTN. 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 PTK2/FAK1 (By similarity). Interacts with FLT4 (tyrosine-phosphorylated). Interacts with the Trk receptors NTRK1, NTRK2 and NTRK3; in a phosphotyrosine-dependent manner. 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) (PubMed:11694516). Interacts (via PID domain) with PEAK1 (when phosphorylated) (By similarity). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (By similarity).
Phosphorylated by activated epidermal growth factor receptor. Phosphorylated in response to KIT signaling. Tyrosine phosphorylated in response to FLT3 signaling and by ligand-activated ALK. Tyrosine phosphorylated by TEK/TIE2 (By similarity). Tyrosine phosphorylated by ligand-activated PDGFRB (By similarity). May be tyrosine phosphorylated by activated PTK2/FAK1 (By similarity). Dephosphorylation by PTPN2 may regulate interaction with GRB2 (By similarity). Phosphorylated in response to FLT4 signaling. Tyrosine phosphorylated by activated PTK2B/PYK2.
Signaling adapter that couples activated growth factor receptors to signaling pathways. Participates in a signaling cascade initiated by activated KIT and KITLG/SCF. Participates in signaling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis (By similarity).
Transcription elongation factor that enhances transcription elongation by RNA polymerase II (RNAPII).
Glycosylation at Asn-74 and/or Asn-78 is required for interaction with VIP36 while glycosylation at Asn-401 modulates ligand-mediated GC-C activation.
Guanylyl cyclase that catalyzes synthesis of cyclic GMP (cGMP) from GTP (PubMed:1701694). Receptor for the E.coli heat-stable enterotoxin; E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GUCY2C (PubMed:1701694).
Homotrimer. Interacts via its C-terminal region with PDZK2. Interacts with the lectin chaperone VIP36.
Detected in various tissues, such as brain, testis, spleen, and heart.
Interacts with RAB11FIP1, RAB11FIP2, RAB11FIP3 (via its C-terminus) and RAB11FIP4 (By similarity). Interacts with EVI5; EVI5 and RAB11FIP3 may be mutually exclusive and compete for binding RAB11A (By similarity). Interacts with SGSM1, SGSM2, SGSM3 and VIPAS39 (By similarity). Interacts with EXOC6 in a GTP-dependent manner. Interacts with RAB11FIP5 (PubMed:11163216). Interacts with STXBP6 (PubMed:12145319). Interacts (GDP-bound form) with ZFYVE27 (PubMed:17082457). Interacts with BIRC6/bruce (By similarity). May interact with TBC1D14 (By similarity). Interacts with UNC119; in a cell cycle-dependent manner (By similarity). GDP-bound and nucleotide-free forms interact with SH3BP5 (By similarity). Interacts (GDP-bound form) with KIF5A in a ZFYVE27-dependent manner (By similarity). Interacts (GDP-bound form) with RELCH (By similarity). Found in a complex composed of RELCH, OSBP1 and RAB11A (By similarity). Interacts with TBC1D12 (By similarity). Interacts with DEF6 (By similarity).
The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (By similarity). 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). The small Rab GTPase RAB11A regulates endocytic recycling (PubMed:11163216). 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 (By similarity). May also play a role in melanosome transport and release from melanocytes (By similarity).
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 (By similarity).
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 (By similarity).
Belongs to the MICOS complex subunit Mic13 family.
Cytosolic CRABPs may regulate the access of retinoic acid to the nuclear retinoic acid receptors.
As part of the MCIA complex, primarily participates in the assembly of the mitochondrial complex I and therefore plays a role in oxidative phosphorylation. This moonlighting protein has also a dehydrogenase activity toward a broad range of substrates with greater specificity for long-chain unsaturated acyl-CoAs. However, in vivo, it does not seem to play a primary role in fatty acid oxidation. In addition, the function in complex I assembly is independent of the dehydrogenase activity of the protein.
Homodimer (By similarity). Interacts with NDUFAF1 and ECSIT (PubMed:22982022). 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:22982022) (By similarity). Interacts with TMEM70 and TMEM242 (By similarity).
Acts as a transcriptional regulator that recognizes and binds to the sequence 5'-[GA]TTA[CT]GTAA[CT]-3', a sequence present in many cellular and viral promoters. Represses transcription from promoters with activating transcription factor (ATF) sites. Represses promoter activity in osteoblasts. Represses transcriptional activity of PER1. Represses transcriptional activity of PER2 via the B-site on the promoter. Activates transcription from the interleukin-3 promoter in T-cells. Competes for the same consensus-binding site with PAR DNA-binding factors (DBP, HLF and TEF). Component of the circadian clock that acts as a negative regulator for the circadian expression of PER2 oscillation in the cell-autonomous core clock. Protects pro-B cells from programmed cell death (By similarity). Represses the transcription of CYP2A5 (By similarity). Positively regulates the expression and activity of CES2 by antagonizing the repressive action of NR1D1 on CES2 (By similarity). Required for the development of natural killer cell precursors (By similarity).
Belongs to the bZIP family. NFIL3 subfamily.
Homodimer (By similarity). Binds DNA as a dimer (By similarity). Interacts with CRY2, DR1 and PER2 (By similarity). Interacts with NR0B2 (By similarity). Interacts with MYSM1 (By similarity).
Up-regulated by dexamethasone and thapsigargin.
Belongs to the polyprenol kinase family.
Expressed in tongue, stomach and duodenum.
Gustducin-coupled receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract. Signals through PLCB2 and the calcium-regulated cation channel TRPM5 (By similarity). In airway epithelial cells, binding of denatonium increases the intracellular calcium ion concentration and stimulates ciliary beat frequency (By similarity).
In extracellular secreted form, promotes proliferation and activation of CD8(+) T cells, suggesting a cytokine-like function. Enhances cytotoxic anti-tumor activity of CD8(+) T cells. May inhibit ERK and JNK signaling activity. May suppress cell migration and invasion activity, via its effects on ERK and JNK signaling. Has a critical role in the regulation of osteogenesis and bone development.
In the nucleus, enhances stability of the PCAF histone acetyltransferase (HAT) complex member TADA2A and promotes 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.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which hydrolyzes the 76-Gln-|-Phe-77 bond and inhibits neurotransmitter release (PubMed:1331807).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which hydrolyzes the 59-Lys-|-Leu-60 bond and inhibits neurotransmitter release (PubMed:8175689).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 58-Gln-|-Lys-59 bond and probably inhibits neurotransmitter release (PubMed:8505288).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type G (BoNT/G, botG) which hydrolyzes the 81-Ala-|-Ala-82 bond and probably inhibits neurotransmitter release (PubMed:8505288).
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type X (BoNT/X) which hydrolyzes the 66-Arg-|-Ala-67 bond and probably inhibits neurotransmitter release (PubMed:28770820). It remains unknown whether BoNT/X is ever produced, or what organisms it targets.
(Microbial infection) Targeted and hydrolyzed by C.tetani toxin (tetX) which hydrolyzes the 76-Gln-|-Phe-77 bond and inhibits neurotransmitter release (PubMed:1331807).
Involved in the targeting and/or fusion of transport vesicles to their target membrane (By similarity). Major SNARE protein of synaptic vesicles which mediates fusion of synaptic vesicles to release neurotransmitters. Essential for fast vesicular exocytosis and activity-dependent neurotransmitter release as well as fast endocytosis that mediates rapid reuse of synaptic vesicles (Probable). Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 (PubMed:19690160).
Nervous system specific. A higher level expression is seen in the brain as compared to the spinal cord (PubMed:2472388). Expressed in hippocampal neurons (PubMed:19196426).
Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A (PubMed:19196426). This complex binds to CPLX1. Interacts with BVES and STX4. Interacts with VAPA and VAPB. Interacts with WDFY2, PRKCZ and PRKCI (By similarity). Interacts (via N-terminus) with KCNB1 (via N-terminus and C-terminus); stimulates the channel inactivation rate of KCNB1 (PubMed:19690160). Forms a complex with WDFY2 and PRKCZ (By similarity). Interacts with SEPT8; the interaction inhibits interaction of VAMP2 with SYP (PubMed:19196426). Interacts with SYP; the interaction is inhibited by interaction with SEPT8 (PubMed:19196426). Interacts with PICALM (By similarity). Interacts with alpha-synuclein/SNCA (By similarity). Interacts with STX3 (By similarity).
Phosphorylated by PRKCZ in vitro and this phosphorylation is increased in the presence of WDFY2.
Homodimer (PubMed:8643556). Interacts with ATP7A; this interaction is copper-dependent and is required for SOD3 activity.
Protect the extracellular space from toxic effect of reactive oxygen intermediates by converting superoxide radicals into hydrogen peroxide and oxygen.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRID2 subfamily.
Expressed at high levels in the cerebellar Purkinje cell layer, almost absent in the forebrain.
Receptor for glutamate. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. Promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses through the beta-NRX1-CBLN1-GRID2 triad complex.
Tetramer; dimer of dimers (By similarity). Interacts with AP4M1 (PubMed:14572453). Interacts with EML2 (PubMed:11829466). Interacts with MAGI2 (via PDZ domains) (PubMed:12589829). Interacts with BECN1, GOPC, GRID2IP, SHANK1 and SHANK2. Interacts with CBLN2, but not with CBLN4 (By similarity). Interacts with CBLN1 (via C1q domain); the interaction is CBLN1-NRX1 complex formation-dependent; CBLN1-binding is calcium-independent; CBLN1 hexamers anchor GRID2 N-terminal domain dimers to monomeric NRXN1 isoform beta; promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis (By similarity).
The PDZ-binding motif mediates interaction with GOPC.
Belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.
Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate.
At 11 dpc, expression was restricted to the olfactory pit, the basal and rostral surface of the telencephalic vesicle, the eye anlage, the epithelium of Rathke pouch, and somites. At later developmental stages, it was widely distributed in neuronal as well as in mesenchymal and epithelial structures outside the nervous system. After birth, mesenchymal levels decreased rapidly and expression became restricted to specific sets of neurons in the CNS. In the mature CNS, it is detectable in mitral cells, neurons of the accessory bulb and cerebral cortex, cerebellar Purkinje cells, as well as a subset of cranial and spinal motoneurons.
General decrease in dorsal root ganglia in response to injury from dorsal rhizotomy, with the greatest decrease evident 21 days post-injury, returning to comparable levels 1 year post-injury (PubMed:28270793). Decreased in dorsal root ganglia in response to sciatic nerve transection 3 days post-injury, returning to comparable levels 14 days post-injury (PubMed:28270793).
May be involved in guiding growing axons towards their targets by forming a molecular boundary that instructs axons to engage in the formation of specific nerve tracts. Binds to neuropilin. Involved in the development of the olfactory system and in neuronal control of puberty (By similarity).
Strong binding to neuropilin is mediated by the carboxy third of the protein.
Degraded by the proteasome; zinc-binding inhibits degradation by the proteasome.
Homodimer. Binds tubulin; binding is inhibited by GTP (By similarity). Interacts with MAPK1. Interacts with GAPDH; the interaction is direct (By similarity). Interacts with LIMK1 (via the PDZ domain); the interaction is direct. Interacts with LIMK2. Interacts with HDAC6; thereby inhibiting the tubulin deacetylase activity of HDAC6. Interacts with aggregated SNCA; may have a pro-aggregatory role in synucleinopathies. Interacts with DYNLL1 (By similarity). Interacts (via C-terminus) with S100A2, S100A6 and S100B; these interactions inhibit TPPP dimerization (By similarity).
Most of the protein is composed of disordered regions. Zinc-binding induces structural rearrangement by promoting molten globule state formation.
Phosphorylated by LIMK1 on serine residues; phosphorylation may alter the tubulin polymerization activity. Phosphorylation by LIMK2, but not LIMK1, regulates astral microtubule organization at early stage of mitosis. Phosphorylation by ROCK1 at Ser-31, Ser-106 and Ser-158 inhibits interaction with HDAC6, resulting in decreased acetylation of tubulin, increased cell motility and entry into S-phase. Phosphorylation by CDK1 inhibits the microtubule polymerizing activity.
Predominantly expressed in mature oligodendrocytes.
Regulator of microtubule dynamics that plays a key role in myelination by promoting elongation of the myelin sheath (PubMed:19606501). Acts as a microtubule nucleation factor in oligodendrocytes: specifically localizes to the postsynaptic Golgi apparatus region, also named Golgi outpost, and promotes microtubule nucleation, an important step for elongation of the myelin sheath (By similarity). Required for both uniform polarized growth of distal microtubules as well as directing the branching of proximal processes (By similarity). Shows magnesium-dependent GTPase activity; the role of the GTPase activity is unclear (By similarity). In addition to microtubule nucleation activity, also involved in microtubule bundling and stabilization of existing microtubules, thereby maintaining the integrity of the microtubule network (By similarity). Regulates microtubule dynamics by promoting tubulin acetylation: acts by inhibiting the tubulin deacetylase activity of HDAC6 (By similarity). Also regulates cell migration: phosphorylation by ROCK1 inhibits interaction with HDAC6, resulting in decreased acetylation of tubulin and increased cell motility (By similarity). Plays a role in cell proliferation by regulating the G1/S-phase transition (By similarity). Involved in astral microtubule organization and mitotic spindle orientation during early stage of mitosis; this process is regulated by phosphorylation by LIMK2 (By similarity).
Strongly up-regulated during the differentiation of primary oligodendrocyte 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. Does not play a role in replication-dependent histone mRNA degradation. Adds a single nucleotide to the 3' end of specific miRNAs, monoadenylation stabilizes and prolongs the activity of some but not all miRNAs.
Interacts with CPEB1, CPEB2, CPSF1 and PABPC1.
Binds to CNTF. The alpha subunit provides the receptor specificity.
Forms a heterotrimer with LIFR and IL6ST. Interacts with heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1. Either alone or in complex with the heterodimer CLCF1-CRLF1 interacts with SORL1; this interaction may promote internalization and lysosomal degradation.
May act as scaffold protein. May stimulate ABRA activity and ABRA-dependent SRF transcriptional activity (By similarity).
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 (By similarity).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ14 subfamily.
Expressed predominantly in motoneurons of cranial nerve motor nuclei within the general somatic and special visceral motor cell column.
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.
Binds Ca(2+). The ions are bound to the C2 1 domain.
Interacts with SNAP25; the interaction is direct. Interacts with STX1; the interaction is direct. Interacts with RAB8B (By similarity).
Isoform 1 is expressed in the cochlea and brain. Expressed in cerebellum (Purkinje cells), hippocampus (granule cells of the dentate gyrus and in pyramidal cells of the CA1-CA3 region) and cortex (stellate and pyramidal cells). Expressed in hair cells of vestibular organs such as the saccule, utricle and crista ampullari. Expressed in the cochlear inner and outer cells (IHCs and OHCs) (at protein level). Expressed in brain: brainstem, cerebellum (granules cells and Purkinje cell layer), cortex (layers IV and V), inferior colliculus, superior colliculus and hippocampus (granule cells of the dentate gyrus and in pyramidal cells of the CA1-CA3 region).
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.
ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins. Functions as part of a cytosolic protein quality control complex, the BAG6/BAT3 complex, which maintains these client 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. 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. Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated by RNF126, an E3 ubiquitin-protein ligase associated with BAG6 and are sorted to the proteasome. SGTA which prevents the recruitment of RNF126 to BAG6 may negatively regulate the ubiquitination and the proteasomal degradation of client proteins. 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. 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. BAG6 is also required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, it may participate in the production of antigenic peptides and play a role in antigen presentation in immune response. BAG6 is 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. BAG6 may ensure the proper degradation of these proteins and thereby protects the endoplasmic reticulum from protein overload upon stress. By inhibiting the polyubiquitination and subsequent proteasomal degradation of HSPA2 it may also play a role in the assembly of the synaptonemal complex during spermatogenesis. Also positively regulates apoptosis by interacting with and stabilizing the proapoptotic factor AIFM1. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway.
Component of the BAG6/BAT3 complex, also named BAT3 complex, at least composed of BAG6, UBL4A and GET4/TRC35. Interacts with GET4; the interaction is direct and localizes BAG6 in the cytosol. Interacts with UBL4A; the interaction is direct and required for UBL4A protein stability. Interacts with AIFM1. Interacts with HSPA2. Interacts with CTCFL. Interacts with p300/EP300. Interacts (via ubiquitin-like domain) with RNF126; required for BAG6-dependent ubiquitination of proteins mislocalized to the cytosol. Interacts (via ubiquitin-like domain) with SGTA; SGTA competes with RNF126 by binding the same region of BAG6, thereby promoting deubiquitination of BAG6-target proteins and rescuing them from degradation. Interacts with ricin A chain. Interacts with VCP and AMFR; both form the VCP/p97-AMFR/gp78 complex. Interacts with SYVN1. Interacts with USP13; the interaction is direct and may mediate UBL4A deubiquitination. Interacts with ZFAND2B. Interacts with KPNA2. Interacts with UBQLN4 (By similarity).
Involved in DNA damage-induced apoptosis: following DNA damage, accumulates in the nucleus and forms a complex with p300/EP300, enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase p53/TP53 transcriptional activity. When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 'Lys-4' dimethylation (H3K4me2).
Released extracellularly via exosomes, it is a ligand of the natural killer/NK cells receptor NCR3 and stimulates NK cells cytotoxicity. It may thereby trigger NK cells cytotoxicity against neighboring tumor cells and immature myeloid dendritic cells (DC).
Ricin can induce a cleavage by the caspase CASP3. The released C-terminal peptide induces apoptosis.
The ubiquitin-like domain mediates interaction with the E3 ubiquitin-protein ligase RNF126 which is responsible for the BAG6-dependent ubiquitination of client proteins. SGTA also binds this domain and competes with RNF126 to antagonize client protein ubiquitination and degradation. The ubiquitin-like domain also mediates the interaction with USP13.
Binds heme and transports it to the liver for breakdown and iron recovery, after which the free hemopexin returns to the circulation.
The isolated N-terminal domain binds one heme. The full-length protein also binds one heme, but at a different site. The physiological significance of this is not clear (By similarity).
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 (By similarity).
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 (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 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. This function in autophagy requires its cholesterol-transfer activity (By similarity).
Expressed at a significantly higher level in postnatal day 1 (PND1) than in PND21 visual cortical.
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.
VASt (VAD1 Analog of StAR-related lipid transfer) domain, also known as ASTER (Greek for star) domain is a sterol-binding domain.
Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. Interacts with ZRSR1 (By similarity).
Expressed at 18 dpc in sympathetic ganglia.
Expressed in sympathetic superior cervical ganglia and in noradrenergic, dopamine beta-hydroxylase (DBH)-positive tissues. Not expressed in brain.
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.
Activated by phosphorylation on Thr-211. Inhibited by phosphorylation on Thr-617 (By similarity).
Interacts with MAPT/TAU. Interacts with DLG5 (via coiled-coil domain) (By similarity). Interacts with STK3/MST2 and STK4/MST1 in the presence of DLG5 (By similarity). Interacts with YWHAB, YWHAG, YWHAQ and YWHAZ (By similarity). Interacts with PKP2 (via N-terminus) (By similarity). Interacts with CDC25C (By similarity). Interacts with KSR1 (By similarity).
Phosphorylated at Thr-211 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-617 by PRKCZ/aPKC inhibits the kinase activity (By similarity).
Serine/threonine-protein kinase. Involved in the specific phosphorylation of microtubule-associated proteins for MAPT/TAU, MAP2 and MAP4. Phosphorylates CDC25C. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Negatively regulates the Hippo signaling pathway and antagonizes the phosphorylation of LATS1. Cooperates with DLG5 to inhibit the kinase activity of STK3/MST2 toward LATS1. Phosphorylates PKP2 and KSR1 (By similarity).
Involved in the maintenance of the Golgi structure. May play a role in hematopoiesis (By similarity).
Visual pigments are the light-absorbing molecules that mediate vision. They consist of an apoprotein, opsin, covalently linked to cis-retinal (By similarity). 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).
Interacts with STAM. Interacts with SMAD6 and SMAD7. Interacts with CHMP3; the interaction appears to relieve the autoinhibition of CHMP3. Interacts with SMURF2 and RNF11; this interaction promotes ubiquitination.
Phosphorylated after BMP type I receptor activation.
The JAMM motif is essential for the protease activity.
Ubiquitinated by SMURF2 in the presence of RNF11.
Zinc metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Does not cleave 'Lys-48'-linked polyubiquitin chains. Plays a role in signal transduction for cell growth and MYC induction mediated by IL-2 and GM-CSF. Potentiates BMP (bone morphogenetic protein) signaling by antagonizing the inhibitory action of SMAD6 and SMAD7. Has a key role in regulation of cell surface receptor-mediated endocytosis and ubiquitin-dependent sorting of receptors to lysosomes. Endosomal localization of STAMBP is required for efficient EGFR degradation but not for its internalization. Involved in the negative regulation of PI3K-AKT-mTOR and RAS-MAP signaling pathways.
Bifunctional enzyme that catalyzes the post-translational modification of inactive peptidylglycine precursors to the corresponding bioactive alpha-amidated peptides, a terminal modification in biosynthesis of many neural and endocrine peptides (By similarity). Alpha-amidation involves two sequential reactions, both of which are catalyzed by separate catalytic domains of the enzyme. The first step, catalyzed by peptidyl alpha-hydroxylating monooxygenase (PHM) domain, is the copper-, ascorbate-, and O2- dependent stereospecific hydroxylation (with S stereochemistry) at the alpha-carbon (C-alpha) of the C-terminal glycine of the peptidylglycine substrate (PubMed:10079066). The second step, catalyzed by the peptidylglycine amidoglycolate lyase (PAL) domain, is the zinc-dependent cleavage of the N-C-alpha bond, producing the alpha-amidated peptide and glyoxylate (PubMed:10079066). Similarly, catalyzes the two-step conversion of an N-fatty acylglycine to a primary fatty acid amide and glyoxylate (PubMed:10079066).
In the C-terminal section; belongs to the peptidyl-alpha-hydroxyglycine alpha-amidating lyase family.
In the N-terminal section; belongs to the copper type II ascorbate-dependent monooxygenase family.
PAM activity is inhibited by EDTA, phenylglyoxal and diethyl pyrocarbonate (By similarity). PAL activity is stimulated by cadmium and inhibited by mercury (PubMed:19604476).
Expressed in all tissues examined; highest levels in fat and skeletal tissue, lowest levels in kidney.
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:7939721). Interacts (via TOS motif) with RPTOR; promoting phosphorylation by mTORC1 (By similarity).
Phosphorylated on serine and threonine residues in response to insulin, EGF and PDGF. Phosphorylation at Thr-36, Thr-45, Ser-64 and Thr-69, 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 (By similarity). Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways (PubMed:7939721).
The TOS motif mediates interaction with RPTOR, leading to promote phosphorylation by mTORC1 complex.
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-36, Thr-45, Ser-64 and Thr-69) or associated with eIF4E.
Non-selective channel that modulates the membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis. Involved in mitochondrial deoxynucleoside triphosphates (dNTP) pool homeostasis and mitochondrial DNA (mtDNA) maintenance (By similarity). May be involved in the regulation of reactive oxygen species metabolism and the control of oxidative phosphorylation (By similarity).
Abundantly expressed in circumvallate and foliate papillae.
Putative taste receptor. TAS1R2/TAS1R3 recognizes diverse natural and synthetic sweeteners.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family.
Cotranslational quality control factor involved in the No-Go Decay (NGD) pathway. In the presence of ABCE1 and PELO, is required for 48S complex formation from 80S ribosomes and dissociation of vacant 80S ribosomes. 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.
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).
Predominantly expressed in the stomach. Localizes strictly to the surface mucus cells in the gastric epithelium and the mucus-secreting goblet cells in the duodenum. Detected in the pituitary after estrogen stimulation.
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.
Expressed in brain, heart, kidney, liver, lung, skeletal muscle, spleen and testis. Within the kidney expression is pronounced within glomeruli.
Acts on retinol bound on cellular retinol-binding protein (CRBP).
Localized to the kidney (PubMed:16079298). Mainly expressed in the late segments of proximal tubules (PubMed:16079298).
Renal transmembrane organic anion/dicarboxylate exchanger that participates in the reabsorption of conjugated steroids, as well as bile acids, driven by an outward gradient of dicarboxylates such as glutarate or succinate (PubMed:16079298). Transports estrone 3-sulfate and estradiol-17-glucuronide (17beta-estradiol 17-O-(beta-D-glucuronate)), but not androstanediol glucuronide (5alpha-androstane-3alpha,17beta-diol 3-O-(beta-D-glucuronate)), nor taurocholate (PubMed:31553721). Prefers sulfate conjugates of steroids rather than glucuronide conjugates (PubMed:16079298).
Binds to filamentous actin (F-actin), but not to monomeric G-actin, independently of its phosphorylation status. Interacts with calmodulin.
Controls cell movement by regulating actin cytoskeleton homeostasis and filopodium and lamellipodium formation. When unphosphorylated, induces cell migration. When phosphorylated by MAPK8, induces actin bundles formation and stabilization, thereby reducing actin plasticity, hence restricting cell movement, including neuronal migration. May be involved in coupling the protein kinase C and calmodulin signal transduction systems.
Phosphorylated. Phosphorylation at Ser-120 and Thr-183 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.
Homodimer. Homodimerization could regulate efficiency of zinc transport.
Probable proton-coupled zinc ion antiporter mediating the import of zinc from cytoplasm into synaptic vesicles and participating to cellular zinc ion homeostasis in the brain.
Involved in control of cellular proliferation. Onconcogenic modifier contributing to the tumor suppressor function of DNMT3B (By similarity).
Belongs to the glycosyltransferase 49 family.
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.
Polyubiquitinated by RNF128 with 'Lys-48'-linked chains, leading to proteasomal degradation.
phosphorylation at Ser-412 by PKC strongly down-regulates the association with actin.
(Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type X (BoNT/X) which hydrolyzes the 173-Lys-|-Ser-174 bond and probably inhibits neurotransmitter release (PubMed:28770820). It remains unknown whether BoNT/X is ever produced, or what organisms it targets.
Farnesylation is required for Golgi targeting.
Highly expressed by neurons in brain and faintly detected in spleen, lung and kidney (at protein level). Ubiquitously expressed.
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.
Plays a role in the regulation of centrosome and Golgi apparatus positioning, with consequences on cell shape and cell migration.
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. Interacts with APP; APP interaction inhibits the E3 ubiquitin-protein ligase activity of the CRL2(APPBP2) complex.
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. 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. The CRL2(APPBP2) complex specifically recognizes proteins with a -Arg-Xaa-Xaa-Gly degron at the C-terminus, leading to their ubiquitination and degradation. 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. May play a role in intracellular protein transport: may be involved in the translocation of APP along microtubules toward the cell surface.
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. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.
Interacts with HTR2A (By similarity). Interacts with TAMALIN.
Is widely distributed in the CNS and prominent expression is seen in Golgi cells of the cerebellum and some particular neuronal cells in other brain regions.
Can form heteromeric complexes with LRFN2, LRFN3 and LFRN4 (By similarity). Weakly interacts with LRFN1. Able to form homomeric complexes across cell junctions, between adjacent cells (By similarity). Does not interact with DLG1, DLG2, DLG3, nor with DLG4 (By similarity).
Lacks a cytoplasmic PDZ-binding motif, which has been implicated in function of related LRFN proteins.
Calcium-independent lectin displaying mannose-binding specificity and able to maintain carbohydrate recognition activity in an acidic environment. May be involved in inflammatory and metaplastic responses of the gastrointestinal epithelium (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. Hemokinin induces plasma extravasation, mast cell degranulation, muscle contraction, salivary secretion and scratching behavior. Increases sperm motility. Induces potent analgesic effects and may play a role in pain modulation. Promotes survival of bone marrow B lineage cells and of cultured LPS-stimulated pre-B cells and may act as an autocrine factor required for B-cell survival and proliferation. Lowers systemic arterial pressure following intravenous injection. Induces interferon-gamma production and may play a role in the inflammatory response. Shows potent affinity and specificity for the NK-1 receptor.
Belongs to the uroporphyrinogen-III synthase family.
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 similarity).
In chronic pancreatitis tissue, expression is suppressed by camostat mesilate, a serine protease inhibitor, and by Saiko-keishi-to, a herbal medicine.
Interacts with p53/TP53 and HIPK2. Interacts with PRKCG, GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C.
Specifically expressed by acinar cells of chronic pancreatitis tissue.
The LC3 interacting region (LIR) motif mediates interaction with GABARAP, GABARAPL1, GABARAPL2, MAP1LC3A, MAP1LC3B and MAP1LC3C.
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. 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. Participates in t(6)A37 formation in cytoplasmic and mitochondrial tRNAs (By similarity). 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.
Interacts with TREML2 and this interaction enhances T-cell activation.
Modulates T-cell-mediated immune responses and the development of acute and chronic transplant rejection. May play a positive regulatory role in bone formation and has a dual role in the bone-immune interface. Induces antitumor immunity as it activates both acquired and innate immunity leading to natural killer cell and CD8 T-cell dependent killing of tumor cells (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.
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.
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 (By similarity). Is a negative regulator of PAX6 expression (By similarity).
Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as phthalazine, as well as aldehydes, such as benzaldehyde and retinal.
Autoubiquitinated in vitro in the presence of UBE2D1 and UBE2E1.
E3 ubiquitin-protein ligase that acts as a regulator of the TORC1 signaling pathway. 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. 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. Also involved in protein trafficking and localization. Acts as a regulator of synaptic transmission by mediating ubiquitination and degradation of AMPAR receptor GluA2/GRIA2. Does not catalyze ubiquitination of GluA1/GRIA1. Also acts as a regulator of the recycling endosome pathway by mediating ubiquitination of VAMP3. Regulates lysosome positioning by catalyzing ubiquitination and degradation of ARL8B. Plays a role in growth regulation involved in G1/S transition by mediating, possibly by mediating ubiquitination of SLC22A18. Acts with a limited set of E2 enzymes, such as UBE2D1 and UBE2N.
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.
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) (By similarity). 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 (By similarity).
Expressed specifically in the brain and the eye (PubMed:12183068). Expressed in both neonatal and adult oligodendrocytes (PubMed:21972082).
Half-transporter that form a functional transporter via homo- or heterodimerization. Homodimer. Heterodimers with ABCG1.
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 (By similarity). 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:21972082).
Belongs to the WD repeat NOL10/ENP2 family.
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. Can also catalyze 'Lys-48'-linked polyubiquitination and proteasomal degradation of viral proteins such as influenza virus PB2. 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. Reduces FGFR1-dependent tyrosine phosphorylation of PKM, inhibiting PKM-dependent lactate production, glucose metabolism, and cell growth.
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. Interacts with IRF7; this interaction promotes IRF7 proteasomal degradation. Interacts with TRAF3; this interaction promotes TRAF3 activation.
The RING finger domain and the coiled-coil region are required for the apoptosis-inducing activity.
Belongs to the selenoprotein M/F family.
Forms a tight complex with UGGT1/UGCGL1 (PubMed:11278576). Interacts with UGGT2/UGCGL2 (By similarity). Interacts with RDH11 (By similarity).
Highest levels in prostate, lower levels in brain, lung, thyroid gland, and large intestine.
May be involved in redox reactions associated with the formation of disulfide bonds (PubMed:15659830). May contribute to the quality control of protein folding in the endoplasmic reticulum (PubMed:11278576). May regulate protein folding by enhancing the catalytic activity of UGGT1/UGCGL1 and UGGT2/UGCGL2 (By similarity).
This protein is distinct from Tes/Testin which is a LIM domain protein.
Glycosylation is required for cell surface expression.
Monomer in the presence of Ca(2+). It oligomerizes in absence of Ca(2+). Forms homooligomers and heterooligomers with STIM2. Interacts (via the transmembrane region and the SOAR/CAD domain) with SPPL3; the interaction promotes the binding of STIM1 to ORAI1. Interacts with ORAI1. Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends. Interacts with CRACR2A/EFCAB4B; the interaction is direct and takes place in absence of Ca(2+). Forms a complex with CRACR2A/EFCAB4B and ORAI1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations. Interacts with SARAF, promoting a slow inactivation of STIM1-dependent SOCE activity, possibly by facilitating the deoligomerization of STIM1 (By similarity). Interacts with EFHB; the interaction takes place upon Ca(2+)-store depletion and inhibits the association with SARAF (By similarity). Interacts with ASPH. Interacts with SLC35G1; intracellular Ca(2+)-dependent. May interact with ATP1A1, ATP2A2, ATP2B1, ATP2B4, KPNB1 and XPO1; through SLC35G1. Interacts with TMEM203. Interacts with STIMATE, promoting STIM1 conformational switch (By similarity). Interacts with TMEM178A (By similarity). Interacts with CASQ1 (via C-terminal end and preferentially with the monomeric form); this interaction increases in response to a depletion of intracellular Ca(2+), decreases both STIM1 aggregation and clustering, interaction of STIM1 with ORAI1 and store-operated Ca(2+) entry (SOCE) activity (By similarity). Interacts with ADCY8 (By similarity).
Phosphorylated predominantly on Ser residues.
Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores (By similarity). Acts as Ca(2+) sensor in the endoplasmic reticulum via its EF-hand domain. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates the Ca(2+) release-activated Ca(2+) (CRAC) channel subunit ORAI1 (PubMed:16208375). Involved in enamel formation (By similarity). Activated following interaction with STIMATE, leading to promote STIM1 conformational switch (By similarity).
The STIM1 Orai1-activating region/CRAC-activating domain (SOAR/CAD) mediates interaction with ORAI1 to activate the channel.
Epidermis-specific type I keratin involved in wound healing. Involved in the activation of follicular keratinocytes after wounding, while it does not play a major role in keratinocyte proliferation or migration. Participates in the regulation of epithelial migration by inhibiting the activity of SRC during wound repair.
Heterodimer of a type I and a type II keratin. KRT6 isomers associate with KRT16 and/or KRT17. Interacts with TCHP.
There are at least six isoforms of human type II keratin-6 (K6), K6A being the most abundant representing about 77% of all forms found in epithelia.
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-histidine N-methyltransferase that specifically mediates 3-methylhistidine (tele-methylhistidine) methylation of actin at 'His-73' (PubMed:30526847). Histidine methylation of actin is required for smooth muscle contraction of the laboring uterus during delivery (By similarity). Does not have protein-lysine N-methyltransferase activity and probably only catalyzes histidine methylation of actin (By similarity).
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.
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 (By similarity).
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 (By similarity).
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. Interacts (via POLO-box domain) with DCTN1. 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. Interacts with HSF1; this interaction increases upon heat shock but does not modulate neither HSF1 homotrimerization nor DNA-binding activities. Interacts with HNRNPU; this interaction induces phosphorylation of HNRNPU in mitosis. Interacts (via its N-terminus) with RIOK2 (By similarity). Interacts with KLHL22 (By similarity). Interacts (via POLO box domains) with NEDD9/HEF1 (via C-terminus) (By similarity).
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. 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. Phosphorylates CEP68 and is required for its degradation. Regulates nuclear envelope breakdown during prophase by phosphorylating DCTN1 resulting in its localization in the nuclear envelope. Phosphorylates the heat shock transcription factor HSF1, promoting HSF1 nuclear translocation upon heat shock. 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. Regulates mitotic progression by phosphorylating RIOK2 (By similarity). Through the phosphorylation of DZIP1 regulates the localization during mitosis of the BBSome, a ciliary protein complex involved in cilium biogenesis (By similarity).
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 (By similarity).
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 (By similarity).
Plays an important role in the control of DNA replication and the maintenance of replication fork stability.
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. Acetylated on Lys-233, Lys-245 Lys-246 by EP300 (By similarity).
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).
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. Interacts with MED1, CCAR1 and CALCOCO1 (By similarity). Interacts with EP300 (By similarity). Interacts with CEBPE (By similarity).
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.
This RNase has marked specificity towards the 3' side of uridine nucleotides.
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 (By similarity).
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 (By similarity).
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).
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 (By similarity). Interacts with SH3RF2 (PubMed:22128169). Interacts with NTRK3/TRKC (By similarity). Interacts with NTRK2/TRKB (PubMed:21775604).
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. 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. 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.
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 (By similarity). 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 (By similarity). This limits the expression of a number of cell death-mediating TP53 target genes, reducing DNA damage-induced cell death (By similarity). 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 (By similarity).
Interacts with SOX6. Interacts with DAZ1 and DAZL. Interacts with IL17RB. May interact with FAM168B. Interacts with INCA1. Interacts with EIF4G1 and EIF4G2 (By similarity). Interacts (via PPAY motif) with NEDD4 (via WW domains) (By similarity). Interacts with transcription factor TCF4; the interaction results in localization of DAZAP2 to the nucleus (By similarity). Interacts with transcription factors TCF7 and TCF7L1 (By similarity). Interacts with transcription factor LEF1 (By similarity). 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 (By similarity). Interacts with ubiquitin ligase SIAH1; the interaction is decreased following phosphorylation of DAZAP2 by HIPK2 (By similarity). Interacts with TP53; the interaction is triggered by DNA damage (By similarity).
Ubiquitinated by SMURF2, leading to proteasomal degradation. Ubiquitinated by NEDD4, leading to proteasomal degradation.
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 (By similarity). The unglycosylated form interacts with PDE4DIP; this interaction, which is PDE4DIP isoform-specific, may connect a pericentrosomal complex to the gamma-tubulin ring complex (gamma-TuRC) to promote microtubule assembly and acetylation (By similarity).
Promotes integrin-mediated cell adhesion. May stimulate host defense against viruses and tumor cells (By similarity).
Up-regulated by virus infection, double-stranded DNA, IFNG and insulin. Down-regulated by hydrocortisone.
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. Interacts with MT-ND3.
Autophagy receptor required for selective macroautophagy (aggrephagy) (By similarity). Functions as a bridge between polyubiquitinated cargo and autophagosomes (By similarity). Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (By similarity). Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin-containing inclusions (p62 bodies, ALIS/aggresome-like induced structures) (By similarity). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (By similarity). 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 (By similarity). May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1 (PubMed:11244088, PubMed:11500922). May play a role in titin/TTN downstream signaling in muscle cells (By similarity). May regulate signaling cascades through ubiquitination (By similarity). 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 (By similarity). 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 (By similarity). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (By similarity). 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 (By similarity). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (By similarity).
By the proteasome inhibitors MG132 and lactacystin. By intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DCC). By okadaic acid and kainate (at protein level). Isoform 1 and isoform 2 relative amounts are changed upon up-regulation of the expression by NGF.
Homooligomer or heterooligomer; may form homotypic arrays. Interacts directly with PRKCI and PRKCZ (Probable). Interacts with EBI3, LCK, RASA1, PRKCZ, PRKCI, NR2F2, NTRK1, NTRK2, NTRK3, TRIM13, MAP2K5 and MAPKAPK5. Interacts with the proteasome subunits PSMD4 and PSMC2. Interacts with K63-polyubiquitinated MAPT/TAU. Interacts with IKBKB through PRKCZ and PRKCI. 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 AJUBA, PRKCZ and TRAF6. Interacts with TRAF6 and CYLD. Identified in a complex with TRAF6 and CYLD. Identified in a heterotrimeric complex with ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the same ubiquitin molecule (By similarity). Forms ternary complexes with PRKCZ and KCNAB2 or PRKCZ and GABBR3. Interacts with KCNAB1, GABRR1, GABRR2 and GABRR3. Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6. Interacts with NGFR through TRAF6 and bridges that complex to NTRK1. Interacts with NBR1 and TRIM55. 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 (By similarity). Interacts with FHOD3 (By similarity). Interacts with TRMI5 (By similarity). Interacts with SESN1 (By similarity). Interacts with SESN2 (By similarity). Interacts with ULK1. Interacts with UBD (By similarity). Interacts with WDR81; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins (By similarity). Interacts with WDFY3; this interaction is required to recruit WDFY3 to cytoplasmic bodies and to PML bodies (By similarity). Interacts with TRIM23 (By similarity). Interacts with LRRC25 (By similarity). Interacts with TRIM50 (By similarity). Interacts with TRIM16 (By similarity). Interacts with STING1; leading to relocalization of STING1 to autophagosomes (By similarity). Interacts (when phosphorylated at Ser-348) with KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering KEAP1 in inclusion bodies, promoting its degradation (By similarity). Interacts with GBP1 (By similarity). Interacts with MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester KEAP1 (By similarity). Interacts with TAX1BP1 (By similarity). Interacts with (ubiquitinated) PEX5; specifically binds PEX5 ubiquitinated at 'Lys-209' in response to reactive oxygen species (ROS) (By similarity). 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 (By similarity). Interacts with IRS1; the interaction is disrupted by the presence of tensin TNS2 (By similarity).
Major isoform except in central nervous system.
Maximal expression is detected at postnatal day 13 (P13) (at protein level).
More potent than isoform 2 to stimulate PRKCZ-dependent phosphorylation of KCNAB2.
Phosphorylated (PubMed:9177193). Phosphorylated in vitro by TTN (By similarity). May be phosphorylated by PRKCZ. Phosphorylation at Ser-402 by ULK1 is stimulated by SESN2 (By similarity). Phosphorylated at Ser-402 by TBK1, leading to promote relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (By similarity). Phosphorylation at Ser-348 by MTOR promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (By similarity).
The PB1 domain mediates homooligomerization and interactions with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81. Both the PB1 and UBA domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies.
The UBA domain binds specifically 'Lys-63'-linked polyubiquitin chains of polyubiquitinated substrates. Mediates the interaction with TRIM55. Both the UBA and PB1 domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies.
The ZZ-type zinc finger mediates the interaction with RIPK1.
Ubiquitinated by UBE2J1 and RNF26 at Lys-434: 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. Deubiquitination by USP15 releases target vesicles for fast transport into the cell periphery. Ubiquitinated by the BCR(KEAP1) complex at Lys-419, increasing SQSTM1 sequestering activity and promoting its degradation. Ubiquitinated via 'Lys-29' and 'Lys-33'-linked polyubiquitination leading to xenophagic targeting of bacteria and inhibition of their replication.
Ubiquitously expressed. In brain, mainly expressed by neurons, especially pyramidal neurons in the cerebral cortex and hippocampus. Also expressed by Purkinje cells and neurons in the dentate nucleus of the cerebellum and neurons of the basal ganglia (at protein level).
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.
Activated by binding to the regulatory factor DNMT3L. Auto-methylation at Cys-706 in absence of DNA inactivates the DNA methyltransferase activity.
Auto-methylated at Cys-706: 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.
Heterotetramer composed of 1 DNMT3A homodimer and 2 DNMT3L subunits (DNMT3L-DNMT3A-DNMT3A-DNMT3L) (By similarity). Interacts with DNMT1 and DNMT3B (By similarity). Interacts with MPHOSPH8 (By similarity). Interacts with histone H3 that is not methylated at 'Lys-4' (H3K4) (By similarity). Binds the ZBTB18 transcriptional repressor (By similarity). Interacts with SETDB1 (By similarity). Associates with HDAC1 through its ADD domain. Interacts with UHRF1. Interacts with the PRC2/EED-EZH2 complex. Interacts with UBC9, PIAS1 and PIAS2. 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 (By similarity).
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. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. Plays a role in paternal and maternal imprinting. Required for methylation of most imprinted loci in germ cells. Acts as a transcriptional corepressor for ZBTB18. Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. Can actively repress transcription through the recruitment of HDAC activity (By similarity). Also has weak auto-methylation activity on Cys-706 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).
Involved in the hydrolysis of N-acylated or N-acetylated amino acids (except L-aspartate).
Detected in adult pituitary and adrenal gland.
Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin. 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.
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 (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.
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. This isozyme seems responsible for metabolism of 2,2',4,4',5,5'-hexachlorobiphenyl.
Inhibitory regulator of the Ras-cyclic AMP pathway. Stimulates the GTPase of normal but not oncogenic Ras p21 (By similarity).
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.
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 (By similarity).
Directs RNA polymerase II nuclear import.
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 (By similarity).
Binds to the FHA domain of MKI67; this interaction is enhanced in mitosis.
In contrast to isoform 1, does not bind poly-ADP-ribose. Represses SOD3 gene expression.
Isoform that specifically binds poly-ADP-ribose and O-acetyl-ADP-ribose and plays a key role in NAD(+) metabolism. Able to bind to the ends of poly-ADP-ribose chains created by PARP1 and cap them. 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. Increases the expression of genes involved in redox metabolism, including SOD3.
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.
Present in brain, thymus, testis, liver and kidney (at protein level).
Present only in liver and brain (at protein level).
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. Interacts with SPOP. Part of a complex consisting of MACROH2A1, CUL3 and SPOP.
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 (PubMed:16107708). Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (PubMed:16107708). DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling (PubMed:16107708). Involved in stable X chromosome inactivation. Inhibits the binding of transcription factors, including NF-kappa-B, and interferes with the activity of remodeling SWI/SNF complexes (By similarity). Inhibits histone acetylation by EP300 and recruits class I HDACs, which induces a hypoacetylated state of chromatin (By similarity).
May be involved in MAP kinase activation, epithelial sodium channel (ENaC) down-regulation and cell cycling.
A catalytically active cytoplasmic form (p65) is produced by proteolytic cleavage of either isoform 1, isoform 2 or isoform 3.
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 is highly expressed in the brain, lung, spleen and testis. Isoform 2 is highly expressed in thymus, spleen and lung. Isoform 1 and isoform 2 are expressed in primary hepatocytes.
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). Acts as a negative regulator of insulin receptor (IR) signaling and is involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.
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-85 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).
Part of the multisubunit transport protein particle (TRAPP) complex.
Interacts with alpha-tubulin (PubMed:16302001). Interacts with CPNE4 (By similarity). Interacts with CEP290 (By similarity).
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 (By similarity).
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.
Acts as a transcriptional activator. Acts by binding to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes. Involved in the auditory system development, required for terminal differentiation of hair cells in the inner ear.
At 14 dpc, strongly expressed in cochlear and vestibular hair cells of the inner ear, in the cochlea at 18 dpc and coninues to the adulthood.
Expressed in the chochlea of the inner ear.
Contains mostly chondroitin sulfate, but also keratan sulfate chains, N-linked and O-linked oligosaccharides.
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. May play a regulatory role in the matrix assembly of the cartilage.
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.
By ferric nitrilotriacetate, NMDA and amphetamine.
Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. 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 (By similarity). Plays an important role in memory formation and synaptic plasticity in the hippocampus.
Monomer. Interacts with fibrinogen, PTPNS1, SIRPG, THBS1, UBQLN1 and UBQLN2 (By similarity).
Expression is restricted to small intestine, stomach and colon. Within colon, expressed in epithelial cells located within the lower to mid region of transverse and distal crypts, but not in proximal colon.
Homopentamer. Pentraxin (or pentaxin) have a discoid arrangement of 5 non-covalently bound subunits (By similarity).
Strongly down-regulated in colon by dietary heme, or by dietary depletion of vitamin E. Up-regulated by calcium.
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 (By similarity).
Expressed at low levels in brains of 1-day old animals but increase to adult levels from 7-day old animals and remain at that level in adults.
Expressed in the brain, not detected in the liver, kidney, spleen, heart, small intestine or testis.
Binds DNA via its HMG boxes. When bound to the mitochondrial light strand promoter, bends DNA into a U-turn shape, each HMG box bending the DNA by 90 degrees (By similarity).
Binds to the mitochondrial light strand promoter and functions in mitochondrial transcription regulation. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA. 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. Required for accurate and efficient promoter recognition by the mitochondrial RNA polymerase. Promotes transcription initiation from the HSP1 and the light strand promoter by binding immediately upstream of transcriptional start sites. Is able to unwind DNA. Bends the mitochondrial light strand promoter DNA into a U-turn shape via its HMG boxes. Required for maintenance of normal levels of mitochondrial DNA. May play a role in organizing and compacting mitochondrial DNA (By similarity).
May also function as a transcriptional activator or may have a structural role in the compaction of nuclear DNA during spermatogenesis.
Monomer; binds DNA as a monomer. Homodimer. Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT. 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. Upon metabolic stress, forms a complex composed of FOXO3, SIRT3, TFAM and POLRMT. Interacts with TFB1M and TFB2M. Interacts with CLPX; this enhances DNA-binding.
Phosphorylation by PKA within the HMG box 1 impairs DNA binding and promotes degradation by the AAA+ Lon protease.
The mitochondrial isoform is widely expressed while the nuclear isoform is testis-specific.
Expressed in mammary, salivary and thyroid gland. Expressed in the brain, in a cluster of cells located between the locus coeruleus (LC) and Barrington's nucleus, as well as in few cells of the dorsomedial hypothalamic nucleus and the amygdala.
May play an important anorexigenic role. Modulates arousal and anxiety as well as increases locomotor activity. Binds to its receptor NPSR1 with nanomolar affinity to increase intracellular calcium concentrations.
Activated in response to stress, such as the addition of ethanol to the culture medium or UV irradiation of cells. Inhibited rather than stimulated, by Magnesium.
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 (By similarity).
Widely expressed. Highest expression observed in kidney, liver and muscle.
Isoform 1 is expressed in skin and testis. Higher level of isoform 2 expressed in skin and intestine, moderate level in the kidney, low level in liver, stomach and placenta.
Prefers pregnenolone over DHEA as a substrate and does not sulfate cholesterol.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation. Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites. Sulfonates cholesterol (PubMed:16368200). Catalyzes sulfation of the 3beta-hydroxyl groups of steroids, such as, pregnenolone and dehydroepiandrosterone (DHEA) (PubMed:16368200). Conjugates efficiently cholesterol but has a greater affinity for pregnenolone sulfation. Does not show high activity with DHEA (PubMed:16368200). Plays a role in epidermal cholesterol metabolism and in the regulation of epidermal proliferation and differentiation (By similarity).
Incorporates a polar amino acid serine into membranes and facilitates the synthesis of two serine-derived lipids, phosphatidylserine and sphingolipids.
Found in saliva, tears, urine and seminal fluid.
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.
Interacts (via N-terminus) with EIF2S1; the interaction is independent of its phosphorylated status. Associates (via both ABC transporter domains) with the ribosomes (By similarity).
Phosphorylated at phosphoserine and phosphothreonine. Phosphorylation on Ser-109 and Ser-140 by CK2; inhibits association of EIF2 with ribosomes (By similarity).
Required for efficient Cap- and IRES-mediated mRNA translation initiation. Not involved in the ribosome biogenesis (By similarity).
Calcium-dependent lectin (PubMed:1436090, PubMed:9033386, PubMed:11850428). Plays a role in the innate immune response by binding mannose, fucose and N-acetylglucosamine moieties on different microorganisms and mediating activation of the lectin complement pathway (PubMed:3584121). 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 (By similarity).
Detected in blood serum (at protein level).
Homotrimer (PubMed:7704532, PubMed:9033386, PubMed:11850428, PubMed:25419660). Forms higher oligomeric complexes formed by the association of two, three or more homotrimers (PubMed:10903744, PubMed:25419660). Oligomerization occurs in the endoplasmic reticulum (By similarity). Interacts with MASP1 and MASP2 (PubMed:10913141).
Hydroxylated on lysine and proline residues within the collagen-like domain.
O-glycosylated. O-linked glycans on hydroxylysine residues consist of Glc-Gal disaccharides bound to the oxygen atom of post-translationally added hydroxyl groups.
The helical collagen-like domains from three protein chains assemble into a coiled coil and mediate trimerization.
Found in a pre-mRNA exonic splicing enhancer (ESE) complex with TRA2B/SFRS10, SNRNP70, SNRPA1 and SRRM1. Binds to A3 enhancer proteins SFRS4, SFRS5, SFRS6 and SFRS9. Interacts with CPSF6, RBMY1A1, RNPS1 and phosphorylated SFRS13A (By similarity). Interacts with RBMX and SAFB/SAFB1 (PubMed:9671816, PubMed:19282290). Interacts with ILDR1 (via C-terminus) and ILDR2 (By similarity).
Induced by reoxygenation following hypoxia and by exposure to silica. Repressed by interferon gamma, LPS and TPA.
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 (By similarity).
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.
Defects in Reln are the cause of the creeping phenotype, which is characterized by tremor, gait ataxia, cerebellar hypoplasia and abnormal neuronal migration (particularly in the cerebral cortex and hippocampus). The mutation is due to a nucleotide insertion at codon 1892 which results in a translational frameshift and truncation of the protein.
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.
Expression enhanced late after interaction of IL-2 with its receptor, approximately when cells enter S phase.
Interacts with U2AF1L4. Component of RCOR-GFI-KDM1A-HDAC complexes. Interacts directly with RCOR1, KDM1A and HDAC2. Also interacts with HDAC1. regions. Interacts (via the zinc-finger domain) with ARIH2; the interaction prevents GFI1 ubiquitination and proteasomal degradation. Interacts with PIAS3; the interaction relieves the inhibitory effect of PIAS3 on STAT3-mediated transcriptional activity. Forms a complex with EHMT2 and HDAC1 to promote 'Lys-9' dimethylation of H3 (H3K9Me2) and repress expression of target genes. Interacts directly with EHMT2. Component of the GFI1-AJUBA-HDAC1 repressor complex. Interacts directly with AJUBA (via ITS LIM domains); the interaction results in the HDAC-dependent corepression of a subset of GFI1 target genes and, occurs independent of the SNAG domain. Interacts with SPI1; the interaction inhibits SPI1 transcriptional activity targeted at macrophage-specific genes, repressing macrophage differentiation of myeloid progenitor cells and promoting granulocyte commitment (By similarity). Interacts with RUNX1T1; the interaction represses HDAC-mediated transcriptional activity. Interacts with RELA; the interaction occurs on liposaccharide (LPS) stimulation controls RELA DNA binding activity and regulates endotoxin-mediated TOLL-like receptor inflammatory response (By similarity). Interacts (via the C-terminal zinc fingers) with ZBTB17; the interaction results in the recruitment of GFI1 to the CDKN1A/p21 promoter and repression of CDKN1A/p21 transcription.
Restricted to lymphoid tissues and testes in adult animals.
The SNAG domain of GFIs is required for nuclear location and for interaction with some corepressors.
Transcription repressor essential for hematopoiesis. Functions in a cell-context and development-specific manner. Binds to 5'-TAAATCAC[AT]GCA-3' in the promoter region of a large number of genes. Component of several complexes, including the EHMT2-GFI1-HDAC1, AJUBA-GFI1-HDAC1 and RCOR-GFI-KDM1A-HDAC complexes, that suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Regulates neutrophil differentiation, promotes proliferation of lymphoid cells, and is required for granulocyte development. Inhibits SPI1 transcriptional activity at macrophage-specific genes, repressing macrophage differentiation of myeloid progenitor cells and promoting granulocyte commitment (By similarity). Mediates, together with U2AF1L4, the alternative splicing of CD45 and controls T-cell receptor signaling. Regulates the endotoxin-mediated Toll-like receptor (TLR) inflammatory response by antagonizing RELA. Cooperates with CBFA2T2 to regulate ITGB1-dependent neurite growth. Controls cell-cycle progression by repressing CDKNIA/p21 transcription in response to TGFB1 via recruitment of GFI1 by ZBTB17 to the CDKNIA/p21 promoter region. Implicated in the maintenance of inner ear hair cells (By similarity).
Zinc fingers 3,4 and 5 are required for DNA binding and for interaction with SPI1.
Belongs to the EGF-CFC (Cripto-1/FRL1/Cryptic) family.
Expressed in brain and liver. Expressed only in some areas of the brain and in the olfactory epithelium.
Olfactory receptor. The activity of this receptor is probably mediated by G-proteins wich induce elevation of intracellular Ca(2+), cAMP and activation of phosphorylation of the protein kinases PKA and MAPK3/MAPK1. Activation of OR51E2 may affect melanocyte proliferation, differentiation, and melanogenesis and may increase proliferation and migration of primary retinal pigment epithelial (RPE) cells. Activated by the short chain fatty acids (SCFA), acetate and propionate. In response to SCFA, may positively regulate renin secretion and increase blood pressure (By similarity). May also be activated by steroid hormones and regulate cell proliferation (By similarity). Activated by L-lactate in glomus cells (By similarity).
Component of the BCR(KLHL20) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL20 and RBX1. Interacts with PDZ-RhoGEF/ARHGEF11, DAPK1, PML and CORO7. Interacts with F-actin. Interacts with IFN-gamma (IFNG) (By similarity). Interacts (via kelch repeats) with IVNS1ABP (via kelch repeats); this interaction blocks the assembly of CUL3-KLHL20 complex (By similarity).
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. The BCR(KLHL20) E3 ubiquitin ligase complex also specifically mediates 'Lys-33'-linked ubiquitination. 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. 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 (By similarity).
Interacts with DDX4, PIWIL1, RANBP9 and TDRD1.
Interacts with RAD51 and PCNA. Interacts with PARP1 (By similarity). Interacts with TASOR (By similarity).
Present in testis (at protein level). Expressed in testis, gastrointestinal tract (jejunum, ileum, and colon) and immune system (thymus and spleen). Weakly expressed in lung, kidney, pituitary gland and muscle.
Required to suppress inappropriate homologous recombination, thereby playing a central role DNA repair and in the maintenance of genomic stability. Antagonizes homologous recombination by interfering with the formation of the RAD51-DNA homologous recombination structure. Positively regulate the poly(ADP-ribosyl)ation activity of PARP1; however such function may be indirect (By similarity). Binds single-strand DNA and poly(A) homopolymers.
The gene encoding Arom is located in the opposite strand of the gene encoding MCH.
During persistent inflammatory pain the expression levels are down-regulated.
Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival. Acts by binding to integrins or membrane receptors such as NOTCH1. Essential regulator of hematopoietic stem and progenitor cell function. Inhibits myogenic differentiation through the activation of Notch-signaling pathway. Inhibits vascular smooth muscle cells proliferation by increasing expression of cell-cycle regulators such as CDKN2B or CDKN1A independently of TGFB1 signaling. 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. 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 (By similarity). 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 (By similarity). 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:22353423).
Interacts with FBLN1. Interacts (via CTCK domain) with NOTCH1 (via the EGF-like repeat region) (By similarity). Interacts with GJA1/CX43 (PubMed:15181016, PubMed:15213231). Interacts with ITGA5:ITGB1, ITGAV:ITGB3 and ITGAV:ITGB5 (By similarity). Interacts with ZDHHC22; the interaction may lead to CCN3 palmitoylation (By similarity).
May be palmitoylated on Cys-238, which is important for extracellular secretion.
Widely expressed. Highly expressed in neurons of dorsal root ganglia and dorsal horn of the spinal cord (at protein level) (PubMed:22353423). Expressed in astrocytes (at protein level) (PubMed:15213231). In cartilage, dominantly expressed in the chondrocyte territorial matrix (PubMed:21871891).
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 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. Interacts with the 34 kDa STX5 isoform.
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.
Competitively inhibited by lysophosphatidic acid.
Enzyme catalyzing the degradation of lysoplasmalogen. Lysoplasmalogens are formed by the hydrolysis of the abundant membrane glycerophospholipids plasmalogens. May control the respective levels of plasmalogens and lysoplasmalogens in cells and modulate cell membrane properties.
Belongs to the sodium channel auxiliary subunit SCN1B (TC 8.A.17) family.
Component of a voltage-sensitive sodium channel complex that consists of a pore-forming alpha subunit and one or more regulatory beta subunits (PubMed:1375395, PubMed:28012039). Interacts with SCN4A (PubMed:28012039). Interacts with NFASC (PubMed:11470829). Interacts with SCN10A (PubMed:15178439). Interacts with SCN1A. Interacts with SCN3A. Interacts with SCN5A. Interacts with SCN8A (By similarity).
Detected in brain (at protein level) (PubMed:11470829). Expressed in brain, heart, skeletal muscle and spinal cord (PubMed:1375395, PubMed:8282123).
In developing nodes of Ranvier, it is localized in the sciatic nerve at postnatal days 3 and 10, during the process of myelination and maturation of the nodes.
Regulatory subunit of multiple voltage-gated sodium channel complexes that play important roles in excitable membranes in brain, heart and skeletal muscle (PubMed:1375395, PubMed:8282123, PubMed:8021275, PubMed:15178439, PubMed:28012039). Enhances the presence of the pore-forming alpha subunit at the cell surface and modulates channel gating characteristics and the rate of channel inactivation (PubMed:1375395, PubMed:8282123, PubMed:8021275, PubMed:15178439, PubMed:28012039). Modulates the activity of a variety of pore-forming alpha subunits, such as SCN1A, SCN2A, SCN3A, SCN4A, SCN5A and SCN10A (PubMed:1375395, PubMed:8282123, PubMed:8021275, PubMed:15178439, PubMed:28012039).
Binds to the intracellular domain of tumor necrosis factor type 1 receptor. Binds to RB1. Interacts with SRC. Interacts with SDHA.
Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.
Belongs to the SMC family. RAD50 subfamily.
Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN. As part of the MRN complex, interacts with MCM8 and MCM9; the interaction recruits the complex to DNA repair sites. Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN. Found in a complex with TERF2. Interacts with RINT1. Interacts with BRCA1 via its N-terminal domain. Interacts with DCLRE1C/Artemis. Interacts with MRNIP (By similarity). 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. The complex may also be required for DNA damage signaling via activation of the ATM kinase. In telomeres the MRN complex may modulate t-loop formation (By similarity).
Present at low levels in the heart at fetal-day 17, at relatively constant levels at postnatal days 10, 17 and 21 and at slightly lower levels in the adult heart. Detected in liver, kidney and lung. Barely detectable in skeletal muscle with slightly higher levels observed in brain and the ventricles of the heart (at protein level).
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).
Interacts with MCM3AP/GANP, 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. May act as a negative regulator of ABCB1 expression and function through the dephosphorylation of ABCB1 by TFPI2/PPP2R3C complex. May play a role in the activation-induced cell death of B-cells.
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 (By similarity). May play a role in cytoplasm movement and removal during spermiogenesis.
Expression is low before postnatal stage on day 20, and increases significantly between days 20 to 28.
Highly expressed in the testis and is mainly localized in the spermatids. Also expressed in the lung, heart, spleen and epididymis.
Homodimer. Interacts with CBX3, CBX5, GMNN, GTF2B, TBPL1 and the polycomb proteins PHCF2, RNF2 and SCMH1 but not with CBX1 or PCGF2 (By similarity).
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).
Subject to inhibition by high substrate concentrations. Inhibited by testosterone concentrations above 10 uM. Inhibited by the primary and secondary bile acids chenodeoxycholic acid and ursodeoxycholic acid.
Expressed only in ventricular and slow twitch skeletal muscle tissues.
Regulatory light chain of myosin. Does not bind calcium.
Exoglycosidase that cleaves the single beta-linked mannose residue from the non-reducing end of all N-linked glycoprotein oligosaccharides.
Homodimer; disulfide-linked. Can also form homotetramers.
In suckling rat, highest levels in liver and in intestine. Lower levels in heart, kidney and cerebellum. Weak expression in brain cortex, medulla and midbrain. Levels decrease slightly during weaning.
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.
Homodimer; disulfide-linked (By similarity). 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).
Interacts with ZFC3H1 in a RNase-insensitive manner.
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 (By similarity). Involved in biosynthesis of N-linked keratan sulfate proteoglycans in cornea, with an impact on proteoglycan fibril organization and corneal transparency (By similarity). May play a role in the maintenance of tissue architecture by suppressing cellular motility and invasion (By similarity).
Interacts with the RPA1 subunit of RPA complex.
Mediates the import of RPA complex into the nucleus, possibly via some interaction with importin beta. Sumoylation mediates the localization of RPA complex into the PML body of the nucleus, thereby participating in RPA function in DNA metabolism (By similarity).
Sumoylated; 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 (By similarity).
Interacts with RAB11A and VIPAS39. Associates with adaptor protein complex 3 (AP-3), clathrin:AP-3 and clathrin:HGS complexes (By similarity).
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. 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. 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).
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.
Expression detected in neutrophilic granulocytes.
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.
Dual endothelin-1/angiotensin-2 receptor that is functionally coupled to a calcium-mobilizing transduction system, responding equivalently to both endothelin-1/EDN1 and angiotensin-2 peptides in a highly specific manner (PubMed:15561758, PubMed:9508787). Also binds the signal peptide of VEGFA (By similarity). May play a role in angiogenesis with a significant role in cardiovascular and neural development (By similarity).
Prominently expressed in brain and heart tissues. Weakly expressed in aorta, adrenal gland, and lung tissues.
Belongs to the eukaryotic RPC34/RPC39 RNA polymerase subunit family.
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. In the complex, it may be required to direct the CPC to centromeric DNA (By similarity).
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. Interacts with SENP3, UBE2I and RANBP2. Interacts (phosphorylated) with SGO1 and SGO2; the association is dependent on CDK1 (By similarity).
Phosphorylated by TTK, essentially at Thr-88 and Thr-94. 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 (By similarity).
The C-terminal region (aa 215-288) represents the dimerization motif.
Expressed in distal colon, proximal colon, ileum, jejunum, stomach, liver, lung, kidney, spleen, and heart (PubMed:9950762). Expressed in the brain, testes and anterior prostate (at protein level) (PubMed:14749213).
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.
Up-regulated in distal colon in response to K(+) free diet.
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.
Homodimer; disulfide-linked, upon oxidation. 5 homodimers assemble to form a ring-like decamer. Interacts with TIPIN.
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).
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 (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 NFE2 (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.
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. Inhibited by SERPINB3 (By similarity). Inhibited by IFN-gamma-induced S-nitrosylation.
Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Phosphorylated by TAOK2 (By similarity). Phosphorylated form is more concentrated at synapses than none-phosphorylated (PubMed:29166604).
Forms a complex with MAPK8IP1 and ARHGEF28 (PubMed:14499478). Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8IP1/JIP1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK9/JNK2 (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. Interacts with TP53, WWOX. Interacts with JAMP. Interacts with NFATC4. Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells. Interacts with MECOM; regulates JNK signaling. Interacts with PIN1; this interaction mediates MAPK8 conformational changes leading to the binding of MAPK8 to its substrates (By similarity). Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs under both normal growth conditions and immediately upon heat shock (By similarity). Interacts with STMN2, STMN3 and STMN4 (PubMed:16618812). Interacts with GRIPAP1 (PubMed:17761173). Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-347'. Interacts with HSF4 (By similarity).
Nitrosylated upon IFN-gamma-induced endogenous NO production, which inhibits the enzyme (PubMed:11121042). May be phosphorylated at Thr-183 and Tyr-185 by MAP3K1/MEKK1 (By similarity).
Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death (PubMed:9516415, PubMed:16618812). 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 MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone (PubMed:21297631). Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH. Phosphorylates the CLOCK-BMAL1 heterodimer and plays a role in the regulation of the circadian clock (By similarity). Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity (By similarity). Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation (By similarity). Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1 (By similarity). In neurons, phosphorylates SYT4 which captures neuronal dense core vesicles at synapses (PubMed:29166604). Phosphorylates EIF4ENIF1/4-ET in response to oxidative stress, promoting P-body assembly (By similarity). Phosphorylates SIRT6 in response to oxidative stress, stimulating its mono-ADP-ribosyltransferase activity (By similarity).
This protein is found in nasal epithelium and it binds a wide variety of chemical odorants.
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 (By similarity). 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-317 creates a binding site for CBL, an adapter protein that serves as a negative regulator of BCR-stimulated calcium ion signaling (By similarity). Phosphorylation at Tyr-342 creates a binding site for VAV1 (By similarity). Phosphorylation on Tyr-342 and Tyr-346 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 (By similarity). Phosphorylation on Ser-291 is very common, it peaks 5 minutes after BCR stimulation, and creates a binding site for YWHAG (By similarity). Phosphorylation at Tyr-624 creates a binding site for BLNK (By similarity). Dephosphorylated by PTPN6 (By similarity).
Interacts with LYN; phosphorylates SYK. Interacts with RHOH (phosphorylated); regulates mast cells activation. Interacts with NFAM1 (phosphorylated); probably involved in BCR signaling. Interacts with VAV1 (via SH2 domain); phosphorylates VAV1 upon BCR activation. Interacts with GAB2 (phosphorylated); probably involved in IgE Fc receptor signaling. Interacts (via its SH2 domains) with CD79A (via its phosphorylated ITAM domain); the interaction stimulates SYK autophosphorylation and activation. Interacts (via SH2 domains) with FCER1G (via ITAM domain); activates SYK and mediates neutrophils and macrophages integrin-mediated activation. Interaction with FCER1G in basophils triggers IL3-induced IL4 production (By similarity). Interacts with ITGB2 and FGR; involved in ITGB2 downstream signaling. 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. 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 (By similarity). Interacts (via SH2 domains) with GCSAM; the interaction increases after B-cell receptor stimulation, resulting in enhanced SYK autophosphorylation and activity (By similarity). Interacts with TNS2; leading to the phosphorylation of SYK (By similarity). Interacts with FLNA (via filamin repeat 5); docks SYK to the plasma membrane (By similarity). Interacts with CEACAM1; lipopolysaccharide activated neutrophils induce phosphorylation of SYK resulting in the formation of a complex including TLR4, 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 (By similarity).
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. 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. Required for the stimulation of neutrophil phagocytosis by IL15 (By similarity). 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 (By similarity).
Ubiquitinated by CBLB after BCR activation; which promotes proteasomal degradation.
Belongs to the EF-1-beta/EF-1-delta family.
EF-1 is composed of 4 subunits: alpha, beta, delta isoform 1, and gamma. Isoform 2 interacts with HSF1 and NFE2L2 (By similarity).
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.
Regulates induction of heat-shock-responsive genes through association with heat shock transcription factors and direct DNA-binding at heat shock promoter elements (HSE).
Enriched in the cerebellum and also expressed in the neocortex and modestly in the hippocampus (at protein level) (PubMed:26660156). Expressed in hippocampal neurons, both in cell body and neurites, however its presence is enriched at excitatory synapses and also found in postsynaptic cells (PubMed:20152115).
Expressed during synaptogenesis with levels peaking during the second week of postnatal development (PubMed:20152115). Expression increases between postnatal days 7 and 14 and remains high at postnatal day 21 and at 2 months of age (PubMed:26660156). As development proceeds, an increasing percentage becomes localized to excitatory synapses (PubMed:20152115).
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.
Microtubule-binding protein required to ensure proper cell division and nuclear envelope reassembly by sequestering the endoplasmic reticulum away from chromosomes during mitosis. Probably acts by clearing the endoplasmic reticulum membrane from metaphase chromosomes (By similarity).
Transposase-derived protein that may have nuclease activity (Potential). Does not have transposase activity (By similarity).
Binds to DNA as a homomultimer. Dimerization is induced by binding to calcium. Interacts with the C-terminus of PSEN1 and PSEN2 and with PSEN2 CTF subunit. Associates with KCN1. Component of heteromultimeric potassium channels (PubMed:16123112). Identified in potassium channel complexes containing KCND1, KCND2, KCND3, KCNIP1, KCNIP2, KCNIP3, KCNIP4, DPP6 and DPP10 (By similarity). Interacts with KCND2 and KCND3 (PubMed:10676964).
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).
Detected in brain cortex, thalamus, dentate gyrus and cerebellum (at protein level) (PubMed:16123112). Expressed in brain. Colocalizes with KCND2 in excitatory neurons including cortical and hippocampal CA1 pyramidal cells.
May play a role in the regulation of PSEN2 proteolytic processing and apoptosis. Together with PSEN2 involved in modulation of amyloid-beta formation (By similarity).
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 (By similarity).
Belongs to the V-ATPase F subunit family.
(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:8243676, PubMed:8103915).
(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:8243676, PubMed:8103915).
Palmitoylated. 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:9759724, PubMed:12496247, PubMed:19196426). Found in a complex containing SYT1, SV2B and syntaxin-1 (By similarity). Found in a ternary complex with STX1A and VAMP8 (PubMed:10336434). 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 (By similarity). Interacts with CENPF (By similarity). Interacts with EQTN (By similarity). Interacts with HGS (PubMed:9039916). Interacts with KCNB1 (via N-terminus); reduces the voltage-dependent potassium channel KCNB1 activity in pancreatic beta cells (PubMed:12403834). Interacts with OTOF (By similarity). Interacts with RIMS1 (PubMed:11438518). Interacts with SNAPIN (By similarity). Interacts with STXBP6 (PubMed:12145319). Interacts with TRIM9 (By similarity). Interacts with ZDHHC13 (via ANK repeats) (PubMed:26198635). Interacts with ZDHHC17 (via ANK repeats) (PubMed:26198635). Associates with the BLOC-1 complex (By similarity). Interacts with PLCL1 (via C2 domain) (PubMed:23341457). Interacts with PRRT2; this interaction may impair the formation of the SNARE complex (By similarity). Interacts with alpha-synuclein/SNCA (By similarity). Interacts with PRPH2 (By similarity). Interacts with ROM1 (By similarity). Interacts with STX3 (By similarity).
t-SNARE involved in the molecular regulation of neurotransmitter release (PubMed:8243676, PubMed:8103915). 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 (PubMed:12403834).
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 (By similarity).
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 in sciatic nerve and dorsal root ganglion (at protein level). Expressed in sensory neurons of dorsal root ganglion. Expressed in Golgi interneurons in the granular layer. Also found in superior cervical ganglia, spinal cord and brain stem.
Expression is first detected at 15.5 dpc. Strongly expressed perinatally.
Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with LIN7B, MAGI1 and GOPC (By similarity). Interacts with DLG4 and ASIC2. Interacts with STOM; this regulates channel activity. Homotrimeric ASIC3 and ASIC3-containing heterotrimers interact with the cono-RFamide CNF-Tx1.1, and probably CNF-Tx1.2 and CNF-Tx1.3 (AC P0DL71) (PubMed:28396446).
Phosphorylated by PKA (By similarity). 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/ACCN3 channel.
Potentiated by FMRFamide-related neuropeptides (By similarity). Sensitized and potentiated by NPFF and NPSF. Regulated by lactate and Ca(2+). Specifically inhibited by APETx2, a sea anemone toxin. Inhibited by anti-inflammatory drugs like salicylic acid.
The PDZ domain-binding motif is involved in interaction with LIN7A, GOPC and MAGI1/BAIAP1.
Transcriptionally regulated by the proinflammatory mediators nerve growth factor, serotonin, interleukin-1 and bradykinin. Up-regulation upon tissue inflammation is abolished by anti-inflammatory drugs.
Interacts with FGFR1 and FGFR2. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors (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 (By similarity).
Seems to have an antagonistic effect compared to that of the isoform Long.
By sodium depletion and angiotensin II in adrenal zona glomerusa (at protein level).
Knockdown in cultured hippocampal neurons shows a complete disruption of the assembly and function of the neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).
Levels decrease during early postnatal development after which it remains stable into adulthood and this decrease occurs to a greater degree in the frontal cortex compared to the hippocampus (at protein level).
May interact with NGFR (PubMed:20685870). 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). 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). 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:26875622). Promotes the expression of the alpha-4(2):beta-2(3) stoichiometric form over the alpha-4(3):beta-2(2) form (By similarity).
Present in adrenal zona glomerusa but not in adrenal medulla (at protein level) (PubMed:20685870). Expressed in the hippocampus (at protein level) (PubMed:26875622).
Activity is stimulated by ZBP1, which senses double-stranded Z-RNA structures. 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.
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. Interacts with MLKL; the interaction is direct and triggers necroptosis. 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. Binds TRAF2 and is recruited to the TNFR-1 signaling complex. Interacts with PYGL, GLUL and GLUD1; these interactions result in activation of these metabolic enzymes. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4. Interacts with ARHGEF2 (By similarity). Interacts with PELI1 (via atypical FHA domain); the phosphorylated form at Thr-185 binds preferentially to PELI1 (By similarity). Interacts with BUB1B, TRAF2 and STUB1 (By similarity). Interacts with CASP6 (By similarity). 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. Ubiquitinated by STUB1 leading to its subsequent proteasome-dependent degradation.
RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Autophosphorylated following interaction with ZBP1. Phosphorylation of Ser-201 plays a role in the necroptotic function of RIPK3. Autophosphorylates at Thr-228 and Ser-229 following activation by ZBP1: phosphorylation at these sites is a hallmark of necroptosis and is required for binding MLKL. Phosphorylation at Thr-185 is important for its kinase activity, interaction with PELI1 and for its ability to mediate TNF-induced necroptosis (By similarity).
Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death. Necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, is triggered by RIPK3 following activation by ZBP1. 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. 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. 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 (By similarity). In some cell types, also able to restrict viral replication by promoting cell death-independent responses. In response to flavivirus 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. 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. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production (By similarity).
The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3).
Laminin alpha-5 receptor. May mediate intracellular signaling (By similarity).
Belongs to the AAA ATPase family. RarA/MGS1/WRNIP1 subfamily.
Forms homooligomers, possibly octamers. Directly interacts with POLD1, POLD2 and POLD4. Interacts with the N-terminal domain of WRN. Interacts (via UBZ4-type zinc finger) with monoubiquitin and polyubiquitin. Interacts with TRIM14 and PPP6C; these interactions positively regulate the RIGI signaling pathway.
Functions as a modulator of initiation or reinitiation events during DNA polymerase delta-mediated DNA synthesis. In the presence of ATP, stimulation of DNA polymerase delta-mediated DNA synthesis is decreased. Also plays a role in the innate immune defense against viruses. Stabilizes the RIGI dsRNA interaction and promotes RIGI 'Lys-63'-linked polyubiquitination. In turn, RIGI transmits the signal through mitochondrial MAVS.
The UBZ4-type zinc finger binds ubiquitin.
Autophosphorylated 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 (By similarity).
Increases during pregnancy (2.2-fold at 4 days) and lactation (1.5-fold at 21 days). Decreases in the early phases of involution (33%, 21%, and 45% on days 1, 2, and 3 respectively).
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 (By similarity). Identified in a complex with SRC and ITGB1 (By similarity).
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 (By similarity).
The first and second Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding. The fourth and fifth Ig-like C2-type (immunoglobulin-like) domains are sufficient for homodimerization. The fifth and seventh Ig-like C2-type (immunoglobulin-like) domains are required for autophosphorylation and further activation.
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. 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' (By similarity).
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. 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 (By similarity).
Interacts with phosphorylated CSF1R. Component of the THO complex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7; together with at least ALYREF/THOC4, DDX39B, SARNP/CIP29 and CHTOP, THO forms the transcription/export (TREX) complex which seems to have a dynamic structure involving ATP-dependent remodeling. Interacts with THOC1, 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 LUZP4. Interacts with NCBP3 (By similarity).
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-327 in insulin-stimulated adipocytes (By similarity).
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 (By similarity).
Expressed in the olfactory bulb, the cerebral cortex, the hippocampus, and the cerebellum in the adult brain (at protein level) (PubMed:25941474). Strongly expressed in the subventricular zone,rostral migrate stream, and the subgranular zone of the dentate gyrus in the hippocampus (PubMed:25941474).
Plays a role in neurogenesis. Prevents motor neuron cell body migration out of the neural tube.
May play roles in cilia formation and/or maintenance.
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 (By similarity).
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 (By similarity).
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) (By similarity).
Ubiquitously expressed, with a higher expression in the retina.
Belongs to the protoporphyrinogen/coproporphyrinogen oxidase family. Protoporphyrinogen oxidase subfamily.
Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.
Catalyzes the conjugation of glutathione to a large variety of electrophilic compounds.
Homodimer or heterodimer of GSTA1 and GSTA2.
Filament-forming cytoskeletal GTPase (By similarity). May play a role in cytokinesis (Potential). 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. 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 (By similarity).
In developing testis, expression increases steadily until sexual maturity (approximately 49 days postpartum) where it remains expressed at a relatively constant level.
Predominantly expressed in testis and epididymis. Component of the sperm tail annulus (at protein level).
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 SEPTIN6 and SEPTIN11. Self-associates. Component of a 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 GTP-binding domains. Interacts with SPAG4 and LMNB1. Associates with alpha- and beta-tubulins (By similarity).
Interacts with neurabin-1 and neurabin-2. Binds preferentially to the dimeric form of neurabin-1.
Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity (By similarity). Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization (By similarity). Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1 (By similarity). Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B (By similarity). Participates in IFNB promoter activation via TICAM1 (By similarity).
Homodimer (By similarity). Interacts with IKBKE, TBK1 and TICAM1 (By similarity). Interacts with TAX1BP1 (By similarity). Interacts with CALCOCO2 (By similarity).
Ubiquitinated via 'Lys-48'-linked polyubiquitination by TRIM38, leading to its degradation.
The GINS complex plays an essential role in the initiation of DNA replication.
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 (By similarity). Interacts with TAP1 (By similarity).
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. May participate in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (By similarity). Required for adipocyte differentiation (By similarity).
Up-regulated by interferon gamma (at protein level). Down-regulated by theophylline (THP), a reprotoxic agent thought to induce infertility.
Acts as an activator of the protein-kinase ILK, thereby regulating cell motility.
Forms the fibrils of tendon, ligaments and bones. In bones the fibrils are mineralized with calcium hydroxyapatite. Expressed in flagella of epididymal sperm.
Proline residues at the third position of the tripeptide repeating unit (G-X-P) are hydroxylated in some or all of the chains. Proline residues at the second position of the tripeptide repeating unit (G-P-X) are hydroxylated in some of the chains.
Trimers of one alpha 2(I) and two alpha 1(I) chains.
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 (By similarity).
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 (By similarity). Interacts with RB. Interacts with FAM168B/MANI (By similarity). Interacts with MCPH1 (By similarity).
Phosphorylated. Phosphorylation on Ser-427 and Thr-447 occurs specifically during mitosis (By similarity).
Acetylated on lysine residues. BLOC1S1 is required for acetylation. Acetylated by CLOCK in a circadian manner.
Belongs to the complex I NDUFA9 subunit family.
Complex I is composed of 45 different subunits (By similarity). This a component of the hydrophobic protein fraction (By similarity). Interacts with BLOC1S1 (By similarity). Interacts with SLC2A4 (PubMed:16396496). Interacts with CLOCK (By similarity). Interacts with RAB5IF (By similarity).
Highest levels in spleen, liver brain and kidney. Lower but significant level are also detected in intestine, stomach, skeletal muscle, testis, heart and lung.
Receptor for ADP. Coupled to G(i)-proteins. May play a role in hematopoiesis and the immune system.
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.
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.
Binds to both calcium-free and calcium-bound calmodulin. The affinity for the calcium-bound form is 50-fold greater.
Detectable in the brain at embryonic day 17. The levels increase to reach a maximal value at postnatal day 18.
Functions as a modulator of calcium-binding by calmodulin. Thereby, regulates calmodulin activity and the different processes it controls. For instance, may play a role in neuronal differentiation through activation of calmodulin-dependent kinase signaling pathways.
Mostly intrinsically disordered, with residual structure localized to the IQ domain which mediates the interaction with calmodulin.
Restricted to the nervous system. Expressed throughout the brain, in particular forebrain regions, including the granular layer of the olfactory bulb, and pyriform cortex. Also expressed in the hippocampus, caudate putamen and the cerebellum, where it is associated predominantly with Purkinje cells.
Interacts with ATG9A. Interacts with MAPK14 (By similarity).
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. Required for starvation-induced ATG9A trafficking during autophagy (By similarity).
Acts as an adapter for the XPO1/CRM1-mediated export of the 60S ribosomal subunit.
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. The NAD-cap is present at the 5'-end of some RNAs and snoRNAs. In contrast to the canonical 5'-end N7 methylguanosine (m7G) cap, the NAD cap promotes mRNA decay (By similarity). Preferentially acts on NAD-capped transcripts in response to environmental stress (By similarity). 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. Specifically degrades pre-mRNAs with a defective 5'-end m7G cap and is part of a pre-mRNA capping quality control. 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). 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. 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. Also possesses RNA 5'-pyrophosphohydrolase activity by hydrolyzing the 5'-end triphosphate to release pyrophosphates (By similarity). Exhibits decapping activity towards FAD-capped RNAs (By similarity). Exhibits decapping activity towards dpCoA-capped RNAs in vitro (By similarity).
Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.
Highly expressed in the brain and ovary. Detected in the pyramidal cells of the hippocampus, granule cells of the dentate gyrus, granular cells of the cerebral cortex and the granulosa cells of the ovary.
Monomer; in the absence of TGF-beta (By similarity). Homooligomer; in the presence of TGF-beta (By similarity). 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 (By similarity). Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (By similarity). Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta (By similarity). Found in a complex composed of SMAD3, RAN and XPO4; within the complex interacts directly with XPO4 (By similarity). 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 (By similarity). 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 (By similarity). Interacts with NEDD9; the interaction promotes NEDD9 ubiquitination and proteasomal degradation (By similarity). 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 (By similarity). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (By similarity). 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 (By similarity). 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 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Interacts with TGFBR1 (By similarity). Interacts with TGFB1I1 (By similarity). Interacts with PRDM16 (By similarity). Interacts with SNW1 (By similarity). Interacts (via MH2 domain) with ZFYVE9 (By similarity). Interacts with HDAC1 (By similarity). Interacts with TGIF2 (By similarity). Interacts with SKOR1 (By similarity). Interacts with SKOR2 (By similarity). Interacts with DACH1; the interaction inhibits the TGF-beta signaling (By similarity). Interacts with RBPMS (By similarity). Interacts (via MH2 domain) with MECOM (By similarity). Interacts with WWTR1 (via its coiled-coil domain) (By similarity). Interacts with SKI; the interaction represses SMAD3 transcriptional activity (By similarity). Interacts with MEN1 (PubMed:11274402). Interacts with IL1F7 (By similarity). Interaction with CSNK1G2 (By similarity). Interacts with PDPK1 (via PH domain) (By similarity). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (By similarity). Interacts with USP15 (By similarity). Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels (By similarity). Interacts with LDLRAD4 (via the SMAD interaction motif) (By similarity). Interacts with PMEPA1 (By similarity). Interacts with ZNF451 (By similarity). Interacts with ZFHX3 (By similarity). Interacts weakly with ZNF8 (By similarity). Interacts with STUB1, HSPA1A, HSPA1B, HSP90AA1 and HSP90AB1 (By similarity). Interacts with YAP1 (when phosphorylated at 'Ser-112') (By similarity). Interacts with AIP1 (By similarity). Interacts (via MH2 domain) with CITED2 (via C-terminus) (PubMed:16619037). 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 (By similarity).
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 (By similarity).
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 (By similarity).
The MH1 domain is required for DNA binding (By similarity). Also binds zinc ions which are necessary for the DNA binding.
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. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes. 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. Undergoes STUB1-mediated ubiquitination and degradation.
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 (By similarity). 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 (By similarity). 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 (By similarity). Promotes osteoclast precursor migration to bone surfaces (By similarity). Signals constitutively through G(i)-alpha, but not G(s)-alpha or G(q)-alpha (By similarity). Signals constitutively also via MAPK1/3 (ERK1/2) (By similarity).
Homodimer and heterodimer. Heterodimerizes with CXCR5; leading to modulate the interaction between of CXCL13 and CXCR5.
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).
Was originally (Ref.1) thought to originate from human.
Acts as a negative growth regulator via p53-mediated apoptosis pathway. Regulates formation of degradative autolysosomes during autophagy.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ8 subfamily.
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium.
Widely expressed, including in pancreatic islets, pituitary, skeletal muscle and heart.
eIF-5A seems to be the only eukaryotic protein to have a hypusine residue which is a post-translational modification of a lysine by the addition of a butylamino group.
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. 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.
Highly expressed in testis and weakly expressed in heart and liver. Highly expressed in small intestine and cecum in a male-dominant sexual dimorphic fashion.
Increased after TCDD exposure in liver. Highly increased after TCDD exposure in kidney, spleen and heart. Up-regulated by 3-MC in small intestine.
Interacts with ARNT, ANKRA2, HDAC4 and HDAC5. Interacts with ARNT; forms a heterodimer with ARNT (By similarity).
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.
Highly expressed in brain and testis and at lower levels in spleen and lung.
Plays a role in the control of the actin cytoskeleton via activation of the JNK pathway.
Expressed in kidney cortex and intestine.
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 via transport of L-arginine, and is involved in the transport of L-arginine in monocytes (By similarity).
Chemotactic activity for lymphocytes but not for monocytes or neutrophils. In thymus, mediates medullary accumulation of thymic dendritic cells and contributes to regulatoy T cell development, playing a role in self-tolerance establishment.
Belongs to the 'GDSL' lipolytic enzyme family. IAH1 subfamily.
Highly expressed in the adrenal gland and at moderate levels in the eye and testis. Expressed widely in the brain with high levels in the hypothalamus and moderate levels in the amygdala, basal forebrain, cortex, medulla oblongata, midbrain and thalamus.
Receptor for the orexigenic neuropeptide QRFP. The activity of this receptor is mediated by G proteins that modulate adenylate cyclase activity and intracellular calcium levels.
Exhibits night/day variations with close to 100-fold increased expression at night (PubMed:15684415, PubMed:19103603). Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway, which activates an alternative promoter within intron 20 resulting in isoform 2 production (PubMed:15684415, PubMed:19103603). Levels rapidly decrease after exposure to daylight and become undetectable at midday and late afternoon (PubMed:15684415, PubMed:19103603).
Expression is restricted to pinealocytes.
Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Primarily responsible for the absorption of dietary di- and tripeptides from the small intestinal lumen.
The extracellular domain (ECD) region specifically binds trypsin.
Anchors the catalytic subunits of asymmetric AChE to the synaptic basal lamina.
Expressed in skeletal muscle, heart, brain, as well as in lung, spleen, testis, but not liver. The short isoform represents about 5% of the transcripts in the soleus muscle and about 15% in the heart ventricle.
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 triple-helical tail is stabilized by disulfide bonds at each end.
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.
Can homooligomerize into hexameric rings, which may be promoted by interaction with microtubules. Interacts with KATNB1, which may serve as a targeting subunit (By similarity). 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). Interacts with KLHL42 (via the kelch domains). Interacts with CUL3; the interaction is enhanced by KLHL42 (By similarity). Interacts with KATNB1 and KATNBL1 (By similarity).
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.
Phosphorylation by DYRK2 triggers ubiquitination and subsequent degradation.
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.
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). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect. Interacts with IRS4 (when Tyr-phosphorylated). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains. It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1. Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1. Interacts with phosphorylated MET. Interacts with phosphorylated TOM1L1. Interacts with the phosphorylated C-terminus of SH2B2. Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation. Interacts with NISCH, PTPNS1 and REPS2. Interacts with syntrophin SNTA1. Interacts (via SH3 domains) with REPS1. Interacts (via SH3 domains) with PIK3C2B. Interacts with CBL and CBLB. Interacts with AJUBA and CLNK. Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2. Interacts with PTPN11. Interacts with PRNP. Interacts with RALGPS1. Interacts also with HCST. Interacts with KDR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with GAPT and PTPRE. Interacts (via SH2 domain) with KIF26A. Interacts (via SH3 2) with GAB2. Interacts with ADAM15. Interacts with THEMIS2. Interacts (via SH2 domain) with AXL (phosphorylated). Interacts (via SH2 domain) with KIT (phosphorylated). Interacts with PTPRJ and BCR. Interacts with PTPN23. Interacts with FLT4 (tyrosine phosphorylated). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration. Part of a complex including TNK2, GRB2 and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2. Interacts with ERBB4. Interacts with NTRK1 (phosphorylated upon ligand-binding). Interacts with PTK2/FAK1 (tyrosine phosphorylated). Interacts with PTK2B/PYK2 (tyrosine phosphorylated). Interacts (via SH2-domain) with SCIMP; this interaction is dependent on phosphorylation on SCIMP 'Tyr-58' (By similarity). Interacts (via SH3 domains) with GAREM1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation. Interacts with DAB2. Interacts with TESPA1. Interacts with THEMIS. Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1. Interacts with CD28. Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA. Interacts with ASAP3 (phosphorylated form) (By similarity). Interacts (via SH2 domain) with CSF1R and IRS1 (tyrosine phosphorylated) (PubMed:8262059, PubMed:8388384). 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) (By similarity). Interacts with DENND2B (By similarity). Interacts with SPRY2 (By similarity). Interacts with LRRC8A (By similarity).
The SH3 domains mediate interaction with RALGPS1 and SHB.
Associates with the BLOC-1 complex. Interacts with BLOC1S6. Forms a complex containing SNAP47, VAMP2 and STX1A (By similarity).
May play a role in intracellular membrane fusion.
As apoptosis proceeds, degraded via an proteasome-independent pathway, probably by caspases.
May play a role in apoptosis suppression.
Forms a heterodimer with the catalytic subunit METTL1.
Required for the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA. In the complex, it is required to stabilize and induce conformational changes of the catalytic subunit.
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). The methyl group of m(6)t(6)A37 may improve the efficiency of the tRNA decoding ability. May bind to tRNA.
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.
Homodimer (By similarity). Interacts with CEP152 (via N-terminus) (By similarity). Interacts with CEP78; this interaction may be important for proper PLK4 localization to the centriole and PLK4-induced overduplication of centrioles (By similarity). Interacts with CEP131 (By similarity). Interacts simultaneously with TENT5C and CEP192. Interacts with TENT5C; this interaction leads to the TENT5C recruitment in the centrosome (By similarity).
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 (By similarity). Phosphorylates CEP131 and PCM1 which is essential for proper organization and integrity of centriolar satellites (By similarity).
Ubiquitinated; leading to its degradation by the proteasome.
Transcription factor required for TBX21/T-bet-dependent maturation of Th1 cells as well as maintenance of Th1-specific gene expression. Involved in embryogenesis and hematopoiesis (By similarity).
Accumulates according to a robust circadian rhythm.
Binds DNA as a homodimer or a heterodimer. Can form a heterodimer with DBP.
Expressed exclusively in the rostral portion of the anterior pituitary during embryogenesis. Found in several tissues in juvenile and adult rats.
Expressed up to embryonic day 14 and specifically in the anterior pituitary during embryogenesis.
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'.
Detected in the superior olivary complex and fibers of the ventral aoustic stria of the auditory hindbrain.
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 preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that 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.
At 17 dpc, isoform 2 is expressed in the CNS and PNS. Isoform 2 is expressed at high levels in the dorsal root ganglia, trigeminal ganglia, and throughout the spinal cord with the highest level in the ventral horn.
Homotetramer, and heterotetramer with CRMP1, DPYSL2, DPYSL4 or DPYSL5 (PubMed:9375656). Interacts with synaptic vesicle protein 2 and SH3A domain of intersectin (PubMed:12684468). Interacts with FLNA (By similarity).
Isoform 2 is expressed in growth cones. Up-regulated in motor neurons during axonal regeneration after sciatic nerve lesion. Overexpression of isoform 2 increased neurite extension and branching. Isoform 1 is expressed throughout neurons and their axons.
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.
Component of the ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), a multisubunit enzyme composed of 3 respiratory subunits cytochrome b, cytochrome c1 and Rieske protein, 2 core protein subunits, and additional low-molecular weight protein subunits.
Glycosylation at Asn-70 and Asn-104 promotes adhesive binding and synapse induction.
Homodimer (via Ig-like V-type domain) (By similarity). 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 (By similarity). Interacts (via C-terminus) with EPB41L3/DAL1 (By similarity). The interaction with EPB41L3/DAL1 may act to anchor CADM1 to the actin cytoskeleton (By similarity). Interacts (via C-terminus) with MPP2 (via PDZ domain) (PubMed:27756895). Interacts (via C-terminus) with MPP3 (via PDZ domain) (By similarity). Interacts (via C-terminus) with PALS2 (via PDZ domain) (By similarity).
Mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner. Also mediates heterophilic cell-cell adhesion with CADM3 and NECTIN3 in a Ca(2+)-independent manner. Interaction with CRTAM promotes natural killer (NK) cell cytotoxicity and interferon-gamma (IFN-gamma) secretion by CD8+ T-cells in vitro as well as NK cell-mediated rejection of tumors expressing CADM1 in vivo (By similarity). In mast cells, may mediate attachment to and promote communication with nerves (By similarity). CADM1, together with MITF, is essential for development and survival of mast cells in vivo. 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. 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. 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. Acts as a synaptic cell adhesion molecule and plays a role in the formation of dendritic spines and in synapse assembly. May be involved in neuronal migration, axon growth, pathfinding, and fasciculation on the axons of differentiating neurons. 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).
The cytoplasmic domain appears to play a critical role in proapoptosis and tumor suppressor activity in NSCLC.
Expressed in the CNS, spleen and testis. Specifically expressed in the suprachiasmatic nuclei (SCN) of the hypothalamus.
Expression has a diurnal peak under light/dark cycling, but remains stable under constant darkness.
Implicated in the regulation of circadian rhythms through autocrine and/or paracrine actions. Stimulates the contraction of rectum and elevation of blood pressure.
Interacts (unphosphorylated form, via the PXDLS motif) with CTBP1, competitively inhibiting CTBP-ZEB1 interaction. Interacts with CTBP2. Interacts with MCRIP2. Interacts with DDX6.
Phosphorylation by MAPK3/1 (ERK1/2) regulates MCRIP1 binding to CTBP(s).
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.
Part of the complex catalyzing the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol, the first step of GPI biosynthesis.
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 (By similarity).
Detected in brain, in neurons, including in hippocampal neurons, and glial cells (at protein level). Detected in heart and skeletal muscle.
In cultured hippocampal neurons, expression levels of both isoform 1 and isoform 2 increases with in vitro development, with prominent expression coinciding with the completion of synaptogenesis and persisting through mature stages.
Interacts with various PKC isoforms through the LIM domains (PubMed:8940095). Interacts with actin and alpha-actinin through the PDZ domain (PubMed:10833443). Interacts (via LIM domains) with SIPA1L1/SPAR; this interaction may occur preferentially with isoform 1 (PubMed:19900557).
May play an important role in the heart development by scaffolding PKC to the Z-disk region (PubMed:8940095, PubMed:20097676). May play a role in the regulation of cardiomyocyte expansion (PubMed:20097676). Isoforms lacking the LIM domains may negatively modulate the scaffolding activity of isoform 1 (PubMed:20097676). Overexpression promotes the development of heart hypertrophy. Contributes to the regulation of dendritic spine morphogenesis in neurons (PubMed:20097676). May be required to restrain postsynaptic growth of excitatory synapses. Isoform 1, but not isoform 2, expression favors spine thinning and elongation (PubMed:19900557).
May act as a mediator of the PTEN growth-suppressive signaling pathway. May play a role in developmental processes (By similarity).
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. 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 (By similarity). During T-cell mediated immune response may inhibit dendritic cells (DC) activation and maturation (By similarity).
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 (By similarity). Involved in the regulation of sleep/wake behaviors (By similarity).
Expressed in cortical neurons and coronary artery smooth muscle cells (at protein level).
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 (By similarity). 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.
Involved in the mineralization and structural organization of enamel.
Calcium-regulated non-lysosomal thiol-protease. Proteolytically cleaves CTBP1 at 'His-399'. Mediates, with UTP25, the proteasome-independent degradation of p53/TP53.
Homodimer; via EF-hand domain 4. Interacts with TTN/titin. Interacts with CMYA5; this interaction, which results in CMYA5 proteolysis, may protect CAPN3 from autolysis. Interacts with SIMC1. Interacts with UTP25; the interaction is required for CAPN3 translocation to the nucleolus.
Forms disulfide-linked homodimers at the cell surface. Interacts with LCK. Interacts with PTK2/FAK1. Binds to P4HB/PDI. Interacts with IL16; this interaction induces a CD4-dependent signaling in lymphocytes. 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.
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 plays an important role for CD4 internalization.
The Ig-like V-type domain mediates the interaction with MHCII.
Acts in vitro to stimulate the secretion of adrenocorticotropic hormone (ACTH) (PubMed:7477349). Binds with high affinity to CRF receptor types 1, 2-alpha, and 2-beta (By similarity). Plays a role in the establishment of normal hearing thresholds (By similarity). Reduces food intake and regulates ghrelin levels in gastric body and plasma (PubMed:21540451).
Interacts with CRHR1 and CRHR2 (via their N-terminal extracellular domain).
Acetylated at Ala-35 following proteolytic cleavage at Leu-34.
Myristoylated at Gly-427 following proteolytic cleavage at Asp-426.
Part of a complex required for lens intermediate filament formation composed of BFSP1, BFSP2 and CRYAA (By similarity). 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 (By similarity). Involved in altering the calcium regulation of MIP water permeability (By similarity).
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 ubiquitously with highest concentrations found in placenta, kidney, spleen, ovary, heart and lung.
Forms a heterodimer, consisting of a large extracellular region non-covalently linked to a seven-transmembrane moiety.
Expressed in adult tissues such as aorta, heart, kidney, lung, muscle and thyroid. Weakly expressed in thyroid and not detected in liver.
Parietal cells, pancreas, brain and various neoplastic tissues.
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.
Major protein kinase C substrate of platelets.
Belongs to the phytoene/squalene synthase family.
Catalyzes the condensation of 2 farnesyl pyrophosphate (FPP) moieties to form squalene (PubMed:9575210). Proceeds in two distinct steps. In the first half-reaction, two molecules of FPP react to form the stable presqualene diphosphate intermediate (PSQPP), with concomitant release of a proton and a molecule of inorganic diphosphate. In the second half-reaction, PSQPP undergoes heterolysis, isomerization, and reduction with NADPH or NADH to form squalene. It is the first committed enzyme of the sterol biosynthesis pathway (By similarity).
Defects in Lss and Fdft1 are the cause of Shumiya cataract rat (SCR). This strain develop mature cataracts at around 11 weeks of age, exhibiting opacity from the perinuclear zone to the cortical intermediate layer. Cholesterol levels in cataractous lenses decreased to about 57% of normal. Cholesterol insufficiency may cause the deficient proliferation of lens epithelial cells in Shumiya cataract rats, resulting in the loss of homeostatic epithelial cell control of the underlying fiber cells and ultimately cataractogenesis.
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)). Interacts with PET100.
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 (By similarity).
The Ubiquitin-like domain mediates interaction with proteasomes.
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 (By similarity). May also play a role in cyclic-nucleotide-mediated signaling through the regulation of adenylate and guanylate cyclases (PubMed:15336960).
Myristoylation facilitates association with membranes.
Neuron-specific in the hippocampus (PubMed:1280427). Also detected in olfactory eptihelium (PubMed:15336960).
Oligomer; oligomerization is calcium-dependent. May interact with the voltage-dependent P/Q- and N-type calcium channels CACNA1A and CACNA1B.
Binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes microtubule growth and microtubule bundling. Links cytoplasmic vesicles to microtubules and thereby plays an important role in intracellular vesicle trafficking. Plays a role macropinocytosis and endosome trafficking.
Interacts with MTOR; phosphorylates and regulates CLIP1. Interacts (via CAP-Gly domains) with tubulin and TUBA1B. Interacts with SLAIN2. Interacts with MAPRE1 and MAPRE3 (By similarity). Interacts (via zinc finger) with DCTN1 (PubMed:20519438, PubMed:26972003). Binds preferentially to tyrosinated microtubules, and only marginally to detyrosinated microtubules (PubMed:26972003).
Intramolecular interaction between the zinc finger domain and the CAP-Gly domains may inhibit interaction with tubulin.
Phosphorylated. Phosphorylation induces conformational changes by increasing the affinity of the N-terminus for C-terminus, resulting in inhibition of its function thus decreasing its binding to microtubules and DCTN1. Exhibits a folded, autoinhibited conformation when phosphorylated and an open conformation when dephosphorylated with increased binding affinity to microtubules and DCTN1. Phosphorylation regulates its recruitment to tyrosinated microtubules and the recruitment of vesicular cargo to microtubules in neurons (PubMed:20519438, PubMed:26972003). Phosphorylation by MTOR may positively regulate CLIP1 association with microtubules (By similarity).
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).
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. Promotes assembly of stress granules (SGs), when overexpressed (By similarity).
Interacts with EIF4G1. Associates with ribosomes (By similarity).
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 (By similarity).
Binds DNA as a dimer. May form homodimers (By similarity). Interacts with ATF6 (By similarity). 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) (By similarity).
N-glycosylation is required for optimal proteolytic activation.
Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes. Activated in response to cAMP stimulation. Binds the cAMP response element (CRE). Activates transcription through box-B element and CRE. Seems to function synergistically with ATF6. In acute inflammatory response, may activate expression of acute phase response (APR) genes (By similarity). 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 (By similarity).
Ubiquitinated at Lys-290 by SYNV1/HRD1 via 'Lys-27'-linked ubiquitin.
Acts as a ligand for C-C chemokine receptor CCR6. Signals through binding and activation of CCR6 and induces a strong chemotactic response and mobilization of intracellular calcium ions. 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 autoimmune diseases. CCL20 acts as a chemotactic factor that attracts lymphocytes and, slightly, neutrophils, but not monocytes. Involved in the recruitment of both the pro-inflammatory IL17 producing helper T-cells (Th17) and the regulatory T-cells (Treg) to sites of inflammation. Required for optimal migration of thymic natural regulatory T cells (nTregs) and DN1 early thymocyte progenitor cells. Positively regulates sperm motility and chemotaxis via its binding to CCR6 which triggers Ca2+ mobilization in the sperm which is important for its motility. May be involved in formation and function of the mucosal lymphoid tissues by attracting lymphocytes and dendritic cells towards epithelial cells.
By TNF in experimental allergic panencaphalomyelitis (EAP) and by TNF and IL-1 in primary astrocytes.
Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate. GlcNAcylation by OGT overcomes allosteric regulation (By similarity).
Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis (By similarity). 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 (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 (M), PFKL (L) and PFKP (P). The composition of the PFK tetramer differs according to the tissue type it is present in. The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues (Probable).
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 (By similarity).
May play a role in hematopoietic cell proliferation or differentiation. Potential mediator of neuronal apoptosis.
Ubiquitously expressed in all tissues examined with highest levels in the brain and testis. Strongly expressed in the pyramidal and granule neurons of the hippocampus and also in the cerebellum.
Weakly expressed in the cerebellum by 20 dpc, levels increase until 28 days after birth.
Exclusively expressed in brain, predominantly in the cerebellum.
Interacts with STX1A and/or STX1B1, VAMP2 and SNAP25.
May play a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. May be involved in the regulation of synaptic transmission at parallel fiber - Purkinje cell synapses (By similarity).
Expressed exclusively in olfactory receptor neurons and their precursors.
Homodimer (By similarity). Interacts with ZNF423 and ZNF521, leading to prevent EBF1 to bind DNA and activate target genes (PubMed:9151733). Interacts with CCR4-NOT component CNOT3 (By similarity).
Key pioneer transcription factor of B-cell specification and commitment. 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.
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.
Belongs to the complex I NDUFB4 subunit family.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM3 sub-subfamily.
Homodimer; the dimers can form tetramers (By similarity). Interacts with NALCN (By similarity). Interacts with TMEM147 (By similarity).
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 (By similarity). 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 (By similarity). May play a key role in the early steps of melanogenesis producing PMEL amyloid fibrils (By similarity). 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 (By similarity). In addition may play a role in the transition metal homeostasis (PubMed:18160489).
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.
To date, the intracellular localization of ABCB6 is a matter of debate, with conflicting reports suggesting mitochondrial or endolysosomal localization, therefore questioning the requirement of ABCB6 in the mitochondrial import of porphyrins.
Ubiquitously expressed. Highly expressed in testis by meiotic pachytene spermatocytes and post-meiotic early spermatids.
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Epsilon/CHRNE sub-subfamily.
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 (By similarity).
V-shaped homodimer. Interacts with CDC16. 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.
Catalyzes the conversion of xanthine monophosphate (XMP) to GMP in the presence of glutamine and ATP through an adenyl-XMP intermediate.
Expressed in the testis, brain, thymus and ovary.
Highly expressed in embryonic cerebral cortex between day 18 and up to birth. Expression levels decrease after birth (at protein level).
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 (PubMed:17068200). Interacts with MILR1 (tyrosine-phosphorylated) (By similarity). Interacts with KIT (By similarity). Interacts with SIRPA/PTPNS1 (By similarity). Interacts with FCRL2 and FCRL4 (By similarity). Interacts with CD84 (By similarity). Interacts with CD300LF (By similarity). Interacts with CDK2 (By similarity). Interacts with KIR2DL1; the interaction is enhanced by ARRB2 (By similarity). Interacts (via SH2 1 domain) with ROS1; the interaction is direct and promotes ROS1 dephosphorylation (By similarity). Interacts with EGFR; inhibits EGFR-dependent activation of MAPK/ERK (By similarity). Interacts with LYN (By similarity). Interacts with the tyrosine phosphorylated form of PDPK1 (By similarity). 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) (By similarity). Interacts with KLRI1 and KLRI2 (PubMed:18713988). 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-566 enhances phosphatase activity (By similarity).
The N-terminal SH2 domain functions as an auto-inhibitory domain, blocking the catalytic domain in the ligand-free close conformation.
Associates with TRADD. Interacts with NGFR. Interacts with N-APP (By similarity).
Detected at low levels in embryonic brain. Expression is increased in newborns and during the first two weeks after birth. Expression decreases thereafter and is low after three weeks and in adult life.
Detected in brain (at protein level). Detected in corpus callosum oligodendrocytes. Detected in embryonic and adult brain.
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). 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 (By similarity). Negatively regulates oligodendrocyte survival, maturation and myelination.
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 (By similarity).
Binds PAWR, POLR2J, RB1/RB, RBL1/P107, RBL2/P130 and SP1 (By similarity). Binds DAPK3/ZIPK and TSG101. May also bind MAPT.
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. May negatively regulate the pro-apoptotic activity of DAPK3/ZIPK. Can act cooperatively with TSG101 to stimulate AR mediated transcription activation (By similarity). May negatively regulate the pro-apoptotic activity of DAPK3/ZIPK. Can act cooperatively with TSG101 to stimulate AR mediated transcription activation.
Expressed in the brain, liver, testes and anterior prostate (at protein level).
Glutathionylated. N-glycosylated (PubMed:14749213).
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 (By similarity). Interacts with catalytic subunit ATP12A (PubMed:14749213). Interacts with regulatory subunit FXYD1 (PubMed:23532852). Interacts with regulatory subunit FXYD3 (PubMed:15743908). Interacts with NKAIN1, NKAIN2 and NKAIN4 (By similarity). Interacts with MLC1 (By similarity). Part of a complex containing MLC1, TRPV4, AQP4 and HEPACAM (By similarity). Interacts with KIRREL3 (By similarity). Interacts with OBSCN (via protein kinase domain 1) (By similarity). Interacts with TRAF3 and TRAF6 (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 beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane (PubMed:22328500). 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 (By similarity).
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 contributing to the responsiveness of the spindle assembly checkpoint. Also required for degradation of CDC20 (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.
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).
Detected at low levels in fetal brain, and at high levels in adult brain.
Nicotinic acid adenine dinucleotide phosphate (NAADP) binding protein required for NAADP-evoked intracellular calcium release. Confers NAADP-sensitivity to the two pore channels (TPCs) complex (By similarity). Enables NAADP to activate Ca(2+) release from the endoplasmic reticulum through ryanodine receptors (PubMed:33758062).
Specific and highly efficient GDP-D-glucose phosphorylase regulating the levels of GDP-D-glucose in cells.
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1 (Probable). 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).
Regulatory subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Regulates channel inactivation kinetics.
A phosphorylation cycle of C-terminal serine cluster (Ser-825-Ser-835) 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.
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). 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. 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). Interacts with FMR1. Interacts with ZFP36. Interacts with RC3H1; the interaction is RNA independent (By similarity). Found in a complex, composed of AGO2, CHD7 and FAM172A (By similarity). Interacts with SND1 and SYT11 (PubMed:24882364). Interacts with CLNK (By similarity). Interacts with GARRE1 (By similarity).
Phosphorylation at Ser-388 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). 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 AGO2 when it is engaged with a TDMD target.
Was originally thought to be membrane-associated.
Involved in vesicle trafficking and required for ciliogenesis, formation of primary non-motile cilium, and recruitment of RAB8A to the basal body of primary cilium. 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 neuronal differentiation. As a positive modulator of classical Wnt signaling, may play a crucial role in ciliary signaling during cerebellum embryonic development.
Self-associates. Part of the tectonic-like complex (also named B9 complex). Interacts with MKS1. Interacts with NPHP1; probably as heterodimers and/or AHI1(2):NPHP1(2) heterotetramers. Interacts (via SH3 domain) with the dynamin GTPase DNM2. Interacts with HAP1; probably as AHI1(2):HAP1(2) heterotetramers. Interacts with RAB8A. Interacts with CEND1 (By similarity). Interacts with SPATA7 (By similarity).
Dorsal root ganglia neurons (at protein level). High levels in spleen, thymus and skeletal muscle, intermediate levels in lung, uterus, pituitary and heart, low levels in brain, and undetected in adrenal gland and liver.
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. Synthesis of iGb3 is the initial step in the formation of the isoglobo-series glycolipid pathway and is the precursor to isogloboside 4 (iGb4) and isoForssman glycolipids. Can glycosylate only lipids and not proteins and is solely responsible for initiating the synthesis of isoglobo-series glycosphingolipids.
Belongs to the importin beta family. Importin beta-1 subfamily.
Forms a complex with an importin alpha subunit (By similarity). Interacts with XPO1 (By similarity). Forms a heterodimer with IPO7 (By similarity). The KPNB1/IPO7 heterodimer interacts with H1 histone (By similarity). Interacts with SNUPN (By similarity). Interacts with H2A, H2B, H3 and H4 histones (By similarity). Component of an import snRNP complex composed of KPNB1, SNUPN, SMN1 and ZNF259 (By similarity). Component of a nuclear export receptor complex composed of KPNB1, Ran, SNUPN and XPO1 (By similarity). Interacts with SRY (By similarity). Interacts with PRKCI/atypical protein kinase C iota (By similarity). Interacts with KPNA2 (By similarity). Interacts with KPNA7 (By similarity). Interacts with SNAI1 (via zinc fingers) and SNAI2 (via zinc fingers) (By similarity). Interacts with SLC35G1 and STIM1 (By similarity). Interacts with DCAF8 (By similarity). Interacts with RAN (By similarity). Interacts with NUMA1 (via C-terminus); this interaction is inhibited by RanGTP (By similarity). Interacts with ZBED1/hDREF; required for nuclear import of ZBED1/hDREF (By similarity). Interacts with SRP19 (By similarity). Interacts with RPL23A (via BIB domain), RPS7 and RPL5 (By similarity). Interacts with PARP16 (By similarity).
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. In association with IPO7, mediates the nuclear import of H1 histone. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. Imports SNAI1 and PRKCI into the nucleus (By similarity).
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 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)) (By similarity). Found in a complex with TMEM177, COA6, COX18, COX20, SCO1 and SCO2. Interacts with TMEM177 in a COX20-dependent manner. Interacts with COX20. Interacts with COX16 (By similarity).
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)) (By similarity). Found in a complex with TMEM177, COA6, COX18, COX20, SCO1 and SCO2. Interacts with TMEM177 in a COX20-dependent manner. Interacts with COX20. Interacts with COX16.
Has a key role in phospholipid metabolism, and catalyzes the first step of phosphatidylethanolamine and phosphatidylcholine biosynthesis.
Component of the TIM22 complex, whose core is composed of TIMM22, associated with peripheral protein FXC1/TIMM10B and the 70 kDa heterohexamer. In most cases, the 70 kDa complex is composed of TIMM9 and TIMM10 (TIMM10A or TIMM10B). A small fraction of the 70 kDa complex is composed of TIMM8 (TIMM8A/DDP1 or TIMM8B/DDP2) and TIMM13. The TIM22 complex also contains AGK and TIMM29. Interacts directly with TIMM9, TIMM10A and FXC1/TIMM10B. Interacts (when oxidized) with TIMM29; interaction is direct.
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).
Key enzyme in the regulation of glycerol uptake and metabolism (By similarity). Increases the binding of activated glucocorticoid-receptor to nuclei in the presence of ATP.
Expressed specifically by the oligodendrocytes. Highest expression seen in the spinal cord followed by brainstem, cerebellum, thalamus, and hypothalamus. In the myelin sheath, found mainly in the abaxon and the lateral few terminal loops. Its apposition to the myelinated axon, through the latter, defines an axonal subregion, termed juxtanode, at the Ranvier node-paranode junction.
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).
Undetected at postnatal day 1 (P1) through P7. Expressed weakly at P10, rapidly increases during the period P14 to P21 and reaches adult levels by P28.
Homodimer. Homodimerization via its N-terminal domain. Interacts with HDAC7. Interacts with MEF2A, MEF2C, MEF2D, MORC2 and NR2C1. Interacts with a 14-3-3 chaperone proteins in a phosphorylation dependent manner. Interacts with 14-3-3 protein YWHAB (By similarity). Interacts with KDM5B and AHRR (By similarity). Interacts with BTBD14B (PubMed:16033423). Interacts with MYOCD. Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2. Interacts with EP300 in the presence of TFAP2C. Interacts with HSPA1A and HSPA1B leading to their deacetylation at 'Lys-77' (By similarity). 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).
Phosphorylated by CaMK4 at Ser-245, Ser-466 and Ser-630. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-349, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high-affinity docking site for 14-3-3 (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 via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1.
Sumoylation on Lys-557 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4.
The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.
Interacts with GABA(A) receptor subunits (PubMed:28279354). Interacts with GABRB3 (By similarity). Interacts with GABRA2 (By similarity). Interacts with GABRG2 (By similarity). Interacts with GABRA1 (PubMed:28279354). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (PubMed:28279354). 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.
Alpha-1,6-mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the second mannose to the glycosylphosphatidylinositol during GPI precursor assembly (By similarity).
Belongs to the eukaryotic-type N-acetylglucosamine kinase family.
Converts endogenous N-acetylglucosamine (GlcNAc), a major component of complex carbohydrates, from lysosomal degradation or nutritional sources into GlcNAc 6-phosphate. Involved in the N-glycolylneuraminic acid (Neu5Gc) degradation pathway. Also has ManNAc kinase activity.
Inhibited by the cysteine modifiers iodoacetamide, N-ethylmaleimide and 5,5'-dithiobis(2-nitrobenzoic acid).
Brain, testis and pituitary gland. Expression is higher in the brain than in the testis and pituitary gland. Highest level expression seen in the developing CNS.
Detected at 11.5 dpc and expression is seen throughout the proliferating cortex neuroepithelium, developing medulla, and spinal cord. At 12.5 dpc found in the nasal epithelium and at 13.5 dpc detected in the trigeminal ganglia, dorsal root ganglia and the ganglion cell layer of the retina. At 14 dpc to 15 dpc, expressed at high levels in the brain and spinal cord and then levels subsequently decrease.
Transcription factor that plays a key role in neuronal differentiation (PubMed:9373037). Acts by specifically repressing expression of non-neuronal genes during neuron differentiation (By similarity). In contrast to other transcription repressors that inhibit specific lineages, mediates repression of multiple differentiation programs (By similarity). Also represses expression of negative regulators of neurogenesis, such as members of the Notch signaling pathway, including HES1 (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). Directly binds the 5'-AAGTT-3' core motif present on the promoter of target genes and represses transcription by recruiting a multiprotein complex containing SIN3B (By similarity). The 5'-AAGTT-3' core motif is absent from the promoter of neural genes (By similarity).
Belongs to the PF07175/osteoregulin family.
Cleaved by CTSB/cathepsin B; the cleavage is blocked by metalloprotease PHEX.
Expressed in osteoblasts and osteocytes.
Interacts (via ASARM motif) with PHEX; the interaction is zinc-dependent.
Phosphorylated on serine residues in the ASARM motif; the phosphorylation is important for the inhibition of bone mineralization.
Regulates renal phosphate excretion (By similarity). Regulates bone mineralization by osteoblasts and cartilage mineralization by chondrocytes (By similarity). Regulates the mineralization of the extracellular matrix of the craniofacial complex, such as teeth, bone and cartilage (By similarity). Increases dental pulp stem cell proliferation.
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. It can also inhibit dentin mineralization.
The dentonin region is sufficient to promote dental pulp stem cell proliferation. It can also stimulate bone formation, osteoblast differentiation, and activate integrin signaling pathways.
Lacks ADP-ribosylation enhancing activity.
Low amounts were found in most tissues examined with highest levels in brain, intestine and thymus.
Binds SUMO1 and UBE2I. Interacts with AR, BCL11A, GFI1, HMGA2, IRF1, MITF, NCOA2, as well as with STAT3, after treatment with IL6, CNTF or OSM and with STAT5, after PRL stimulation. Interacts with PLAG1 (By similarity). Interacts with ZFHX3. Interacts with MTA1. Interacts with CCAR2 (via N-terminus) (By similarity). Interacts with TRIM8 (By similarity). Interacts with PRDM1 (By similarity).
Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway and the steroid hormone signaling pathway. The effects of this transcriptional coregulation, transactivation or silencing, may vary depending upon the biological context. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Sumoylates CCAR2 which promotes its interaction with SIRT1. Diminishes the sumoylation of ZFHX3 by preventing the colocalization of ZFHX3 with SUMO1 in the nucleus (By similarity).
Has been shown to interact with voltage-gated potassium channels, including the KCNB1 subunit, and to be critical for current enhancement. However, in view of its mostly nuclear subcellular location and its established function as a transcriptional coregulator, promoting the sumoylation of several transcription factors, the effect on potassium channels awaits further experimental confirmation.
Widely expressed, with highest levels in lung, kidney and spleen.
Activity is strongly promoted by Co(2+), Ni(2+), Mg(2+) and Mn(2+). Activity is inhibited by EDTA.
Despite belonging to the type II pantothenate kinase family, the pantothenate kinase domain contains a Val residue at position 147 and a Trp residue at position 211 instead of the two conserved active site residues, Glu and Arg. Lacks pantothenate kinase activity.
In the C-terminal section; belongs to the damage-control phosphatase family. Phosphopantetheine phosphatase (II) subfamily.
In the N-terminal section; belongs to the type II pantothenate kinase family.
Phosphatase which shows a preference for 4'-phosphopantetheine and its oxidatively damaged forms (sulfonate or S-sulfonate), providing strong indirect evidence that the phosphatase activity pre-empts damage in the coenzyme A (CoA) pathway. Hydrolyzing excess 4'-phosphopantetheine could constitute a directed overflow mechanism to prevent its oxidation to the S-sulfonate, sulfonate, or other forms. Hydrolyzing 4'-phosphopantetheine sulfonate or S-sulfonate would forestall their conversion to inactive forms of CoA and acyl carrier protein. May play a role in the physiological regulation of CoA intracellular levels.
Subfamily II proteins have an EGMGR motif about 50 residues from the C-terminus (By similarity). This motif lies near the metal-binding residues in the putative substrate-binding cleft 2 (By similarity). Subfamily II proteins occur only in eukaryotes, in two forms: as a stand-alone unit in plants, and as a C-terminal domain of pantothenate kinases in plants, animals, and chytrid fungi (By similarity).
Belongs to the WD repeat LIS1/nudF family.
Can self-associate. 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 DCX, dynactin, IQGAP1, KATNB1, NDE1, 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. Interacts with dynein and NDEL1 (PubMed:11163260, PubMed:16481446). Interacts with INTS13. Interacts with DCDC1 (By similarity).
Dimerization mediated by the LisH domain may be required to activate dynein.
Expressed in most tissues, with highest expression in brain. Expressed in fetal and adult brain. In neural cells, expressed in granule cells, astroglial cells, and oligodendrocytes (PubMed:9660828).
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. 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 (By similarity). May modulate the Reelin pathway through interaction of the PAF-AH (I) catalytic dimer with VLDLR (By similarity).
Expressed in neurons cells of neuropil-rich areas of the brain, in the Purkinje cells of the cerebellum, in cells of the cerebral cortex, hippocampus, brainstem nuclei and glial processes and sheaths. Expressed in the medulla of the adrenal chromaffin cells and renal duct cells (at protein level).
Expressed in pyramidal neurons of the hippocampus at 18 dpc.
Involved in plasma membrane dynamics and cell process formation. Necessary for axonal and dendritic filopodia induction, for dendritic spine maturation and synapse formation in a palmitoylation-dependent manner (By similarity).
Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.
Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN4. Interacts with CAVIN1, CAV3, ADRA1A and ADRA1B. Interacts with CAVIN2; this augments the transactivation of NPPA (By similarity). Interacts with MAPK1 and MAPK3 (PubMed:24567387).
Expressed at much higher levels in cardiomyocytes than in non-cardiomyocytes.
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).
Interacts with MCL1 (By similarity). Interacts with BCL2A1 (By similarity). Interacts with BAX (By similarity). Interacts with BCL2L10 (By similarity).
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 and with BIM/BCL2L11 for binding to MCL1; can displace BAK1 and BIM/BCL2L11 from their binding sites (By similarity).
The BH3 motif is essential for pro-apoptotic activity.
May function as an inhibitor of Wnt/beta-catenin signaling by indirectly interacting with LRP6 and blocking Wnt3a-dependent LRP6 internalization.
The C-terminus of LRR N-terminal cap (LRRNT) and LRR 1 are essential for the inhibition of the Wnt signaling pathway.
Interacts with TGFB1I1 (PubMed:11134073). Interacts with LIMS1 (via LD motifs) (By similarity). Interacts with ARHGAP31 (By similarity). Interacts with the actin cytoskeleton (PubMed:11134073). Interacts (via C-terminus) with ILK (By similarity). 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:11134073).
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.
Detected in brain stem, brain cortex, cerebellum, stomach, colon, heart, lung, liver, spleen and kidney. Detected in utricle, cochlea, outer hair cell bundle cuticular plate and vestibular epithelia (at protein level). Detected in cochlea and vestibular tissues. Detected in kidney, lung, spleen and intestine.
Interacts with CALM and F-actin (PubMed:7730414). Interacts (via SH3 domain) with SYNJ1, DNM1 and DNM2. Interacts with ARL14EP. Interacts with CARMIL1 (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. 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 (By similarity). 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 (By similarity).
Component of the spliceosome B complex. Associated with U2 snRNPs. Binds splicing factors SNRPB, SNRPC and SF1 (By similarity). 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 (By similarity). Interacts with SNRNP200 (By similarity).
Involved in pre-mRNA splicing as a component of the spliceosome. May play a role in cross-intron bridging of U1 and U2 snRNPs in the mammalian A complex.
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.
A disulfide bond is formed between rather than within filaments and promotes the formation of a keratin filament cage around the nucleus.
Expressed in most cells of squamous cell carcinomas, in spinous and suprabasal cells around the branching papillary region of papillomas, and weakly in a few proliferative cells of hyperplastic tissue.
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) (By similarity). Forms a heterodimer with KRT1; the interaction is more abundant in the absence of KRT5 (By similarity). Interacts with TRADD and with keratin filaments (By similarity). Associates with other type I keratins (By similarity). Interacts with EPPK1 (By similarity). Interacts with KLHL24 (By similarity). Interacts with PKP1 (via N-terminus) and PKP2 (By similarity).
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.
Belongs to the GTP cyclohydrolase I family.
By cytokines such as insulin, interferon-gamma, and phytohemagglutinin in adrenal gland, macrophages, and T-cell respectively.
GTP shows a positive allosteric effect, and tetrahydrobiopterin inhibits the enzyme activity. Zinc is required for catalytic activity. Inhibited by Mg(2+).
May positively regulate nitric oxide synthesis in endothelial cells. May be involved in dopamine synthesis (By similarity). May modify pain sensitivity and persistence.
Toroid-shaped homodecamer, composed of two pentamers of five dimers. Interacts with AHSA1 and GCHFR/GFRP.
Forms homodimers and heterodimers with PHETA. Interacts with OCRL and INPP5B.
High-affinity sodium/citrate cotransporter that mediates citrate entry into cells, which is a critical participant of biochemical pathways (PubMed:12177002, PubMed:12826022, PubMed:14656221). May function in various metabolic processes in which citrate has a critical role such as energy production (Krebs cycle), fatty acid synthesis, cholesterol synthesis, glycolysis, and gluconeogenesis (By similarity). Transports citrate into the cell in a Na(+)-dependent manner, recognizing the trivalent form of citrate (physiological pH) rather than the divalent form (PubMed:12177002, PubMed:12826022, PubMed:14656221). Can recognize succinate as a substrate, but its affinity for succinate is several fold lower than for citrate (PubMed:12177002, PubMed:14656221). The stoichiometry is probably 4 Na(+) for each carboxylate, irrespective of whether the translocated substrate is divalent or trivalent, rendering the process electrogenic (PubMed:12177002, PubMed:14656221). Involved in the regulation of citrate levels in the brain (By similarity).
Detected in embryonic cerebellum, in spinal cord motor neurons and in dorsal root ganglia (PubMed:12426574). Detected in adult brain, in neocortex, hippocampus, striatum, thalamus and dorsal root ganglion neurons (at protein level).
Homodimer (By similarity). Interacts with MAG (PubMed:15673660, PubMed:19420245). Interacts with RTN4 and OMG (PubMed:15673660, PubMed:19420245). Interacts with LINGO1 and NGFR (By similarity). Interacts with KIAA0319L (By similarity). Interacts with OLFM1; this inhibits interaction with LINGO1 and NGFR (By similarity).
N-glycosylated. O-glycosylated. Contains terminal sialic acid groups on its glycan chains.
Receptor for RTN4, OMG and MAG (PubMed:12037567, PubMed:15673660, PubMed:19420245). Functions as receptor for the sialylated gangliosides GT1b and GM1. Besides, functions as receptor for chondroitin sulfate proteoglycans. Can also bind heparin. Intracellular signaling cascades are triggered via the coreceptor NGFR (By similarity). Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton (PubMed:18411262). Mediates axonal growth inhibition (PubMed:12037567). May play a role in regulating axon regeneration and neuronal plasticity in the adult central nervous system. Plays a role in postnatal brain development. Required for normal axon migration across the brain midline and normal formation of the corpus callosum (By similarity). Protects motoneurons against apoptosis; protection against apoptosis is probably mediated via interaction with MAG (PubMed:26335717). Acts in conjunction with RTN4 and LINGO1 in regulating neuronal precursor cell motility during cortical development. Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development (PubMed:22325200).
Belongs to the class I-like SAM-binding methyltransferase superfamily. CLNMT methyltransferase family.
Catalyzes the trimethylation of 'Lys-116' in calmodulin.
Monomer (Probable). Interacts with HSP90, probably as a client (By similarity).
Aldehyde oxidase able to catalyze the oxidation of retinaldehyde into retinoate. Acts as a negative modulator of the epidermal trophism. May be able to oxidize a wide variety of aldehydes into their corresponding carboxylates and to hydroxylate azaheterocycles (By similarity).
Possible splicing regulator involved in the control of cellular survival.
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.
Interacts with ARF1. Interacts with the COPI coat proteins, KDELR1 and TMED2. It is probably a component of the COPI coat protein complex. The interaction with TMED2 inhibits the GAP activity.
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.
Widely expressed. Highly expressed in brain and liver.
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 (via the PDZ-binding motif) with GPOC (via its PDZ domain). Interacts with RSPO1 and RSPO3 (By similarity). Interacts with glypican GPC3 (By similarity).
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 signalsomes. 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 (By similarity).
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. Interacts with MBOAT7; the interaction facilitates MBOAT7 location to mitochondria-associated membranes (MAMs).
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. Plays a role in MBOAT7 location to mitochondria-associated membranes (MAMs), may me involved in fatty acid remodeling phosphatidylinositol (PI).
Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron (PubMed:3865203, PubMed:1935972, PubMed:1575508). Affords protection against programmed cell death and this cytoprotective effect relies on its ability to catabolize free heme and prevent it from sensitizing cells to undergo apoptosis (By similarity).
Induced by its substrate heme and CoCl2.
Brain, kidney, lung, heart, spleen, muscle and liver.
Forms a ternary complex of about 140 to 150 kDa with IGF-I or IGF-II and IGFBP-3.
May have an important role in regulating the access of circulating IGFs to the tissues.
mRNA-binding protein involved in proper cytoplasmic distribution of mitochondria. Specifically binds mRNAs of nuclear-encoded mitochondrial proteins in the cytoplasm and regulates transport or translation of these transcripts close to mitochondria, playing a role in mitochondrial biogenesis.
Belongs to the metallo-dependent hydrolases superfamily. HutI family.
Cell surface proteoglycan that bears heparan sulfate. Regulates exosome biogenesis in concert with SDCBP and PDCD6IP.
Homodimer. Interacts with CDCP1 and SDCBP. Interacts (via its cytoplasmic domain) with GIPC (via its PDZ domain). Interacts (via its cytoplasmic domain) with NUDT16L1 (By similarity).
Expression is low during embryogenesis and increases around postnatal day 21.
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) (By similarity). Interacts with ADRA2B (By similarity).
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. Required for hepatocyte growth factor (HGF)-induced cell migration (By similarity).
Stimulation of D1 (but not D2) dopamine receptors induces Ser-94 and Ser-177 phosphorylation. Dephosphorylation of these residues is mediated by PP1 and possibly PP2A. Spinophilin unphosphorylated or phosphorylated at Ser-94 is concentrated in the postsynaptic density, whereas spinophilin phosphorylated at Ser-177 is absent from the postsynaptic density and enriched in the cytosol. Phosphorylation of spinophilin disrupts its association with F-actin, but does not affect its binding to PP1.
Ubiquitous. Abundantly expressed in the brain. Expressed at highest levels in hippocampus and at lower levels in the cortex, cerebellum and brainstem. Localizes to the dendritic spines of neurons. Also localizes to aspiny neurons, such as GABAergic interneurons.
Immunoglobulin-like receptor which plays an inhibitory role in degranulation of mast cells. Negatively regulates IgE-mediated mast cell activation and suppresses the type I immediate hypersensitivity reaction (By similarity).
Mast cell-specific. Expressed in primary and transformed mast cells.
Monomer. Interacts (tyrosine-phosphorylated) with PTPN6, PTPN11 and INPP5D.
Up-regulated in response to mast cell activation.
Expressed in brain, heart, skin and in costameres of myoplasm at the sarcolemmal membrane in skeletal and cardiac muscle fibers. Undifferentiated gonads and somatic cells of ovarian cords throughout the fetal ovary development.
Found in somatic cells of ovarian cords throughout the fetal ovary development.
Heterotetramer of two type I and two type II keratins. Interacts with PNN (By similarity). Interacts with the actin-binding domain of DMD.
Involved in the organization of myofibers. Together with KRT8, helps to link the contractile apparatus to dystrophin at the costameres of striated muscle (By similarity).
This keratin differs from all other IF proteins in lacking the C-terminal tail domain.
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).
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.
Monomer. Homodimer. Interacts with CPS1. Interacts with PCCA (By similarity).
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. Activates SHMT2 by mediating its desuccinylation. 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.
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 (By similarity). Through this complex, may interact with ERLEC1 and HSPA5 (By similarity). Interacts with HSP90B1 (By similarity). Interacts with CREB3 (By similarity).
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 (By similarity).
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.
Transcription factor. Binds to specific sequence motif 5'-TAATTA-3' in regulatory elements of target genes, such as histone demethylase KDM5C. Positively modulates transcription of KDM5C. 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. Required for normal brain development (By similarity). Plays a role in neuronal proliferation, interneuronal migration and differentiation in the embryonic forebrain. May also be involved in axonal guidance in the floor plate (By similarity).
Interacts with ATG5; the interaction is direct. Interacts with WIPI2. Interacts with the ATG5-ATG12 conjugate, the interaction is however mutually exclusive with ATG16, since it does not interact with ATG12-ATG5-ATG16 complex.
Tethering factor involved in autophagy. Involved in autophagosome maturation by promoting the autophagosome fusion with lysosomes: acts by associating with both the ATG5-ATG12 conjugate and phosphatidylinositol-3-phosphate (PtdIns(3)P) present at the surface of autophagosomes. Also involved in selective autophagy against bacterial pathogens, by being required for phagophore/preautophagosomal structure biogenesis and maturation (By similarity).
The PH domain mediates the binding to phosphatidylinositol-3-phosphate (PtdIns(3)P).
Homodimer. Interacts (via MIT domain) with CHMP1A, CHMP1B, CHMP2A and IST1 (By similarity).
Required for efficient abscission at the end of cytokinesis, together with components of the ESCRT complexes. Seems not to be involved in endosomal transport (By similarity).
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.
Cytochrome b5 is a membrane-bound hemoprotein functioning as an electron carrier for several membrane-bound oxygenases. It is also involved in several steps of the sterol biosynthesis pathway, particularly in the C-6 double bond introduction during the C-6 desaturation.
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 (By similarity).
Activated by GUCA1B when free calcium ions concentration is low, and inhibited by GUCA1B when free calcium ions concentration is high (By similarity). Inhibited by RD3 (By similarity).
Homodimer (PubMed:9153227). 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. Plays an essential role in phototransduction, by mediating cGMP replenishment (PubMed:7831337). May also participate in the trafficking of membrane-asociated proteins to the photoreceptor outer segment membrane (By similarity).
Homodimer (PubMed:10099786). Interacts with TBP (By similarity). Interacts with TAF1A (By similarity). Interacts with PHF6 (By similarity). Interacts with CEBPA (isoform 1 and isoform 4) (PubMed:20075868). Interacts with DDX11 (By similarity). Interacts with NOP53 (By similarity). Interacts with RASL11A (By similarity). Interacts with DHX33 (By similarity). Binds to IRS1 and PIK3CA (By similarity). Interacts with ALKBH2.
Recognizes the ribosomal RNA gene promoter and activates transcription mediated by RNA polymerase I through cooperative interactions with the transcription factor SL1/TIF-IB complex. It binds specifically to the upstream control element (By similarity).
Abundant in male subcutaneous white adipose tissue after weaning. In white adipose tissue, it is preferentially detected in mature adipocytes but not in preadipocytes. The expression in primary preadipocytes increases during the adipocyte differentiation. In brain, it is expressed in the midbrain, pons/medulla, cerebral cortex, hippocampus and cerebellum. The expression in the cerebellum is restricted primarily to glial cells, while in the cerebral cortex, it is restricted to neuronal cells.
Converts acetoacetate to acetoacetyl-CoA in the cytosol. Ketone body-utilizing enzyme, responsible for the synthesis of cholesterol and fatty acids.
Belongs to the PtdIns transfer protein family. PI transfer class IIA subfamily.
Catalyzes the transfer of phosphatidylinositol (PI) between membranes (By similarity). Binds PI, phosphatidylcholine (PC) and phosphatidic acid (PA) with the binding affinity order of PI > PA > PC (By similarity). Regulates RHOA activity, and plays a role in cytoskeleton remodeling (By similarity). Necessary for normal completion of cytokinesis (By similarity). Plays a role in maintaining normal diacylglycerol levels in the Golgi apparatus (By similarity). Necessary for maintaining the normal structure of the endoplasmic reticulum and the Golgi apparatus (By similarity). Required for protein export from the endoplasmic reticulum and the Golgi (By similarity). Binds calcium ions (By similarity).
Interacts with PIK4CA and VAPB. 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 (By similarity).
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 (By similarity).
Phosphorylated on threonine residues upon treatment with oleic acid.
Phosphorylated on tyrosine residues by PTK2B.
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.
Belongs to the adrenodoxin/putidaredoxin family.
Essential for the synthesis of various steroid hormones. Participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis. Transfers electrons from adrenodoxin reductase to CYP11A1, a cytochrome P450 that catalyzes cholesterol side-chain cleavage. Does not form a ternary complex with adrenodoxin reductase and CYP11A1 but shuttles between the two enzymes to transfer electrons.
Found in all tissues, most abundant in adrenals, ovaries and testes.
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 similarity).
Homodimer and heterodimer: mainly forms homodimers and, to a lesser extent, heterodimers with E2F8. Dimerization is important for DNA-binding. Interacts with HIF1A (By similarity). Interacts with MN1 (By similarity).
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).
Forms homodimers (via head domain) (By similarity). Interacts with CEP170 (By similarity). Interacts with PCM1 and CEP131 (By similarity). Binds tubulin (By similarity).
Microtubule-binding centrosomal protein required for centriole cohesion, independently of the centrosome-associated protein/CEP250 and rootletin/CROCC linker. In interphase, required for anchoring microtubule at the mother centriole subdistal appendages and for centrosome positioning. During mitosis, may be involved in spindle assembly and chromatin alignment by regulating the organization of spindle microtubules into a symmetrical structure. Plays a non-essential role in ciliogenesis.
The N-terminal 3D structure (head domain) resembles that of NHEJ1/XLF, PAXX, SASS6 and XRCC4.
The coiled-coil domains are involved in microtubule-binding.
Acts as 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. 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 (By similarity).
Interacts with SCRIB; interaction is direct and may play a role in regulation of apoptosis (By similarity). Interacts with PAK kinases through the SH3 domain. Interacts with GIT1 and probably TGFB1I1. Interacts with ITCH and PARVB. Interacts with FRMPD4 (via N-terminus). Interacts with CaMK1. Interacts with PTK2/FAK1 and RAC1. Interacts with BIN2 (By similarity). Interacts with YWHAZ (By similarity).
Phosphorylated on Ser-516 by CaMK1; enhancement of GEF activity and downstream activation of RAC1. Phosphorylated by PTK2/FAK1; this promotes interaction with RAC1 (By similarity).
Accumulates steadily during G2 and is abruptly destroyed at mitosis.
Essential for the control of the cell cycle at the G2/M (mitosis) transition.
Interacts with the CDC2 protein kinase to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Binds HEI10. Interacts with catalytically active RALBP1 and CDC2 during mitosis to form an endocytotic complex during interphase. Interacts with CCNF; interaction is required for nuclear localization. Interacts with CDK5RAP3. Interacts with RFPL4A and UBE2A. Interacts with INCA1.
Phosphorylated by PLK1 at Ser-123 on centrosomes during prophase: phosphorylation by PLK1 does not cause nuclear import. Phosphorylation at Ser-137 was also reported to be mediated by PLK1 but Ser-123 seems to be the primary phosphorylation site (By similarity).
Ubiquitinated by the SCF(NIPA) complex during interphase, leading to its destruction. Not ubiquitinated during G2/M phases (By similarity).
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:7939721). In addition to its role in translation initiation, also acts as a regulator of translation and stability in the cytoplasm (PubMed:8558852). 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. 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 (By similarity). May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development (PubMed:8558852).
Very high levels in post-meiotic testicular germ cells of rats of reproductive age.
eIF4F is a multi-subunit complex, the composition of which varies with external and internal environmental conditions (By similarity). It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3. EIF4E is also known to interact with other partners (By similarity). Interacts with EIF4ENIF1/4E-T; promotes recruitment to P-bodies and import into the nucleus. 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. Interacts mutually exclusive with EIF4A1 or EIF4A2 (PubMed:7939721). Interacts with NGDN and PIWIL2. Component of the CYFIP1-EIF4E-FMR1 complex composed of CYFIP, EIF4E and FMR1. Interacts directly with CYFIP1. Interacts with CLOCK (By similarity). Binds to MKNK2 in nucleus. Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3G in an RNA-dependent manner. Interacts with LARP1. Interacts with METTL3. Interacts with RBM24; this interaction prevents EIF4E from binding to p53/TP53 mRNA and inhibits the assembly of translation initiation complex. 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. DDX3X competes with EIF4G1 for interaction with EIF4E (By similarity). Interacts with BTG4 and CNOT7 (By similarity).
Interacts with IGF1R (By similarity). Associates with the Elongin BC complex (By similarity). Interacts with AREL1 and PRKCA (By similarity). Interacts with DCUN1D1 (By similarity).
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 ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity).
Ubiquitinated; mediated by AREL1 and leading to its subsequent proteasomal degradation. Ubiquitination is dependent on phosphorylation at Ser-52, by PKC and is stimulated by LPS.
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 (By similarity) (PubMed:11677594). 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:11460888, PubMed:10482243, PubMed:9003024, PubMed:11677594). 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) (PubMed:10482243, PubMed:9003024). 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 (By similarity). 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). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (By similarity). 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 (Probable). 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 (By similarity). 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 (By similarity).
Mannosyltransferase involved in glycosylphosphatidylinositol-anchor biosynthesis. Transfers the first alpha-1,4-mannose to GlcN-acyl-PI during GPI precursor assembly (By similarity).
Heterodimer with DR1. Binds BTAF1 (By similarity).
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 (By similarity).
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 (By similarity). 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 (By similarity).
The N-terminal and the C-terminal halves of the protein can associate with each other, thereby hindering interactions with ZYX.
Monomer. Can form homodimers. Interacts with CD164. Interacts with ARRB2; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with ARR3; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates calcium mobilization. Interacts with RNF113A; the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and subsequent degradation. Interacts (via the cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and leads to its degradation. Interacts with extracellular ubiquitin. Interacts with DBN1; this interaction is enhanced by antigenic stimulation. Following LPS binding, may form a complex with GDF5, HSP90AA1 and HSPA8.
O- and N-glycosylated. N-glycosylation can mask coreceptor function. The O-glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity.
Phosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-321 and Ser-322 leads to recruitment of ITCH, ubiquitination and protein degradation.
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation. Involved in the AKT signaling cascade (By similarity). Plays a role in regulation of cell migration, e.g. during wound healing. Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (By similarity). Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (By similarity).
Sulfation is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization.
Ubiquitinated after ligand binding, leading to its degradation. Ubiquitinated by ITCH at the cell membrane on agonist stimulation. The ubiquitin-dependent mechanism, endosomal sorting complex required for transport (ESCRT), then targets CXCR4 for lysosomal degradation. This process is dependent also on prior Ser-/Thr-phosphorylation in the C-terminal of CXCR4. Also binding of ARRB1 to STAM negatively regulates CXCR4 sorting to lysosomes though modulating ubiquitination of SFR5S.
A connexon is composed of a hexamer of connexins. Interacts with TJP1 (By similarity).
Mainly expressed by oligodendrocytes in the central nervous system. Expressed in optic nerve (at protein level).
One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a role in myelination in central and peripheral nervous systems (By similarity).
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. Binds to ERBB4 and ERBB3. 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 (By similarity). Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1, and ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons (PubMed:17250808).
N- and O-glycosylated (By similarity). Extensive glycosylation precedes the proteolytic cleavage.
The cytoplasmic domain interacts with the LIM domain region of LIMK1 (PubMed:9685409). Forms a ternary complex with ERBB3 and ITGAV:ITGB3 or ITGA6:ITGB4 (By similarity). Interacts with NRDC and BACE1 (By similarity).
The cytoplasmic domain may be involved in the regulation of trafficking and proteolytic processing. Regulation of the proteolytic processing involves initial intracellular domain dimerization.
Widely expressed. Most tissues contain isoform alpha2A and isoform alpha2B. Isoform Alpha2 and isoform beta2 are the predominant forms in mesenchymal and non-neuronal organs. Isoform Beta1 is enriched in brain and spinal cord, but not in muscle and heart. Isoform Alpha2C is highly expressed in spinal cord, moderately in lung, brain, ovary, and stomach, in low amounts in the kidney, skin and heart and not detected in the liver, spleen, and placenta.
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 (By similarity).
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.
Binds ROCK1 and MARF1 (By similarity). Interacts with NISCH (By similarity).
Found in various tissues at moderate levels, except for testis, which shows very low expression.
Phosphorylated on serine and/or threonine residues by ROCK1.
Serine/threonine-protein kinase that plays an essential role in the regulation of actin filament dynamics. Acts downstream of several Rho family GTPase signal transduction pathways. Involved in astral microtubule organization and mitotic spindle orientation during early stages of mitosis by mediating phosphorylation of TPPP. Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro. Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, directional trafficking of ciliary vesicles to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (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) (By similarity). Interacts with DHX33; the interaction is independent of RNA (By similarity).
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. 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 can bind 18S rRNA.
In brain, isoform 5-HT4S is restricted to the striatum, but isoform 5-HT4L is expressed throughout the brain, except in the cerebellum. In peripheral tissues, differential expression is also observed in the atrium of the heart where only isoform 5-HT4S is detectable.
May interact with PATJ, MAGI2, MPP3, NOS1, SLC9A3R1, SEC23A and SNX27. May form 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) (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.
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. Interacts with MAGI1, MAGI2, MAGI3 and MPDZ (By similarity). 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 (PubMed:22658936). Interacts with NOTCH1 (PubMed:28089369).
O-fucosylated. Can be elongated to a disaccharide by MFNG.
Phosphorylated in a membrane association-dependent manner. Phosphorylation at Ser-688 requires the presence of Ser-685, whereas phosphorylation at Thr-630 and Ser-685 occur independently of the other sites. Phosphorylation is required for full ligand activity in vitro and affects surface presentation, ectodomain shedding, and endocytosis.
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 (By similarity). 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) (PubMed:22658936). 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 (By similarity). 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 (By similarity). 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. Mono- and multi-ubiquitinated. Multi-ubiquitination of Lys-605 by MIB1 promotes both cis and trans-interaction with NOTCH1, as well as activation of Notch signaling. Ubiquitinated by NEURL1B (By similarity).
Regulates intra- and extracellular levels of inorganic pyrophosphate (PPi), probably functioning as PPi transporter.
Centrosomal protein involved in regulation of centriole duplication. Required to limit centriole duplication to once per cell cycle by preventing centriole reduplication.
Absence of tyrosine and threonine phosphorylation is demonstrated in PubMed:17376771. However, tyrosine and threonine phosphorylation may still occur in different experimental conditions.
Brain-specific (peripheral sensory neurons).
Constitutively phosphorylated by CDK5 in nerve terminals and dephosphorylated by calcineurin when synaptic vesicle endocytosis (SVE) is stimulated by depolarization-dependent calcium influx.
Diffuse cytoplasmic distribution with some localization to the Golgi apparatus.
Interacts with CAV1 and SH3GLB1. Interacts with SNX9. Interacts with SNX33 (via SH3 domain) (By similarity). Interacts with PHOCN. Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity). Binds SH3GL1, SH3GL2 and SH3GL3. Interacts with MYO1E (via SH3 domain). Interacts with UNC119; leading to a decrease of DNM1 GTPase activity (By similarity). Interacts with DIAPH1 (By similarity). Interacts with AMPH, BIN1 and SYNJ1 (PubMed:9341169).
Localized to numerous punctate spots of various sizes distributed along the plasma membrane and throughout the cytoplasm.
Microtubule-associated force-producing protein involved in producing microtubule bundles and able to bind and hydrolyze GTP. Most probably involved in vesicular trafficking processes. Involved in receptor-mediated endocytosis (By similarity).
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as CGAS, HRAS and LCK. Acts as a negative regulator of the cGAS-STING pathway be mediating palmitoylation and inactivation of CGAS. May also have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling.
Abundantly and specifically expressed in the floor plate region of the spinal cord at embryonic day 13 (13 dpc) and 15 dpc and at lower levels at postnatal day 1 (P1). A high level expression was also observed in the ventral hindbrain and midbrain. No expression was seen in the notochord at these stages. Prominent expression in the nervous system was also seen in the choroid plexus. At 13 dpc, expression was also seen in the dorsomedial forebrain and roof of the hind brain. Robust and specific expression was detected in the choroid plexus epithelium of the lateral, 3rd and 4th ventricles at 15 dpc and P1 and persisted into adulthood. In the CNS, expression was detected in thalamic and hypothalamic regions at 13 dpc, 15 dpc and P1. In embryos, it was highly expressed in the limb buds, face region, large blood vessels, olfactory pits and pleural epithelium. In particular, expression was robust and specific in bone-forming regions of the face and in the mesenchymal cells surrounding the developing cartilages of the extremities.
May be involved in the desulfation of sulfated glycosaminoglycans in the biosynthetic pathway and may play a role as an extracellular regulator of proteoglycan mediated signaling.
Strongly expressed in the floor plate, choroid plexus and cartilage. Weaker expression seen in the eye, lung brain, spinal cord, urinary bladder, testis, ovary and uterus.
Belongs to the UbiA prenyltransferase family.
Mediates the second step in the final reaction sequence of coenzyme Q (CoQ) biosynthesis (PubMed:20526342). Catalyzes the prenylation of para-hydroxybenzoate (PHB) with an all-trans polyprenyl group (such as all-trans-nonaprenyl diphosphate) (PubMed:20526342). The length of the polyprenyl side chain varies depending on the species, in humans, the side chain is comprised of 10 isoprenyls producing CoQ10 (also known as ubiquinone), whereas rodents predominantly generate CoQ9 (PubMed:20526342). However, this specificity is not complete, human tissues have low amounts of CoQ9 and rodent organs contain some CoQ10 (By similarity). Plays a central role in the biosynthesis of CoQ9 (By similarity). CoQ9 is a vital molecule that transports electrons from mitochondrial respiratory chain complexes (By similarity). CoQs also function as cofactors for uncoupling protein and plays a role as regulator of the extracellularly-induced ceramide-dependent apoptotic pathway (By similarity). Regulates mitochondrial permeability transition pore (mPTP) opening and ROS production (pivotal events in cell death) in a tissue specific manner (PubMed:22387164).
Belongs to the metallophosphoesterase superfamily. MPPE1 family.
Interacts with GPI-anchor proteins. Interacts with TMED10 (By similarity).
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 (By similarity).
Highly specific for ethanolamine phosphorylation. Does not have choline kinase activity.
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 (By similarity).
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.
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 (By similarity).
Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-278 is likely to be the main autophosphorylation site. Phosphorylation of Ser-556 and Ser-557 is induced by CDC42 (By similarity).
Homodimer; undergoes dimerization during activation. Interacts with MAP2K4/MKK4 (By similarity). Interacts with MAP2K7/MKK7 (PubMed:14575811). Found in a complex with SH3RF1, RAC1, MAP2K7/MKK7, MAPK8IP1/JIP1 and MAPK8/JNK1 (By similarity).
Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation (By similarity).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A12 subfamily.
Transports betaine and GABA. May have a role in regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation (By similarity).
Transports betaine and GABA. May have a role in regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation.
Homodimer. Component of the multisubunit transport protein particle (TRAPP) complex, which includes at least TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L, TRAPPC4, TRAPPC5, TRAPPC8, TRAPPC9, TRAPPC10, TRAPPC11 and TRAPPC12. Heterodimer with TRAPPC6A. The heterodimer TRAPPC3-TRAPPC6A interacts with TRAPPC2L. Heterodimer with TRAPPC6b. The heterodimer TRAPPC6B-TRAPPC3 interacts with TRAPPC1 likely providing a core for TRAPP complex formation.
Acyl-CoA synthases catalyze the initial reaction in fatty acid metabolism, by forming a thioester with CoA. Has some preference toward medium-chain substrates. Plays a role in adipocyte differentiation.
Negative regulator of autophagy. Involved in mediating interferon-gamma-induced cell death (By similarity).
Phosphorylated. Phosphorylation by MTOR inhibits the suppressive activity of DAP toward autophagy (By similarity).
C4 is a major histocompatibility complex class-III protein.
Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory processes. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.
Induced in hepatic stellate cells by iron overload and by gamma-interferon.
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 (By similarity).
This protein is synthesized as a single-chain precursor and, prior to secretion, is enzymatically cleaved to form a trimer of non-identical chains alpha, beta and gamma.
Homodimer. Interacts (phosphorylated on Ser-423 and Ser-426) with PLK1. Interacts with AKAP9/CG-NAP; the interaction occurs in interphase and is lost upon mitotic entry. Interacts with PCNT/Kendrin; the interaction occurs in interphase and is lost upon mitotic entry. Directly interacts with PDCD6IP; this interaction is required for PDCD6IP targeting to the midbody; CEP55 binds PDCD6IP in a 2:1 stoichiometry; PDCD6IP competes with TSG101 for the same binding site. Interacts with TSG101; TSG101 competes with PDCD6IP for the same binding site; interaction is required for cytokinesis. Interacts with MVB12A, VPS37B, VPS37C and VPS28 (By similarity).
Plays a role in mitotic exit and cytokinesis. Recruits PDCD6IP and TSG101 to midbody during cytokinesis. Required for successful completion of cytokinesis. Not required for microtubule nucleation. Plays a role in the development of the brain and kidney.
There is a hierachy of phosphorylation, where both Ser-423 and Ser-426 are phosphorylated at the onset of mitosis, prior to Ser-434. Phosphorylation at Ser-423 and Ser-426 is required for dissociation from the centrosome at the G2/M boundary. Phosphorylation at the 3 sites, Ser-423, Ser-426 and Ser-434, is required for protein function at the final stages of cell division to complete cytokinesis successfully (By similarity).
Homodimer. Binds LGALS3BP. Interacts with CD2, CD3, CD4, CD6, CD7, CD43, ALCAM and CD45. Interacts with laminin (via poly-N-acetyllactosamine). Interacts with SUSD2. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.
Lectin that binds beta-galactoside and a wide array of complex carbohydrates. Plays a role in regulating apoptosis, cell proliferation and cell differentiation. Inhibits CD45 protein phosphatase activity and therefore the dephosphorylation of Lyn kinase. Strong inducer of T-cell apoptosis.
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) (By similarity).
A beta-galactoside alpha2-3 sialyltransferase involved in terminal sialylation of glycoproteins and glycolipids. 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 (By similarity). 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 (By similarity). 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 (By similarity). Metabolizes brain c-series ganglioside GT1c forming GQ1c (Probable). Synthesizes ganglioside LM1 (IV3Neu5Ac-nLc4Cer), a major structural component of peripheral nerve myelin (By similarity).
Regulator required for centriole duplication, for proper bipolar spindle formation and chromosome congression in mitosis.
This beta interferon does not have a disulfide bond.
Type I interferon cytokine that plays a key role in the innate immune response to infection, developing tumors and other inflammatory stimuli. 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 (By similarity). Signals mostly via binding to a IFNAR1-IFNAR2 heterodimeric receptor, but can also function with IFNAR1 alone and independently of Jak-STAT pathways. 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. 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. IFNB1 is more potent than interferon-alpha (IFN-alpha) in inducing the apoptotic and antiproliferative pathways required for control of tumor cell growth (By similarity).
Component of a calcium channel complex consisting of a pore-forming alpha subunit (CACNA1S) and the ancillary subunits CACNB1 or CACNB2, CACNG1 and CACNA2D1 (PubMed:26680202). 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 (PubMed:26680202). Interacts with CACNA1C (PubMed:15141227). Interacts with RRAD. Interaction with RRAD regulates the trafficking of CACNA1C to the cell membrane (By similarity). Interacts with TMIGD2 (By similarity). Interacts with CAMK2D (PubMed:20194790). Interacts with CBARP (PubMed:24751537). Interacts with CAMK2A (By similarity).
Highly expressed in heart and brain, and at lower levels in lung.
Regulated through phosphorylation at Thr-549 by CaMK2D.
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 (By similarity).
The Ig-like domain is required for the anti-apoptotic ability.
Acetyltransferase activity toward tubulin in vitro is unclear (PubMed:28681565). Crystallographic studies with the human protein demonstrated that it does not share any similarity with other acetyltransferases and instead forms a crotonase-like fold.
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). Part of multimeric repressive chromatin complexes, where it is required for transmission and restoration of repressive histone marks, thereby preserving the epigenetic landscape. 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. Acts as a corepressor for REST by facilitating histone-lysine N-methyltransferase EHMT2 recruitment and H3K9 dimethylation at REST target genes for repression (By similarity). 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 (By similarity). 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 (PubMed:28842554). In addition to acting as a chromatin reader, acts as a hydro-lyase. 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 (By similarity). 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). Displays acetyltransferase activity toward tubulin in vitro; such activity is however unsure in vivo and additional evidences would be required to confirm this result (PubMed:28681565).
Down-regulated upon neuronal activity in response to an enriched environment, NMDA injection in the brain or seizures induced by kainic acid (at protein level) (PubMed:28842554). Up-regulated after social defeat stress (PubMed:30665597).
Expressed in the brain, with expression in the hippocampal dentate gyrus, CA1, striatum and cortex (at protein level) (PubMed:28842554). Expressed in the prelimbic cortex (PubMed:30665597).
Forms multimers and multimerization is required for stable binding to chromatin (By similarity). Interacts with HDAC1 and HDAC2 via its C-terminal acetyl-CoA-binding domain (By similarity). Interacts with EZH2, EED, SUZ12, REST, EHMT1 and EHMT2. 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. Interacts with CHAF1A and CHAF1B; bridging the CAF-1 complex to the MCM2-7 (MCM) complex. Interacts with MCM3 and MCM5; bridging the CAF-1 complex to the MCM2-7 (MCM) complex (By similarity). 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 presence of a N-terminal extension that inactivates the chromo domain.
The acetyl-CoA-binding domain mediates crotonyl-coA hydratase activity (By similarity). The acetyl-CoA-binding domain is required for recruitment to sites of DNA double strand breaks and for binding to poly (ADP ribose) moieties (By similarity).
The chromo domain recognizes and binds histone H3K9me3, histone H3K27me2 and histone H3K27me3.
Homodimer; homodimerization requires the C4-type zinc finger motif and decreases during mitosis in a phosphorylation-dependent manner.
Plays a role in determining ER morphology.
The C4-type zinc finger motif is necessary both for its ER three-way tubular junction localization and formation.
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Role in neural transmission (By similarity).
Widely expressed, with highest expression in skeletal muscle, heart and brain.
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. Interacts with the MRN complex, composed of MRE11, RAD50, and NBN. This interaction is independent of DNA and does not appear to be regulated by phosphorylation of MDC1. Interacts with CHEK2, which is also independent of DNA and requires ATM-mediated phosphorylation 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) (By similarity).
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 (By similarity).
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 (By similarity).
Sumoylation at Lys-1034 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 (By similarity).
Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination.
Interacts with SDC4/syndecan-4 and SEMA4C/semaphorin-4C (By similarity). Interacts with RGS19 (C-terminus), GLUT1 (C-terminus), ACTN1, KIF1B, MYO6 and PLEKHG5.
May be involved in G protein-linked signaling.
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 (By similarity).
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.
Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. PB-cadherins may have a role in the morphological organization of pituitary gland and brain tissues.
Strongly expressed in the pituitary gland and the brain (in the inner granular and glomerular layers of the olfactory bulb, anterior olfactory nucleus, primary olfactory cortex, Purkinje cell layer of cerebellum, and pineal gland). Low expression in lung and heart. No expression in submandibular gland, thymus, liver, spleen, adrenal, and kidney.
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 an important role in translational accuracy.
Hydroxylation at Pro-62 affects translation termination efficiency.
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.
Plays an important role in cardiomyocyte hypertrophy via activation of the calcineurin/NFAT signaling pathway.
Dimerization and MBL2 binding requires calcium ions.
Highly expressed in liver. Secreted in plasma.
Homodimer; disulfide-linked. Binds MBL2. Isoform 2 binds to MASP1. Binds SERPING1 (By similarity).
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.
Belongs to the SMC family. SMC2 subfamily.
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. 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. May play a role in cell proliferation.
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. Interacts directly with BLOC1S1, BLOC1S3, BLOC1S4, BLOC1S5 and SNAPIN. The BLOC-1 complex associates with the AP-3 protein complex and membrane protein cargos. Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN. Interacts with gamma-tubulin. Interacts with IFT57.
Widely expressed. Highly expressed in most brain regions, spinal cord, kidney and ovary. In the brain, expressed in the frontal cortex and the superior thalamic radiation, with the strongest expression in the granule cells of hippocampal CA1, CA3 and dentate gyrus regions. In the spinal cord, mainly expressed in the gray matter. Expression level is high in laminae I-II and V-VI small sensory neurons in the dorsal horn, as well as in the large motor neurons of the ventral horn.
Bimane-S-cysteinylglycine-hydrolyzing activity is inhibited by o-phenanthroline or bestatin, and is activated by the addition of zinc chloride.
Binds two metal ions per subunit. Two metal binding sites with different affinities are located in the enzyme active site and can be occupied in vitro by different metals: site 1 is occupied by Zn(2+), Mn(2+), Mg(2+) or Co(2+), while the tight binding site 2 can be occupied by only Zn(2+) or Co(2+). One Zn(2+) ion is tightly bound to site 2 and essential for enzyme activity in vivo, while site 1 can be occupied by different metals to give different enzymatic activities. Mn(2+) is required for Cys-Gly hydrolysis activity. A third metal binding site may serve a structural role, possibly stabilizing part of the interface between the N-terminal and the catalytic domain.
Cytosolic metallopeptidase that catalyzes the removal of unsubstituted N-terminal hydrophobic amino acids from various peptides (PubMed:6108111, PubMed:12675513). The presence of Zn(2+) ions is essential for the peptidase activity, and the association with other cofactors can modulate the substrate spectificity of the enzyme (By similarity). For instance, in the presence of Mn(2+), it displays a specific Cys-Gly hydrolyzing activity of Cys-Gly-S-conjugates (By similarity). Involved in the metabolism of glutathione and in the degradation of glutathione S-conjugates, which may play a role in the control of the cell redox status (PubMed:12675513).
Detected in the Golgi apparatus of pachytene spermatocytes beginning at stage VII and extending up to stage XIV. Detected in the Golgi apparatus of spermatids at steps 1-15 of 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.
N-glycosylated. O-glycosylated; further modified with terminal sialic acid residues.
Catalyzes the transamination between L-serine and pyruvate and weakly contributes to gluconeogenesis from the L-serine metabolism.
Catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.
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.
Expressed in brain, lungs, stomach and intestines (at protein level). Strongly expressed in the epithelial layer on the small intestinal luminal side.
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 (By similarity).
Interacts with PPP3CA. Interacts with SLC9A1/NHE1; the interaction occurs in a calcium-dependent manner (By similarity). Interacts with SLC9A1/NHE1.
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 (By similarity).
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.
Belongs to the peptidase C19 family. USP20/USP33 subfamily.
Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. In the eye, it is expressed in the pigmented epithelium of the retina and the nonpigmented epithelium of the iris and ciliary body, and accumulates within the interphotoreceptor matrix, photoreceptors, and aqueous and vitreous humors. In the male reproductive system, it is expressed in the testis and epididymis, and is secreted into the seminal fluid. It has also been detected in the cochlea.
By IL-1 beta and thyroid hormone. Probably induced by dexamethasone, dihydrotestosterone, 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. 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:10387044, PubMed:10650953, PubMed:11058225, PubMed:9188476). 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).
In the brain it is localized in many neurons at 1-2 weeks after birth, whereas in mature animals it is localized to tissues of the blood-brain barrier.
The glycine cleavage system catalyzes the degradation of glycine.
The glycine cleavage system is composed of four proteins: P, T, L and H.
Defects in Pax6 are the cause of a condition known as small eye (Sey) which results in the complete lack of eyes and nasal primordia.
Expressed in the embryonic headfolds and to a lesser extent in the trunk of neurula at 10 dpc.
Interacts with MAF and MAFB (By similarity). Interacts with TRIM11; this interaction leads to ubiquitination and proteasomal degradation, as well as inhibition of transactivation, possibly in part by preventing PAX6 binding to consensus DNA sequences (By similarity). Interacts with TLE6/GRG6 (By similarity).
Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas. Required for the differentiation of pancreatic islet alpha cells. Competes with PAX4 in binding to a common element in the glucagon, insulin and somatostatin promoters (By similarity). Regulates specification of the ventral neuron subtypes by establishing the correct progenitor domains. Acts as a transcriptional repressor of NFATC1-mediated gene expression (By similarity).
Ubiquitinated by TRIM11, leading to ubiquitination and proteasomal degradation.
Up-regulated in response to transient cerebral ischemia in cerebral cortex, striatum and subcortical white matter fibers in the ischemic region starting from 24 hours after initiating the ischemia.
Found almost exclusively in brain and skin. Ubiquitously detected in different brain regions with very prominent expression in lower brain regions such as the midbrain, pons, medulla, and spinal cord. Expressed predominantly within white matter tracts of the brain. Corpus callosum, optic nerve, olfactory tract, anterior commissure, internal and external capsules, fimbra of the hippocampus, mammillary tract, stria medullaris, and white matter of the cerebellum and brain stem all express the receptor. Within the striatum itself white matter fascicles express the receptor. Detected also in spleen and lung. Not observed in heart, liver, skeletal muscle, kidney, or testes.
In PC-12 cells, nerve growth factor induces neuronal differentiation and represses expression of the receptor. Down-regulated also by fibroblast growth factor and dibutyryl cAMP. Epidermal growth factor, an agent that does not induce differentiation, does not repress expression. Protein kinase A appears to be an obligatory cellular component in regulation.
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/O)alpha and G(12) subclass of heteromeric G-proteins. Displays antiproliferative effects in transfected CHO-K1 and HEK293 cells.
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.
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 POU transcription factor family. Class-5 subfamily.
Expressed in pancreas, colon, duodenum, and much less in stomach.
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.
Expressed in brain, lung, heart, stomach, intestine, cultured aortic smooth muscle cells and cardiac myocytes.
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.
Autophosphorylated (PubMed:7759525). Phosphorylated by aPKC which promotes dissociation from the cell cortex (By similarity).
Monomer. Interacts with MTA1 (short isoform) in the cytoplasm. Interacts with SMAD3 (By similarity).
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 (By similarity). 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 (By similarity).
Activation requires autophosphorylation of Ser-332. Phosphorylation of Ser-328 also promotes increased activity (By similarity).
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WNK subfamily.
Interacts with the C-terminal region of KCNJ1. Interacts with WNK1 and WNK3. Interacts with KLHL3.
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. Acts as a scaffold to inhibit SLC4A4 as well as CFTR activities and surface expression, recruits STK39 which mediates the inhibition. Phosphorylates NEDD4L (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 (By similarity).
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.
Homodimer. Interacts (via PTS2-type peroxisomal targeting signal region) with PEX7; leading to its translocation into peroxisomes.
Responsible for the thiolytic cleavage of straight chain 3-keto fatty acyl-CoAs (3-oxoacyl-CoAs) (PubMed:9325339). Plays an important role in fatty acid peroxisomal beta-oxidation (PubMed:9325339). Catalyzes the cleavage of short, medium, long, and very long straight chain 3-oxoacyl-CoAs (PubMed:9325339). Medium chain straight 3-oxoacyl-CoAs are preferred substrates (PubMed:9325339).
Acetylated by lysine acetyltransferase EP300; which activates transcriptional capacity. Lysine residues that are sumoylated also seem to be target for acetylation (By similarity).
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 (By similarity).
Expressed in heart, spleen, lung, kidney, brain, testis and epididymis but not in salivary glands.
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 (By similarity).
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 (By similarity).
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. Cooperates with CBFB-MYH11 (By similarity).
Part of the neuronal tubulin polyglutamylase complex which contains TPGS1, TPGS2, TTLL1, LRRC49 and NICN1. Interacts with CSTPP1 and LRRC49.
Subunit of the tubulin polyglutamylase complex (TPGC). The complex mediates cilia and flagella polyglutamylation which is essential for their biogenesis and motility.
Associated with AP-1 and AP-2 complexes.
May be involved in endocytic recycling of growth factor receptors such as EGFR.
Expressed in the brain, skeletal muscle, heart muscle, lung, gut, liver, and kidney (at protein level) (PubMed:20652957). In the brain, expressed in the cortex, striatum, ventral tegmentum, nucleus accumbens and to a lesser extent in the Purkinjie cells in the cerebellum (PubMed:20652957). Expressed in eye iridocorneal angle (PubMed:15326124).
Interacts with WNT3A. Interacts with WNT1, WNT3 and WNT5A.
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. Also plays an important role in establishment of the anterior-posterior body axis formation during development (By similarity).
Involved in the regio- and stereoselective transformation of naphthalene to trans-1R-hydroxy-2R-glutathionyl-1,2-dihydronaphthalene in the presence of glutathione and glutathione S-transferases. It specifically catalyzes the production of a very reactive and potentially toxic intermediate, the 2R,2S arene oxide, that is associated with necrosis of the unciliated bronchiolar epithelial cells or club cells in lung.
Interacts with DDI2; probably also interacts with DDI1.
Replication termination factor which is a component of the elongating replisome. 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. Interacts with nascent DNA.
Undergoes proteasomal degradation, via DDI1 and DDI2. Removal from stalled replisomes and degradation are required for genome stability.
Isoform 2 is expressed in testis, brain, skeletal muscle and in the male germline.
NADH-cytochrome b5 reductase involved in endoplasmic reticulum stress response pathway. Plays a critical role in protecting pancreatic beta-cells against oxidant stress, possibly by protecting the cell from excess buildup of reactive oxygen species (ROS).
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).
Expressed in the kidney where it localizes to the distal convoluted tubule and the thick ascending limb of the loop of Henle (at protein level) (PubMed:21075169). In the ovary, highly expressed in interstitial cells (at protein level) (PubMed:3948785). Also expressed in adrenal gland and testis (PubMed:3123325).
Induced by FSH or pregnant mare's serum gonadotropin in ovaries of estrogen-treated immature rats in vivo.
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.
Homotetramer (PubMed:12032348). Interacts with CABP1 (PubMed:12032348). Interacts with BOK; regulates ITPR2 expression (PubMed:23884412). Interacts with BCL2L10 (By similarity). Interacts with TRPC4 (PubMed:11163362).
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).
Highly expressed in embryonic brain but its expression decrease during development.
Identified in the spliceosome C complex. Present in a spliceosome complex assembled in vitro containing CRNKL1, HPRP8BP and SNRPB2. Interacts with PPIL2 (via the PPIase cyclophilin-type domain); they may form a trimeric complex with HSP90.
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.
Monomer. Homodimer. The monomeric form has a higher catalytic activity.
Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and is involved in a variety of cellular processes (PubMed:19596852, PubMed:21343290, PubMed:25589740). 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 (PubMed:25589740). In dendrites, mediates the palmitoylation of DLG4 when synaptic activity decreases and induces synaptic clustering of DLG4 and associated AMPA-type glutamate receptors (PubMed:19596852). 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 (PubMed:21343290). Also probably plays a role in cell adhesion by palmitoylating CD9 and CD151 to regulate their expression and function. Palmitoylates the endoplasmic reticulum protein CKAP4 and regulates its localization to the plasma membrane. Could also palmitoylate LCK and regulate its localization to the plasma membrane (By similarity).
Postsynaptic recycling endosome membrane
Belongs to the class I-like SAM-binding methyltransferase superfamily. TPMT family.
Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) using S-adenosyl-L-methionine as the methyl donor. TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified.
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.
Homodimer (By similarity). Interacts with oxidized form of GAPDH (By similarity).
Proteolytic cleavage generates 2 forms; T1-TrpRS and T2-TrpRS.
T1-TrpRS has aminoacylation activity while T2-TrpRS lacks it. T1-TrpRS and T2-TrpRS possess angiostatic activity. 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 (By similarity).
Belongs to the eukaryotic ribosomal protein eL28 family.
Belongs to the Mediator complex subunit 11 family.
By pregnenolone 16-alpha-carbonitrile (PNCN) and dexamethasone.
May act as a guanine nucleotide exchange factor (GEF).
Interacts with PRKCABP. Interacts with PI4KB and NCS1/FREQ at the Golgi complex.
Binds PTPN11 when tyrosine-phosphorylated, except in macrophages, where it primarily binds PTPN6. Binds GRB2 in vitro. Binds FGR. Binds JAK2 irrespective of its phosphorylation status and forms a stable complex. Binds SCAP1 and/or SCAP2. The resulting complex recruits FYB1. Binds PTK2B (By similarity).
Highly expressed in brain, spleen, lung, liver and kidney. Detected at lower levels in heart. Highly expressed in alveolar and peritoneal macrophages, and at lower levels in dendritic cells.
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. 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. May play a role in the release of nitric oxide by macrophages. Plays a role in antiviral immunity and limits new world arenavirus infection by decreasing virus internalization (By similarity).
Phosphorylated on tyrosine residues in response to insulin, cell adhesion or epidermal growth factors. Dephosphorylated by PTPN11.
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 and CTCF. 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 (By similarity). Interacts with CTNNB1 (PubMed:10921920). Interacts with PIAS3 (PubMed:16452319). Interacts with TLK2 (By similarity).
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.
Expressed exclusively in neurons (at protein level). In all age groups, expressed at significantly higher levels in the medial prefrontal and orbital frontal cortices of spontaneously hypertensive rats (SHR), a model of attention deficit-hyperactivity disorder, than Wistar Kyoto (WKY) animals. In the motor cortex, dorsal striatum and nucleus accumbens, expression is significantly elevated in SHR only in younger animals.
Interacts with clathrin light chain A and stimulates clathrin self-assembly and clathrin-mediated endocytosis.
The human ortholog 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.
Inhibitor of protein-phosphatase 1. This protein may be important in hormonal control of glycogen metabolism. Hormones that elevate intracellular cAMP increase I-1 activity in many tissues. I-1 activation may impose cAMP control over proteins that are not directly phosphorylated by PKA. Following a rise in intracellular calcium, I-1 is inactivated by calcineurin (or PP2B). Does not inhibit type-2 phosphatases.
Phosphorylation of Thr-35 is required for activity.
Protein phosphatase inhibitor that specifically inhibits protein phosphatase 2A (PP2A) during mitosis.
Interacts with the DNA-binding domain of p53/TP53.
May play a role in cell survival and cell growth. May suppress the transcriptional activity of p53/TP53 (By similarity).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A13 subfamily.
Brain, retina, and peripheral tissues. Expressed in hepatocytes (at protein level).
GABA transport is inhibited by beta-alanine, L-2,4-Diaminobutyric acid, hypotaurine and nipecotic acid (PubMed:1400419, PubMed:22896705). Taurine transport is inhibited by hypotaurine, beta-alanine and nipecotic acid (PubMed:22896705).
Mediates sodium- and chloride-dependent transport of gamma-aminobutyric acid (GABA) (PubMed:1400419, PubMed:22896705). Mediates transport of taurine and is the major taurine transporter in hepatocytes (PubMed:22896705). Can also mediate transport of beta-alanine and hypotaurine (By similarity).
Performs a specialized role during sperm development and maturation.
Expressed in brain and in peripheral nervous system (at protein level). Weakly expressed in neurites.
Interacts with MCHR1 (By similarity). Interacts with SEMA4C. Interacts with DIAPH1 (via FH3 domain) (By similarity). Interacts with GRM5 (PubMed:20007903).
Palmitoylated (PubMed:23687301). Palmitoylation by ZDHHC1, ZDHHC3 and ZDHHC11 regulates the association of NCDN with endosome membranes (PubMed:23687301). May also be palmitoylated by ZDHHC7 (PubMed:23687301).
Probably involved in signal transduction, in the nervous system, via increasing cell surface localization of GRM5 and positively regulating its signaling. Required for the spatial learning process. Acts as a negative regulator of Ca(2+)-calmodulin-dependent protein kinase 2 (CaMK2) phosphorylation. May play a role in modulating melanin-concentrating hormone-mediated functions via its interaction with MCHR1 that interferes with G protein-coupled signal transduction. May be involved in bone metabolism. May also be involved in neurite outgrowth.
Upon tetraethylammonium (TEA) treatment.
Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1. Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1. Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD. On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.
Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity (By similarity).
Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A. It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits. The MLST8 subunit forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex and interaction with RICTOR is enhanced by deubiquitination of RICTOR by USP9X. 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. Interacts with PLPP7 and PML. Interacts with UBQLN1. Interacts with TTI1 and TELO2. Interacts with CLIP1; phosphorylates and regulates CLIP1. Interacts with NBN. Interacts with BRAT1. Interacts with MEAK7 (via C-terminal domain); the interaction increases upon nutrient stimulation (By similarity). Interacts with TM4SF5; the interaction is positively regulated by arginine and is negatively regulated by leucine (By similarity). Interacts with GPR137B (By similarity). Interacts with NCKAP1L (By similarity). Interacts with TPCN1 and TPCN2; the interaction is required for TPCN1 and TPCN2 sensitivity to ATP (By similarity). Interacts with ATP6V1A and with CRYAB, forming a ternary complex (By similarity). Interacts with SLC38A7; this interaction mediates the recruitment of mTORC1 to the lysosome and its subsequent activation (By similarity).
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (By similarity). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (By similarity). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (By similarity). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (By similarity). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:9465032). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:9465032). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (By similarity). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (By similarity). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (By similarity). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (By similarity). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (By similarity). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (By similarity). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (By similarity). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (By similarity). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (By similarity). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (By similarity). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (By similarity). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (By similarity). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-421' (By similarity). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity).
The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (By similarity).
The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.
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.
Interacts with PCNA. Interacts with PAXX; promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL. Interacts with XRCC4; promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL. Interacts with NHEJ1/XLF; promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL.
Interleukin-16 stimulates a migratory response in CD4+ lymphocytes, monocytes, and eosinophils. Primes CD4+ T-cells for IL-2 and IL-15 responsiveness. Also induces T-lymphocyte expression of interleukin 2 receptor. Ligand for CD4.
Amino acid transporter that specifically mediates the pH-dependent export of the cationic amino acids arginine, histidine and lysine from lysosomes.
The di-leucine motif mediates lysosomal localization.
Highest kidney expression is found in weaning rat followed by adult. Lowest expression is found in suckling rat.
Highly expressed in the kidney. Not found in any of the other tested tissues.
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).
Exists as monomer or homodimer; disulfide-linked. Exists also as heterodimer with LCN2. Macrophages and transformed cell lines produce only the monomeric form. Interacts with ECM1.
Matrix metalloproteinase that plays an essential role in local proteolysis of the extracellular matrix and in leukocyte migration (By similarity). Could play a role in bone osteoclastic resorption (By similarity). Cleaves KiSS1 at a Gly-|-Leu bond (By similarity). Cleaves NINJ1 to generate the Secreted ninjurin-1 form (By similarity). Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide (By similarity).
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 (By similarity).
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 integrin alpha-v/beta3 on the surface of blood vessels (By similarity).
Phosphorylation on multiple sites modulates enzymatic activity. Phosphorylated by PKC in vitro (By similarity).
The propeptide is processed by MMP14 (MT-MMP1) and MMP16 (MT-MMP3) (By similarity). Autocatalytic cleavage in the C-terminal produces the anti-angiogenic peptide, PEX. This processing appears to be facilitated by binding integrin integrinv/beta3 (By similarity).
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 (By similarity).
ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:8662992, PubMed:10421658, PubMed:10220572, PubMed:11248200). Mediates hepatobiliary excretion of mono- and bis-glucuronidated bilirubin molecules and therefore play an important role in bilirubin detoxification (PubMed:10421658). Mediates also hepatobiliary excretion of others glucuronide conjugates such as 17beta-estradiol 17-glucosiduronic acid and leukotriene C4 (PubMed:10220572, PubMed:8662992). Transports sulfated bile salt such as taurolithocholate sulfate (PubMed:11248200). Transports various anticancer drugs, such as anthracycline, vinca alkaloid and methotrexate and HIV-drugs such as protease inhibitors (By similarity).
Defects in Abcc2 are a cause of hereditary conjugated hyperbilirubinemia (EHBR).
Allosterically activated by phosphatidylserine and/or phosphatidylinositol 4-phosphate (PtdIns(4)P), and phosphatidylinositol 5-phosphate (PtdIns(5)P) (By similarity). Interaction with MTMR9 increases catalytic activity towards phosphatidylinositol 3,5-bisphosphate (By similarity).
Homodimer. Heterodimer (via C-terminus) with MTMR9 (via C-terminus). Interacts with ALKBH4. Interacts with KCNN4. Interacts (via GRAM domain) with RAB1B (in GDP-bound form); the interaction regulates MTMR6 recruitment to the endoplasmic reticulum-Golgi intermediate compartment.
Phosphatase that acts on lipids with a phosphoinositol headgroup. Dephosphorylates phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,5-bisphosphate. 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 (By similarity). Negatively regulates ER-Golgi protein transport (PubMed:23188820). Probably in association with MTMR9, plays a role in the late stages of macropinocytosis by dephosphorylating phosphatidylinositol 3-phosphate in membrane ruffles. Acts as a negative regulator of KCNN4/KCa3.1 channel activity in CD4(+) T-cells possibly by decreasing intracellular levels of phosphatidylinositol 3-phosphate. Negatively regulates proliferation of reactivated CD4(+) T-cells. In complex with MTMR9, negatively regulates DNA damage-induced apoptosis. The formation of the MTMR6-MTMR9 complex stabilizes both MTMR6 and MTMR9 protein levels (By similarity).
The C-terminus domain (aa 540-655) mediates interaction with MTMR9.
The GRAM domain is required for cell membrane localization.
Expressed mainly in ileum and kidney, low levels in cecum and proximal colon.
Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine (PubMed:7860756). Transports various bile acids, unconjugated or conjugated, such as cholate and taurocholate. Also responsible for bile acid transport in the renal proximal tubules, a salvage mechanism that helps conserve bile acids. 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 (By similarity).
Transcriptionally regulated increases in mRNA and protein levels at the time of weaning.
Monokine with inflammatory and chemokinetic properties. Has chemotactic activity for monocytes, neutrophils, eosinophils, basophils, and lymphocytes. Required for lung TNF-alpha production, neutrophil recruitment and subsequent lung injury and may function as an autocrine mediator for the macrophage production of TNF-alpha which in turn up-regulates vascular adhesion molecules required for neutrophil influx. This protein binds heparin.
Expressed in striatal neurons (at protein level). Expressed in the hematopoietic system. Detected in olfactory structures and deep cortical layers of brain.
Forms a signaling complex with RAP1 and BRAF. Interacts with F-actin (By similarity). Interacts with RAP1 (By similarity).
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.
The N-terminal Ras-GEF domain mediates association with F-actin.
May be involved in podosome and invadosome formation.
Forms homodimers or heterodimers with ARFIP1. Interacts with RAC1. Specifically binds to GTP-bound ARF1 and ARF6, but binds to RAC1.GTP and RAC1.GDP with similar affinities. Interacts with ARL1. Interacts (via N-terminus) with IKBKB and IKBKG; these interactions inhibit activation of NF-kappa-B.
Plays a role in constitutive metalloproteinase (MMP) secretion from the trans Golgi network. May have important functions during vesicle biogenesis at certain cargo subdomains, which could be predominantly utilized by secreted MMPs, such as MMP7 and MMP2. 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. Involved in phagophore growth during mitophagy by regulating ATG9A trafficking to mitochondria. In addition, plays a role in NF-kappa-B inhibition by interacting with IKBKB and IKBKG.
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.
Component of the nexin-dynein regulatory complex (N-DRC). 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. May form a complex with CAMK4 and HSP70.
The IQ domain mediates interaction with calmodulin when cellular Ca(2+) levels are low.
Expressed in both the central nervous system (CNS) and in non-CNS tissues, including the kidney, lung, bone, heart, liver, spleen, sciatic nerve and blood (PubMed:7696586). Expressed in brain (at protein level) (PubMed:21994944). Localizes at the proximal ligature of the hypoglossal nerve (PubMed:10828539).
Homodimer; disulfide-linked (PubMed:8493557). Interacts with RET (By similarity). Interacts (via propeptide) with SORL1 (via N-terminal ectodomain), either alone or in complex with GFRA1; interaction with SORL1 affects GDNF-regulated, but not constitutive secretion (PubMed:21994944). Also interacts with SORL1 in complex with GFRA1; this interaction leads to GDNF endocytosis and lysosomal degradation (By similarity).
Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.
Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake. May also modulate local neuronal effects in distal regions of the motor neuron.
Belongs to the potassium channel family. G (TC 1.A.1.2) subfamily. Kv6.1/KCNG1 sub-subfamily.
Heterotetramer with KCNB1 (PubMed:8980147).
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:8980147).
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.
Activity increases in response to increased acetyl-CoA and NADH levels and upon 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. Reactive oxygen species cause the formation of disulfide bonds, and thereby inhibit the enzyme.
Detected in heart (at protein level). Highest level of expression in heart and skeletal muscle and the lowest in spleen and lung. Liver, kidney, brain and testis levels are intermediate.
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.
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.
Cleaved following oxidative stress resulting in HSP90AB1 protein radicals formation; disrupts the chaperoning function and the degradation of its client proteins.
In the resting state, through the dimerization of its C-terminal domain, HSP90 forms a homodimer which is defined as the open conformation. Upon ATP-binding, the N-terminal domain undergoes significant conformational changes and comes in contact to form an active closed conformation. After HSP90 finishes its chaperoning tasks of assisting the proper folding, stabilization and activation of client proteins under the active state, ATP molecule is hydrolyzed to ADP which then dissociates from HSP90 and directs the protein back to the resting state.
Methylated by SMYD2; facilitates dimerization and chaperone complex formation; promotes cancer cell proliferation.
Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone. After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle. Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at three different levels. They first alter the steady-state levels of certain transcription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression. Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation. Promotes cell differentiation by chaperoning BIRC2 and thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery. Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription. Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10.
Monomer. Homodimer (By similarity). Forms a complex with CDK6 and CDC37. Interacts with UNC45A; binding to UNC45A involves 2 UNC45A monomers per HSP90AB1 dimer (By similarity). Interacts with CHORDC1 (By similarity). Interacts with DNAJC7. Interacts with FKBP4. May interact with NWD1. Interacts with SGTA. Interacts with HSF1 in an ATP-dependent manner. Interacts with MET; the interaction suppresses MET kinase activity. Interacts with ERBB2 in an ATP-dependent manner; the interaction suppresses ERBB2 kinase activity. Interacts with HIF1A, KEAP1 and RHOBTB2. Interacts with STUB1 and SMAD3. Interacts with XPO1 and AHSA1. Interacts with BIRC2. Interacts with KCNQ4; promotes cell surface expression of KCNQ4. Interacts with BIRC2; prevents auto-ubiquitination and degradation of its client protein BIRC2. Interacts with NOS3. Interacts with AHR; interaction is inhibited by HSP90AB1 phosphorylation on Ser-226 and Ser-255. Interacts with STIP1 and CDC37; upon SMYD2-dependent methylation. Interacts with JAK2 and PRKCE; promotes functional activation in a heat shock-dependent manner. Interacts with HSP90AA1; interaction is constitutive. HSP90AB1-CDC37 chaperone complex interacts with inactive MAPK7 (via N-terminal half) in resting cells; the interaction is MAP2K5-independent and prevents from ubiquitination and proteasomal degradation. Interacts with CDC25A; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (By similarity). Interacts with TP53 (via DNA binding domain); suppresses TP53 aggregation and prevents from irreversible thermal inactivation (PubMed:8663025). Interacts with TGFB1 processed form (LAP); inhibits latent TGFB1 activation (By similarity). Interacts with TRIM8; prevents nucleus translocation of phosphorylated STAT3 and HSP90AB1 (By similarity). Interacts with NR3C1 (via domain NR LBD) and NR1D1 (via domain NR LBD) (By similarity). Interacts with PDCL3 (PubMed:27496612).Interacts with TTC4 (via TPR repeats) (By similarity). Interacts with IL1B; the interaction facilitates cargo translocation into the ERGIC (By similarity).
Phosphorylation at Tyr-301 by SRC is induced by lipopolysaccharide. Phosphorylation at Ser-226 and Ser-255 inhibits AHR interaction.
S-nitrosylated; negatively regulates the ATPase activity.
The TPR repeat-binding motif mediates interaction with TPR repeat-containing proteins.
Ubiquitinated in the presence of STUB1-UBE2D1 complex (in vitro).
Detected in skin, esophagus, tongue, skin, muscle, uterus, ovary, testis and epididymis.
In neonatal animals, highly expressed in skin.
Transcriptional repressor. Specifically binds DNA and probably acts by recruiting chromatin remodeling multiprotein complexes.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel (By similarity). 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 ATP5MPL. Interacts with PRICKLE3 (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 (By similarity).
Expression in brain declines from 18 dpc to P8 and is undetectable from P14 onwards.
Homodimerizes, the dimers can polymerize end-to-end to form filamentous structures. Interacts with GTP-bound CDC42. Interacts with DAAM1, DIAPH1, DIAPH2, DNM1, DNM2 and WASL/N-WASP. Interacts with ATG3. Interacts (via SH3 domain) with ABI1, WASF2, CDC42 and WIPF1.
Isoform 1 is expressed in brain. Isoform 2 is expressed in brain, kidney and lung. Within the brain expression is seen in cortical neurons, hippocampal pyramidal neurons, hypothalamus and piriform cortex.
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-WASPIP 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 (By similarity). May negatively regulate neurite extension and axon branching in developing neurons.
Interacts with STX17 (Probable). 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 as subunit of 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 (By similarity).
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.
Expressed in heart, liver, brain, spleen, lung, skeletal muscle, kidney and testis.
Mainly autophosphorylated on serine/threonine residues. Also autophosphorylated on Tyr-198 (By similarity).
Membrane-associated protein kinase that phosphorylates on serine and threonine residues. In vitro substrates include DRG1, ENO1 and EIF4EBP1. Also autophosphorylates (By similarity). May be involved in secretory vesicle trafficking or intracellular signaling. May have a role in regulating stromal-epithelial interactions that occur during ductal morphogenesis in the mammary gland. May be involved in TGF-beta signaling. Able to autophosphorylate on Tyr residue; it is however unclear whether it has tyrosine-protein kinase toward other proteins.
Monomer. Interacts with DRG1 (via its N-terminal); the interaction phosphorylates DRG1.
Interacts with CD48. Following phosphorylation, it is able to recruit PTPN11/SHP-2 and SH2D1A/SAP. Binding of SH2D1A/SAP to CD244 prevents its association with PTPN11/SHP-2 (By similarity).
Modulate other receptor-ligand interactions to enhance leukocyte activation.
Expressed in the central nervous system. Isoform RGS9L is found in striatum, hypothalamus and nucleus accumbens while isoform RGS9S is expressed in retina and pineal gland.
Heterodimer with GNB5. Interacts with RGS7BP, leading to regulate the subcellular location of the heterodimer formed with GNB5. Component of the RGS9-1-Gbeta5 complex composed of RGS9 (RGS9-1), Gbeta5 (GNB5) and RGS9BP. Interacts with PDE6G and GNAT1.
Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to GNAT1. Involved in phototransduction; key element in the recovery phase of visual transduction (By similarity).
Interacts with VPS33B. Associates with the homotypic fusion and vacuole protein sorting (HOPS) complex; impaired by VPS33B. Interacts with RAB11A (By similarity).
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. 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. May play a role in vesicular trafficking during spermatogenesis. May be involved in direct or indirect transcriptional regulation of E-cadherin (By similarity).
Contributes to the organization of the actin cytoskeleton and cell shape (PubMed:18768925). Plays a role in the formation of lamellipodia and in cell migration (PubMed:18768925). Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones (PubMed:21210813). Through its interaction with CTTNBP2, involved in the regulation of neuronal spine density (By similarity). Plays a role in focal adhesion assembly and turnover (PubMed:18768925, PubMed:22952866). In complex with ABL1 and MYLK regulates cortical actin-based cytoskeletal rearrangement critical to sphingosine 1-phosphate (S1P)-mediated endothelial cell (EC) barrier enhancement (By similarity). Plays a role in intracellular protein transport and endocytosis, and in modulating the levels of potassium channels present at the cell membrane (By similarity). Plays a role in receptor-mediated endocytosis via clathrin-coated pits (PubMed:12612086, PubMed:19995918). Required for stabilization of KCNH1 channels at the cell membrane (By similarity).
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 (By similarity). Interacts (via N-terminus) with NEDD9 (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Forms a complex with ABL1 and MYLK (By similarity). Interacts with SHANK2 and SHANK3 (via its SH3 domain). Interacts with PLXDC2 and SRCIN1. Interacts with SAMSN1 (via SH3 domain). Interacts (via SH3 domain) with ASAP1 (via Pro-rich region). Interacts with FER. Interacts with FGD1. Interacts with ABL2. 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 (By similarity). Interacts (via SH3 domain) with DNM2 (PubMed:21210813). Interacts with ACTN1 (PubMed:21210813). Interacts with KCNA2 (via non-phosphorylated C-terminus) (PubMed:12151401, PubMed:17959782). Interacts with PTK2/FAK1 (PubMed:22952866). 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 FER. Phosphorylated in response to FGR activation. Phosphorylation by SRC promotes MYLK binding (By similarity). Tyrosine phosphorylation in transformed cells may contribute to cellular growth regulation and transformation. 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 associate with filamentous actin (By similarity). Phosphorylated on tyrosine residues in response to CHRM1 activation (PubMed:12151401). Phosphorylated by PTK2/FAK1 in response to cell adhesion (PubMed:22952866).
The SH3 motif may mediate binding to the cytoskeleton.
Belongs to the DEAD box helicase family. DDX59 subfamily.
Interacts (via HIT-type zinc finger) with the RUVBL1/RUVBL2 complex in the presence of ADP.
The Q motif is unique to and characteristic of the DEAD box family of RNA helicases and controls ATP binding and hydrolysis.
This enzyme scavenges exogenous and endogenous cytidine and 2'-deoxycytidine for UMP synthesis.
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:24070791). 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) (PubMed:24070791).
Highly abundant in adrenal gland and mammary tissue and moderately in liver, kidney, lung, spleen, thymus, brain, and eye.
Regulated by dietary vitamin A and exogenous retinoic acid in liver.
Cells overexpressing Sh3gl3 show inhibition of transferrin uptake. Olfactory epithelium-derived cells overexpressing SH3GL3, DRD2 and GRK2 show accelerated differentiation upon addition of apomorphine due to reduced agonist-induced endocytosis of DRD2.
Expressed at high level in testis and at lower level in brain and liver.
Implicated in endocytosis. May recruit other proteins to membranes with high curvature.
Interacts with SGIP1 and DYDC1 (By similarity). Interacts with FASLG. Interacts with ATXN2. Interacts with BIN2 (By similarity). Interacts with ARC, DNM1 and SYNJ1.
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 (By similarity).
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 binding to Complement factor B Bb fragment (Bb), which is then stabilized by binding CFP, allowing the complex to become active (By similarity). The interaction with Bb is dependent on Mg2+ (By similarity). C3b interacts with CR1 (via Sushi 8 and Sushi 9 domains). C3b interacts with CFH. C3d interacts with CFH. 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 with S.aureus immunoglobulin-binding protein sbi, this prevents interaction between C3dg and CR2. Interacts with S.aureus fib. 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 dietary chylomicrons (By similarity).
Derived from proteolytic degradation of complement C3, C3a 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. In chronic inflammation, acts as a chemoattractant for neutrophils (PubMed:8352775).
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 (By similarity). Receptor for netrin required for axon guidance independently of and in collaboration with the receptor DCC (PubMed:18585357). 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. Mediates intracellular signaling by stimulating the activation of MAPK8 and MAP kinase p38 (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).
Expressed in spinal cord at 11 dpc. Expressed in precrossing commissural axons and growth cones of neurons that crossed the midline at 12 dpc. Expressed in axons coursing in the ventral and dorsal funiculus ar 13 dpc. Expressed in postcrossing axons at 15 dpc (at protein level).
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 (By similarity). Interacts (via extracellular domain) with UNC5C (via Ig-like C2-type domain) (By similarity). 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.
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 (By similarity).
Homodimer. Interacts with CSF1R (By similarity).
Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins.
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:23382512). 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. Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss. May also play a role in the regulation of the expression of airway mucins (By similarity).
Belongs to the glycosyltransferase 14 family.
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.
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. Regulates macrophage activation. Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance. 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. In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN. Expressed on Treg cells can inhibit Th17 cell responses. Receptor for LGALS9. 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. However, the function as receptor for LGALS9 has been challenged (By similarity). Also reported to enhance CD8+ T cell responses to an acute infection such as by Listeria monocytogenes. 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. Can enhance mast cell production of Th2 cytokines Il-4, IL-6 and IL-13. Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity. Negatively regulates NK cell function in LPS-induced endotoxic shock.
Expression is up-regulated in the spinal cord during experimental autoimmune encephalomyelitis (EAE) and following antigen restimulation of the encephalitogenic TCRBV8S2+ population. Expression was also detected by in situ hybridization in resident cells of the nervous system.
Interacts with HMGB1; impairs HMGB1 binding to B-DNA and likely HMGB1-mediated innate immune response. Interacts with BAG6. Interacts (phosphorylated) with PIK3R1 and PIK3R2. Interacts (not dependent on its phosphorylation status) with FYN. 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. Interacts with ILF3; this interaction promotes ILF3 ubiquitination and degradation.
Converts inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5). Converts 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4 (By similarity).
Belongs to the calcium channel flower family.
Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. It may be involved in the development of some ectoderm-derived structures (PubMed:10811609). Acts as a negative regulator of type I interferon production via the complex formed with VCP and NPLOC4, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI (By similarity).
Interacts with USP13 (By similarity). Heterodimer with NPLOC4, this heterodimer binds VCP and inhibits Golgi membrane fusion (PubMed:10811609). Interacts with ZFAND2B; probably through VCP (By similarity).
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.
Tryptase is the major neutral protease present in mast cells and is secreted upon the coupled activation-degranulation response of this cell type. Plays a role in innate immunity.
Homodimer; the homodimer is independent of 2Fe-2S clusters. Heterotrimer; forms a heterotrimeric complex composed by two BOLA2 molecules and one GLRX3 molecule; linked by [2Fe-2S] clusters. Interacts (via N-terminus) with PRKCQ/PKC-theta (By similarity). Interacts (via C-terminus) with CSRP3 (PubMed:18258855). Interacts with CSRP2 (By similarity).
In neonatal cardiomyocytes after exposure to the hypertrophic agonists EDN1 (ET-1) or phenylephrine (PE). In transverse aortic constriction (TAC) induced cardiac hypertrophy in adult hearts.
The thioredoxin domain lacks the two redox-active cysteines. This strongly suggests that it lacks thioredoxin activity.
Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins (By similarity). Acts as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator (PubMed:16809552, PubMed:18258855). Required for hemoglobin maturation (By similarity). Does not possess any thyoredoxin activity since it lacks the conserved motif that is essential for catalytic activity (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 THOC1, POLDIP3 and ZC3H11A.
Acts as an E3 ubiquitin-protein ligase. Plays an essential role in autophagy activation during viral infection. Mechanistically, activates TANK-binding kinase 1/TBK1 by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor SQSTM1. In order to achieve this function, TRIM23 mediates 'Lys-27'-linked auto-ubiquitination of its ADP-ribosylation factor (ARF) domain to induce its GTPase activity and its recruitment to autophagosomes.
Homodimer. Interacts with PSCD1. Interacts with UBE2D2. Interacts with TBK1 (via N-terminal kinase domain) and p62/SQSTM1.
In the C-terminal section; belongs to the small GTPase superfamily. Arf family.
Growth factor active on keratinocytes. Possible major paracrine effector of normal epithelial cell proliferation.
Interacts with FGFBP1. Interacts with FGFR2 (By similarity). Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.
Can also autophosphorylate on serine and threonine residues (in vitro) (By similarity). Autophosphorylated on numerous tyrosine residues (PubMed:8631952).
Detected in brain (at protein level). Ubiquitous.
Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities (PubMed:8631952, PubMed:9748265, PubMed:18938227, PubMed:22998443). Exhibits a substrate preference for proline at position P+1 and arginine at position P-3 (By similarity). Plays an important role in double-strand breaks (DSBs) repair following DNA damage (By similarity). Mechanistically, phosphorylates RNF169 and increases its ability to block accumulation of TP53BP1 at the DSB sites thereby promoting homologous recombination repair (HRR) (By similarity). 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 (By similarity). May play a role in a signaling pathway regulating nuclear functions of cell proliferation (By similarity). Modulates alternative splicing by phosphorylating the splice factor SRSF6 (PubMed:22767602). Has pro-survival function and negatively regulates the apoptotic process. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1. This in turn inhibits p53/TP53 activity and apoptosis (By similarity). Phosphorylates SEPTIN4, SEPTIN5 and SF3B1 at 'Thr-434' (PubMed:18938227).
Inhibited by RANBP9 (By similarity). Inhibited by harmine, leucettamine B and leucettine L41 (PubMed:22998443).
Interacts RAD54L2/ARIP4 (By similarity). Interacts with CRY2 (By similarity). Interacts with RANBP9. Interacts with WDR68 (By similarity). 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.
Forms a ternary complex with IGFR1 and ITGAV:ITGB3. Forms a ternary complex with IGFR1 and ITGA6:ITGB4.
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. Ca(2+)-dependent exocytosis of IGF1 is required for sensory perception of smell in the olfactory bulb. 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 (By similarity).
Highly expressed in lung, spleen, small and large intestine, stomach and brain. Expressed in neonatal microglia.
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) (By similarity).
The extracellular domain forms a stable trimer. The extracellular domain interacts with fibrillar amyloid-beta peptide (By similarity).
Co-chaperone that binds directly to HSC70 and HSP70 and regulates their ATPase activity.
Expressed in many tissues, including brain, heart, kidney, liver, lung, prostate, skin, spleen and stomach.
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 (By similarity). Inhibits plasmin.
Transcription factor required in complex with TAF3 for the differentiation of myoblasts into myocytes. The complex replaces TFIID at specific promoters at an early stage in the differentiation process (By similarity).
Detected in retina, entire eyecups and in liver (at protein level).
Retinol dehydrogenase with a clear preference for NADP. Converts all-trans-retinol to all-trans-retinal.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR2B/GRIN2B subfamily.
Channel activity is inhibited by micromolar levels of zinc ions (PubMed:19910922). Channel activity is inhibited by ifenprodil (PubMed:19910922, PubMed:21677647).
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:1350383, PubMed:19910922, PubMed:21677647, PubMed:24876489, PubMed:27135925, PubMed:27916457). Sensitivity to glutamate and channel kinetics depend on the subunit composition (Probable). 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).
Expressed during postnatal days P3 to P60, with decreased expression after postnatal day 14.
Expressed in the hippocampus including the dentate gyrus (at protein level) (PubMed:22960932). Detected in adult olfactory bulb, brain cortex, hippocampus, striatum, thalamus, superior colliculus, with much lower levels in inferior colliculus, midbrain and cerebellum.
Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:1350383, PubMed:19910922, PubMed:21677647, PubMed:24876489, PubMed:27135925, PubMed:27916457). 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. Found in a complex with GRIN1 and GRIN3B. Interacts with MAGI3. Interacts with HIP1 and NETO1. Interacts with PDZ domains of PATJ, DLG3 and DLG4. Interacts with DAPK1 (By similarity). Found in a complex with GRIN1 and PRR7 (PubMed:27458189). Interacts with PRR7 (PubMed:27458189). Interacts with CAMK2A (By similarity). Interacts with ARC; preventing ARC oligomerization (PubMed:31080121). Interacts with TMEM25 (By similarity).
Phosphorylated on tyrosine residues (PubMed:7513428). Phosphorylation at Ser-1303 by DAPK1 enhances synaptic NMDA receptor channel activity (By similarity).
Calcium-dependent nucleotidase with a preference for UDP. The order of activity with different substrates is UDP > GDP > IDP >> UTP > CDP = GTP = ITP. Has very low activity towards ADP and even lower activity towards ATP. Does not hydrolyze AMP and GMP (PubMed:12167635). Involved in proteoglycan synthesis (By similarity).
Detected in intestine, thymus, heart, lung, spleen, kidney, liver, testis, skeletal muscle and brain.
Monomer. Homodimer; dimerization is Ca(2+)-dependent.
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. Regulates cholesterol homeostasis by catalyzing the conversion of excess cholesterol to bile acids via both the 'neutral' (classic) and the 'acid' (alternative) pathways. 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. 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. 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. May play a redundant role in vitamin D biosynthesis (By similarity). Catalyzes 25-hydroxylation of vitamin D3 that is required for its conversion to a functionally active form (PubMed:2175615).
Interacts with HSP70; this interaction is required for initial targeting to mitochondria.
Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination.
Homodimer or heterodimer with MID2. Interacts with IGBP1.
Belongs to the glycosyl hydrolase 1 family.
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.
Heterodimer of a type I and a type II keratin. Colocalizes with KRT8/KRT18 filament network (By similarity).
Belongs to the Engrailed homeobox family.
This sequence represents the precursor of the major form of trypsin produced by the adult pancreas.
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:15024004). 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:15024004). 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).
Expression gradually increases in the first weeks after birth (at protein level).
Has a decreased affinity for ATP and a reduced diacylglycerol kinase activity. Has no preference for any of the diacylglycerols in terms of the acyl chain composition.
Interacts (via PDZ-binding motif) with DLG4; controls the localization of DGKI to the synapse (PubMed:21119615). Interacts (via PDZ-binding motif) with DLG1 (PubMed:21119615). Interacts (via PDZ-binding motif) with DLG2 (PubMed:21119615). Interacts (via PDZ-binding motif) with DLG3 (PubMed:21119615). May interact with RASGRP3; involved in the regulation of RASGRP3 activity (By similarity).
Major isoform in brain (at protein level).
Minor isoform in brain (at protein level).
Specifically expressed in brain (at protein level) (PubMed:15024004, PubMed:21119615). Expressed in hippocampus, cerebellum, brain stem and spinal cord (at protein level) (PubMed:21119615). Highly expressed in hippocampus, cerebellar cortex, olfactory bulb, and olfactory tubercle and to lower extent in the cerebral cortex, caudate putamen, and thalamus. Not detected in the white matter (PubMed:15024004). Also expressed in eye (PubMed:15024004).
Both isoforms down-regulated during muscle development. Up-regulated after denervation.
Expressed in the aorta, primary bronchus, uterus, heart, skeletal muscle, sciatic nerve and spinal cord but not in the intestine.
High expression at 14 dpc. Sharp decline in expression between 16 dpc and 18 dpc. Absent in adulthood.
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 (By similarity). 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 (By similarity). Interacts with MFAP5 (By similarity).
Multifunctional protein that regulates various processes such as angiogenesis and heart 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-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. 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.
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.
Transforming growth factor beta-2: Homodimer; disulfide-linked (By similarity). Transforming growth factor beta-2: Interacts with TGF-beta receptors (TGFBR1 and TGFBR2), leading to signal transduction (By similarity).
Arginine methylation by PRMT5 enhances repression activity of metabolic genes in liver in response to bile acid signaling, by increasing interaction with cofactors.
Detected in kidney, testis, heart and liver.
Heterodimer; efficient DNA binding requires dimerization with another bHLH protein (By similarity). Interacts (via N-terminus) with NEUROD1 (via N-terminus and C-terminus) (By similarity). Interacts with ID2 (By similarity). Interacts with NR1I3 and EID1 (By similarity). Interacts with RARA, RXRA, THRB, NR5A1, NR5A2, PPARA and PPARG (PubMed:9003453, PubMed:15976031, PubMed:15721253). Interacts with RORG, NFIL3, NR1D1 and BHLHE41 (By similarity). Interacts with HNF4A; the resulting heterodimer is transcriptionnally inactive (By similarity). 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 (By similarity).
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 (By similarity). 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).
Interacts (via N-terminus) with RAB2B (in GTP-bound form).
RAB2B effector protein required for accurate acrosome formation and normal male fertility.
May facilitate PTTG1 nuclear translocation.
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 current is blocked by barium and tetraethylammonium whereas 4-aminopyridine and charybdotoxin have no effect on KCNQ2 current. Tyrosine kinase inhibitors genistein or herbimycin a markedly down-regulate KCNQ2 current. As the native M-channel, the potassium channel composed of KCNQ2 and KCNQ3 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1.
Belongs to the potassium channel family. KQT (TC 1.A.1.15) subfamily. Kv7.2/KCNQ2 sub-subfamily.
Expressed in brain and sympathetic ganglia. In brain, expressed in cortex, hippocampus, and cerebellum. In sympathetic ganglia, expressed at lower levels in celiac ganglia and superior mesenteric ganglia than in superior cervical ganglia.
Heterotetramer with KCNQ3; form the heterotetrameric M potassium channel (PubMed:11230508). Interacts with calmodulin; the interaction is calcium-independent, constitutive and participates in the proper assembly of a functional heterotetrameric M channel. May associate with KCNE2 (By similarity). Interacts with IQCJ-SCHIP1 (By similarity).
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.
When coexpressed with KCNQ3 subunit in CHO cells or Xenopus oocytes, isoform B was found to have significantly different deactivation-activation kinetics. The kinetics was 2.5 times more slowly than the kinetics of other isoforms. The presence of exon 15a in isoform B accounts for the slow deactivation-activation kinetics. Alternative splicing of the KCNQ2 gene may contribute to the variation in M-current kinetics seen in vivo.
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 (By similarity).
Transcription factor that controls lens epithelial cell growth through regulation of proliferation, apoptosis and cell cycle (By similarity). 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 (By similarity).
Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle (PubMed:8042990). 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. Regulates the release of lumenal Ca(2+) via the calcium release channel RYR1; this plays an important role in triggering muscle contraction (By similarity). Negatively regulates store-operated Ca(2+) entry (SOCE) activity (By similarity).
Detected in skeletal muscle and in smooth muscle from vas deferens, aorta and stomach (at protein level).
Monomer; increases in response to a depletion of intracellular calcium. Homodimer. 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. Interacts with ASPH and TRDN.
Activated by light stimulation at night through the suppression of beta-adrenergic signaling.
Highly expressed in the brain, in the pineal gland specifically during the daylight hours, and weakly in the olfactory bulb and pineal gland during the night. First detected between postnatal days 5 and 10.
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. Catalyzes the O-sulfation of glucosamine in GlcA2S-GlcNS. Unlike HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate (By similarity). May contribute to the pineal circadian physiology (PubMed:12601002).
Histone deacetylase that catalyzes 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. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility. In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones.
Interacts with CBFA2T3. Interacts with phosphorylated SMG5/EST1B; this interaction protects SMG5 from ubiquitin-mediated degradation. Associates with alpha-SMA (smooth muscle alpha-actin) (By similarity).
Its activity is inhibited by trichostatin A (TSA) and butyrate, 2 well known histone deacetylase inhibitors.
Phosphorylated by PKA on serine 39. Phosphorylation reduces deacetylase activity observed preferentially on histones H3 and H4 (By similarity).
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 (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.
Selectively expressed by cultured astrocytes but not endothelial cells, microglia or neurons.
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A17 subfamily.
Found exclusively in the central nervous system and is more abundant in the cerebellum and the cerebral cortex. Expressed in PC-12 cell line.
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.
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 (By similarity).
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. In a neuroblastoma cell line, protects cells from ER stress-induced death. In vitro activates transcription of target genes via direct binding to the CRE site.
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.
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).
Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits.
Homotrimer. Interacts with PKD2. Interacts with STOML3.
Moderate expression in lung and kidney. Very weak expression in heart, spleen and liver.
Piezo comes from the Greek 'piesi' meaning pressure.
Pore-forming subunit of a mechanosensitive non-specific cation channel. Generates currents characterized by a linear current-voltage relationship that are sensitive to ruthenium red and gadolinium. Plays a key role in epithelial cell adhesion by maintaining integrin activation through R-Ras recruitment to the ER, most probably in its activated state, and subsequent stimulation of calpain signaling. In the kidney, may contribute to the detection of intraluminal pressure changes and to urine flow sensing. Acts as shear-stress sensor that promotes endothelial cell organization and alignment in the direction of blood flow through calpain activation. Plays a key role in blood vessel formation and vascular structure in both development and adult physiology. Acts as sensor of phosphatidylserine (PS) flipping at the plasma membrane and governs morphogenesis of muscle cells. In myoblasts, flippase-mediated PS enrichment at the inner leaflet of plasma membrane triggers channel activation and Ca2+ influx followed by Rho GTPases signal transduction, leading to assembly of cortical actomyosin fibers and myotube formation.
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-244 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7 (By similarity). 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-376 and Tyr-379 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-244 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-376 and Tyr-379 by INSR in response to insulin (By similarity).
Monoubiquitinated in the kinase domain, deubiquitinated by USP4.
Phosphorylation on Ser-244 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-244, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2. 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-376 and Tyr-379 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-244 and palmitate-induced phosphorylation at Ser-532 and Ser-504 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-357 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-397 and Ser-401 by MAP3K5 (By similarity).
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 (By similarity).
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.
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. Binds to N6-methyladenosine (m6A)-containing mRNAs and contributes to MYC stability by binding to m6A-containing MYC mRNAs. May bind to specific miRNA hairpins.
Part of a complex consisting of SFPQ, NONO and MATR3. Interacts with AGO1 and AGO2 (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. 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. Interacts with FUS. Interacts with IGF2BP1. Interacts with IGF2BP2 and IGF2BP3.
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). May play a role in coupling of proton transport and ATP hydrolysis (By similarity). Regulator of osteoclast fusion and bone formation (By similarity).
May act as a component of a corepressor complex that represses transcription.
Activated by phosphorylation on Ser-356 by an unknown kinase (may be mTORC2 but not confirmed), transforming it into a substrate for PDPK1 which then phosphorylates it on Thr-193.
Expressed in the proximal tubule and thick ascending limb of the loop of Henle (TALH).
Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, survival and proliferation. Up-regulates Na(+) channels: SCNN1A/ENAC, K(+) channels: KCNA3/Kv1.3, KCNE1 and KCNQ1, amino acid transporter: SLC6A19, glutamate transporter: SLC1A6/EAAT4, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase.
Two specific sites, one in the kinase domain (Thr-193) and the other in the C-terminal regulatory region (Ser-356), need to be phosphorylated for its full activation.
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 (By similarity). Overexpression in cultured neurons significantly inhibits neuronal transferrin endocytosis, secretory vesicle retrieval, cell migration, and oxidative stress from glutamate toxicity (PubMed:26195140).
Expressed in the brain and central nervous system (at protein level). Isoform 1 and isoform 2 are expressed in the brain, kidney, liver, heart, lung, skeletal muscle, testis and spleen. Isoform 2 shows a higher expression in the brain, heart and skeletal muscle.
High expression in liver and brain, lower in lung and heart and very low in kidney and skeletal muscle (at protein level). Present in all brain regions and spinal cord (at protein level).
Interacts with ATG13, OPRK1, RB1CC1 and ULK1. Interacts with TP53INP1 and TP53INP2. Directly interacts with SQSTM1. Interacts with ATG3, ATG7 and MAP15. Interacts with TECPR2. Interacts with TBC1D5. Interacts with MAPK15. Interacts with TRIM5. Interacts with MEFV and TRIM21. Interacts with WDFY3. Interacts with the reticulophagy receptor TEX264. Interacts with UBA5. Interacts with KBTBD6 and KBTBD7; the interaction is direct. Interacts with reticulophagy regulators RETREG1, RETREG2 and RETREG3.
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. 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. During non-canonical autophagy, the processed form is conjugated to phosphatidylserine (PS) phospholipid. ATG4 proteins also mediate the delipidation of PE-conjugated forms required for GABARAPL1 recycling when autophagosomes fuse with lysosomes. In addition, ATG4B and ATG4D mediate delipidation of ATG8 proteins conjugated to PS during non-canonical autophagy. ATG4B constitutes the major protein for proteolytic activation (By similarity). 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. Involved in formation of autophagosomal vacuoles. While LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation. 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.
Contributes to normal sperm motility, but not essential for male fertility.
In testis: weakly expressed in newborns, increases remarkably at 3 weeks postpartum, and peaks at 2 months postpartum (at protein level).
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:21389246). 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 the hippocampus and cerebral cortex (at protein level) (PubMed:15519747). Expressed in stem and progenitor cells in the subventricular zone of the hippocampus (at protein level) (PubMed:16554442). Expressed in hippocampal neurons, with highest levels of expression in the CA4 and CA3 neurons and lower levels in CA1 neurons (at protein level) (PubMed:11948657, PubMed:17577668, PubMed:25692578). Expressed in the dorsal root ganglion (at protein level) (PubMed:12957493). Expressed in the superior cervical ganglion (PubMed:17234598).
Expression in dentate granule cells of the hippocampus at postnatal day 7, with disappearing expression in dentate granule cells as early as P14.
Methylated by CARM1, which leads to reduced RNA-binding activity and enhanced interaction with SMN (By similarity). 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 (PubMed:16508003). Methylation is inhibited by NGF, which facilitates neurite outgrowth (PubMed:16508003).
RNA-binding protein that is involved in the post-transcriptional regulation of mRNAs (PubMed:10982410, PubMed:16508003, PubMed:17577668). Plays a role in the regulation of mRNA stability, alternative splicing and translation (PubMed:10982410, PubMed:16508003, PubMed:17577668). 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:10982410). 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 (By similarity). Also binds to the polyadenylated (poly(A)) tail in the 3'UTR of mRNA, thereby increasing its affinity for mRNA binding (By similarity). 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:10982410, PubMed:17577668). 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 (By similarity). Protects CDKN1A mRNA from decay by binding to its 3'-UTR (PubMed:16508003). May bind to APP and BACE1 mRNAS and the BACE1AS lncRNA and enhance their stabilization (By similarity). 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:10982410, PubMed:17234598). By promoting the stabilization of GAP43 mRNA, plays a role in NGF-mediated neurite outgrowth (PubMed:10982410). Binds to BDNF long 3'UTR mRNA, thereby leading to its stabilization and increased dendritic translation after activation of PKC (PubMed:25692578). 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 (By similarity). 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 form ELAVL4 and translational inhibition is abolished (By similarity). Also plays a role in the regulation of alternative splicing (By similarity). 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 sequences of CALCA pre-mRNA (By similarity).
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).
Up-regulated by kainic acid-induced seizures (PubMed:17577668). Up-regulated after contextual fear conditioning (PubMed:15519747). Down-regulated at day 2 after axotomy and up-regulated at day 7 after axotomy (PubMed:17234598, PubMed:12957493).
Transcription factor that binds to the octamer motif (5'-ATTTGCAT-3') (By similarity). Acts as a transcriptional activator when binding cooperatively with SOX4, SOX11, or SOX12 to gene promoters (By similarity). Acts as a transcriptional repressor of myelin-specific genes (PubMed:1975954).
Transiently increased in rapidly dividing Schwann cells in response to sciatic nerve transection 2 days post-injury.
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 (By similarity).
Highly expressed in pulmonary vein endothelial cells, lung and brain (at protein level). Isoform 1 is expressed at high levels in the brain (hippocampus, cerebral cortex and olfactory bulb) and poorly in the spleen and other tissues, whereas isoforms 2 and 3 are expressed in the spleen and brain (highest in cerebellum).
Homodimer, or homooligomer. 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 RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with PDPK1. Interacts with LPXN and PTPN12 (By similarity). Interacts with SIRPA and SH2D3C. Interacts (hypophosphorylated) with PXN. Interacts with ARHGAP10. Interacts with KCNA2 (PubMed:11739373).
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' (By similarity). 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 (By similarity).
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 (By similarity).
Detected in adult intestine, especially in mucosal epithelium, longitudinal and circular layers of muscularis externa and myenteric plexuses. Highly expressed in Paneth cells, and detected at lower levels in enterocytes (at protein level). Detected in brain cortex.
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). 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). 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 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. Affects neural activity, perception, cognition and mood. 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. May interact (via C-terminus) with MPP3, PRDX6, DLG4, DLG1, CASK, APBA1 and MAGI2. Interacts with GRM2 and DRD2; this may affect signaling.
The PDZ domain-binding motif is involved in the interaction with PATJ, CASK, APBA1, DLG1 and DLG4.
Homodimer. Part of a ternary complex that contains CEP350, CEP43 and MAPRE1. Interacts directly with CEP350 and MAPRE1. Interacts with CEP19. Interacts (via N-terminus) with CEP350 (via C-terminus).
Required for anchoring microtubules to the centrosomes. Required for ciliation.
A conserved histidine residue in the third TMD (His-107) may play an essential role in the pH sensitivity of SLCO1A5/OATP1A5-mediated substrate transport.
Highly expressed in the kidney, moderately abundant in the retina, and even lower in the liver (PubMed:9712861). Expressed (at protein level) in the small intestine (PubMed:11093941). Expressed at lower levels in brain,lung, and retina (PubMed:11093941).
Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), estrone 3-sulfate and prostaglandin E2, at the plasma membrane (PubMed:9712861, PubMed:11093941, PubMed:19129463). Responsible for intestinal absorption of bile acids (PubMed:11093941). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:9712861, PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (By similarity). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463).
Belongs to the ROX family. NO66 subfamily.
Interacts with SP7/OSX; the interaction is direct (By similarity). Interacts with MYC. Interacts with PHF19; leading to its recruitment to H3K36me3 sites (By similarity).
Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase (By similarity). Specifically demethylates 'Lys-4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3, thereby playing a central role in histone code. 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). 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. 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. Participates in MYC-induced transcriptional activation (By similarity).
Acetylated at Lys-166; deacetylated at Lys-166 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 (PubMed:18667415). 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 (By similarity). Interacts with C1QBP (By similarity). Interacts with MCUR1 (By similarity). Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF (PubMed:9874241). Interacts with SPG7 (By similarity).
Binds cyclosporin A (CsA). 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 (By similarity). Involved in regulation of the mitochondrial permeability transition pore (mPTP) (PubMed:8567677, PubMed:9309684, PubMed:9820802). 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:8567677, PubMed:9309684, PubMed:9820802). In cooperation with mitochondrial p53/TP53 is involved in activating oxidative stress-induced necrosis (PubMed:8567677, PubMed:9309684, PubMed:9820802). Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels (PubMed:8567677, PubMed:9309684, PubMed:9820802). Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis (PubMed:19228691).
The polyclonal antibody used in PubMed:9820802 and PubMed:9874241 and initially thought to detect SLC25A4/ANT1 in interactions with Ppif/CyP-D is rather detecting SLC25A3.
Associates with the spliceosome. Component of a large chromatin remodeling complex, at least composed of MYSM1, PCAF, RBM10 and KIF11/TRIP5 (By similarity).
Not known. Binds to RNA homopolymers, with a preference for poly(G) and poly(U) and little for poly(A) (PubMed:8760884). May bind to specific miRNA hairpins (By similarity).
Belongs to the mitochondrion-specific ribosomal protein mL53 family.
Associates with PDIA3 through the tip of the extended arm formed by the P-domain.
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. Interacts with the DNA-binding domain of NR3C1 and mediates its nuclear export (By similarity). 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 (By similarity).
Monomer. Component of an EIF2 complex at least composed of CELF1/CUGBP1, CALR, CALR3, EIF2S1, EIF2S2, HSP90B1 and HSPA5. Interacts with GABARAP, NR3C1 and TRIM21. Interacts with PPIB and SPACA9. Interacts (via P-domain) with PDIA5 (By similarity). Interacts with PDIA3/ERp57 (PubMed:11842220). Interacts with CLCC1 (By similarity).
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 (Ref.9) thought to be D-beta-hydroxybutyrate dehydrogenase.
Acts as a growth inhibitor. Can activate p53/TP53, causes G1 arrest and collaborates with CDKN2A to restrict proliferation, but does not require either protein to inhibit DNA synthesis. Redistributes CDKN2A into the nucleoplasm. Involved in maintaining chromosomal stability (By similarity).
Ubiquitinated; mediated by MDM2 and leading to its subsequent proteasomal degradation.
Necessary for the splicing of pre-mRNA. Has a role in the recognition of the branch site (5'-UACUAAC-3'), the pyrimidine tract and the 3'-splice site at the 3'-end of introns.
Binds DNA as a dimer. Can form homodimer or heterodimer with HNF1-alpha (By similarity). Interacts (via HNF-p1 domain) with PCBD1; the interaction increases its transactivation activity (By similarity).
Transcription factor that binds to the inverted palindrome 5'-GTTAATNATTAAC-3' (By similarity). Binds to the FPC element in the cAMP regulatory unit of the PLAU gene (By similarity). Transcriptional activity is increased by coactivator PCBD1 (By similarity).
Binds to type II regulatory subunits (RII).
Binds to type II regulatory subunits of protein kinase A and anchors/targets them.
Expressed at detectable levels 30 days after birth and increased greatly during the next 10 days.
Apoptosis regulator. Has anti-apoptotic activity, both for apoptosis triggered via death-receptors and via mitochondrial factors (By similarity).
Interacts with CASP8, BCL2 and BCL2L1 through SAM domain and also with HIP1, IFT57, ESRRBL1 and BCAP31.
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 a critical role in the assembly of N-DRC and also stabilizes the assembly of multiple inner dynein arms and radial spokes. Coassembles with DRC1 to form a central scaffold needed for assembly of the N-DRC and its attachment to the outer doublet microtubules.
Homo- and heterotetramers (By similarity). Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (M), PFKL (L) and PFKP (P). The composition of the PFK tetramer differs according to the tissue type it is present in. 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).
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. 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. Involved in polyadenylation of mRNA precursors. Connects PAF1C to Wnt signaling (By similarity).
Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8 (By similarity). The PAF1 complex interacts with PHF5A (By similarity). Interacts with TCEA1, SUPT5H and CTNNB1 (By similarity). Interacts with SETD5 (By similarity).
Component of the chaperonin-containing T-complex (TRiC), a heterooligomeric complex of about 850 to 900 kDa that forms two stacked rings, 12 to 16 nm in diameter. Interacts with PACRG. Interacts with GBA1 (By similarity). Interacts with DLEC1 (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. 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 (By similarity).
ATPase component of the INO80 complex which remodels chromatin by shifting nucleosomes and is involved in DNA repair.
Component of the INO80 chromatin-remodeling complex.
The DBINO region is involved in binding to DNA.
Expressed immediately after neuronal birth and is dramatically down-regulated in the adult.
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 by DYRK2 at Ser-522 is required for subsequent phosphorylation by GSK3B. Phosphorylation at Thr-514 by GSK3B abolishes tubulin-binding leading to destabilization of microtubule assembly in axons and neurodegeneration (By similarity).
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 (By similarity).
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 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 (By similarity). 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).
Expressed in brain during neonatal period. Not detected in adult brain (at protein level).
Homodimer. Forms a heterooligomer with SRGAP1 and SRGAP3 through its F-BAR domain. Interacts (via SH3 domain) with GPHN. Interacts (via SH3 domain) with FMNL1 (activated by RAC1); regulates the actin filament severing activity of FMNL1 and actin dynamics. Interacts (via SH3 domain) with FMNL3. Interacts with RAC1; specifically stimulates RAC1 GTPase activity. Interacts (via F-BAR domain) with HOMER1. Interacts with ROBO1 and ROBO2 (By similarity). Interacts with FASLG. Interacts with PRMT5 (By similarity).
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. Regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons. 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. Mechanistically, acts by binding and deforming membranes, thereby regulating actin dynamics to regulate cell migration and differentiation. Promotes cell repulsion and contact inhibition of locomotion: localizes to protrusions with curved edges and controls the duration of RAC1 activity in contact protrusions. In non-neuronal cells, may also play a role in cell migration by regulating the formation of lamellipodia and filopodia.
The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions.
Crystallins are the dominant structural components of the vertebrate eye lens. Also plays an important role for integrity and function of auditory nuclei.
Detected in the auditory hindbrain where it is highly expressed in the medial nucleus of the trapezoid body, but also present in other nuclei of the superior olivary complex.
Seems to be a major component of sperm tail outer dense fibers (ODF). ODFs are filamentous structures located on the outside of the axoneme in the midpiece and principal piece of the mammalian sperm tail and may help to maintain the passive elastic structures and elastic recoil of the sperm tail. May have a modulating influence on sperm motility. Functions as a general scaffold protein that is specifically localized at the distal/subdistal appendages of mother centrioles. Component of the centrosome matrix required for the localization of PLK1 and NIN to the centrosomes. Required for the formation and/or maintenance of normal CETN1 assembly.
Self-associates. Associates with microtubules and forms a fibrillar structure partially linked to the microtubule network. Interacts through its C-terminus with PLK1. Interacts with ODF1 (PubMed:9045620). Interacts with MARK4; the interaction is required for localization of ODF2 to centrioles (By similarity). Interacts with TSSK4 (By similarity). Interacts with AKNA (By similarity). Interacts with QRICH2 (By similarity). Interacts with CFAP58 (By similarity).
Testis-specific (PubMed:9045620). Expressed in the proximal compartment of the elongated spermatid tail; later expression progresses to the distal spermatid tail compartment located in the lumen of the seminiferous epithelium (PubMed:9698445). In spermatids (stages II-III) expression of the tails peaks and remains strong during the remaining steps of spermiogenesis (at protein level) (PubMed:9698445). Expression correlates with the onset of spermatogenesis and is first detected at 30 days. Higher expression is seen in testis of 40-day-old and adults that are older than 50 days (PubMed:9092585). No expression is seen in 10- and 20-day-old testes (PubMed:9092585).
Tyrosine phosphorylated. Phosphorylated on Ser-90 by TSSK4.
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 (By similarity).
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.
Activated by the ototoxic drug cisplatin. 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 (By similarity).
Expressed in the inner ear by the spiral glanglia and the organ of Corti.
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 (By similarity).
Major connective tissue mitoattractant secreted by vascular endothelial cells. Promotes proliferation and differentiation of chondrocytes (By similarity). Mediates heparin- and divalent cation-dependent cell adhesion in many cell types including fibroblasts, myofibroblasts, endothelial and epithelial cells (By similarity). Enhances fibroblast growth factor-induced DNA synthesis (By similarity).
At low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis.
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1: Homodimer (By similarity). Ectonucleotide pyrophosphatase/phosphodiesterase family member 1: Interacts with INSR; leading to inhibit INSR autophosphorylation and subsequent activation of INSR kinase activity (By similarity). Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, secreted form: Monomeric (By similarity).
It is uncertain whether Met-1 or Met-35 is the initiator.
Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels. PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals. 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. 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. 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. Also involved in melanogenesis (By similarity). Also able to hydrolyze 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production (By similarity). 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. Not able to hydrolyze the 2',3'-cGAMP linkage isomer 3'-3'-cGAMP (By similarity).
The di-leucine motif is required for basolateral targeting in polarized epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells.
The secreted form is produced through cleavage at Lys-85 by intracellular processing.
Cell adhesion molecule which is required for leukocyte transendothelial migration (TEM) under most inflammatory conditions. Tyr-660 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. Trans-homophilic interaction may play a role in endothelial cell-cell adhesion via cell junctions. Heterophilic interaction with CD177 plays a role in transendothelial migration of neutrophils. Homophilic ligation of PECAM1 prevents macrophage-mediated phagocytosis of neighboring viable leukocytes by transmitting a detachment signal. 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. Modulates bradykinin receptor BDKRB2 activation. Regulates bradykinin- and hyperosmotic shock-induced ERK1/2 activation in endothelial cells. Induces susceptibility to atherosclerosis.
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. In endothelial cells Fyn mediates mechanical-force (stretch or pull) induced tyrosine phosphorylation. Phosphorylated on tyrosine residues by FER and FES in response to FCER1 activation.
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. Forms a complex with BDKRB2 and GNAQ. Interacts with BDKRB2 and GNAQ. Interacts with PTPN11. Interacts with FER. Interacts with CD177; the interaction is Ca(2+)-dependent; the interaction is direct.
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).
Brain (cerebellum), adrenal gland and spleen. In the adrenal gland, expressed at high levels in the zona glomerulosa and at low levels in the zona fasciculata-reticularis.
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).
Acts as an inhibitor of mitochondrial fission. Interacts with MFF and prevents DNM1L recruitment to mitochondria, promoting a more fused mitochondrial network.
Can homodimerize. Interacts with MFF; the interaction inhibits MFF interaction with DNM1L.
Belongs to the TPT transporter family. SLC35C subfamily.
Has peptide-independent ATPase activity.
Catalyzes the three-step monooxygenation required for the demethylation of 4,4-dimethyl and 4alpha-methylsterols, which can be subsequently metabolized to cholesterol.
Exhibits microtubule-destabilizing activity.
Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity.
By cocaine in the lateral septum. Up-regulated in the failing heart.
Inhibited by calmodulin with an IC(50) of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid (By similarity).
Interacts with ST13 (via the C-terminus 303-319 AA) (By similarity). Interacts with TP53/p53 (By similarity). Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) (By similarity). Interacts with HDAC5 (By similarity). Interacts with GIT1 (PubMed:9826657).
Not expressed ubiquitously in brain but is mainly localize in limbic brain regions with a very prominent expression in the lateral septal area.
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 (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro) (By similarity).
Plays a role in dendrite formation by melanocytes.
Belongs to the TMEM97/sigma-2 receptor family.
Intracellular orphan receptor that binds numerous drugs and which is highly expressed in various proliferating cells. Corresponds to the sigma-2 receptor, which is thought to play important role in regulating cell survival, morphology and differentiation. May play a role as a regulator of cellular cholesterol homeostasis. May function as sterol isomerase. May alter the activity of some cytochrome P450 proteins.
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.
Interacts with MAF (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a homodimer or a heterodimer (USF1/USF2).
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.
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.
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).
Belongs to the bacterial ribosomal protein bS21 family.
G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (PubMed:7816802). Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (By similarity). The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system (By similarity). The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (By similarity).
Homodimer; disulfide-linked (By similarity). Interacts with VCP and RNF19A (By similarity). Interacts with ARRB1 (PubMed:17623778).
In resting state, adopts an open conformation, anion-binding promoting the inactive configuration. Upon aromatic amino acid-binding, the groove in the extracellular venus flytrap module is closed, thereby inducing the formation of a novel homodimer interface between subunits. Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor.
The extracellular regions of the homodimer interact in a side-by-side fashion while facing opposite directions. Each extracellular region consists of three domains, LB1 (ligand-binding 1), LB2 and CR (cysteine-rich). The two lobe-shaped domains LB1 and LB2 form a venus flytrap module. In the inactive configuration, the venus flytrap modules of both protomers are in the open conformation associated with the resting state (open-open) and the interdomain cleft is empty. In addition, each protomer contains three anions, which reinforce the inactive conformation, and one calcium ion. In the active configuration, both protomers of extracellular regions have the closed conformation associated with agonist-binding (closed-closed). The ligand-binding cleft of each protomer is solely occupied by an aromatic amino-acid. Calcium is bound at four novel sites, including one at the homodimer interface. Agonist-binding induces large conformational changes within the extracellular region homodimer: first, the venus flytrap module of each protomer undergoes domain closure. Second, the LB2 regions of the two protomers approach each other, resulting in an expansion of the homodimer interactions involving LB2 domains. Third, the CR regions of the two subunits interact to form a large homodimer interface that is unique to the active state. The CR regions are brought into close contact by the motion involving LB2 since the two domains are rigidly associated within each subunit.
Ubiquitinated by RNF19A; which induces proteasomal degradation.
Transcription factor that acts as a transcriptional activator (By similarity). 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).
Forms a water-specific channel that participates in distinct physiological functions such as glomerular filtration, tubular endocytosis and acid-base metabolism.
Can convert androstan-3-alpha,17-beta-diol (3-alpha-diol) to androsterone in vitro, suggesting that it may participate in androgen metabolism during steroidogenesis. May act by metabolizing compounds that stimulate steroid synthesis and/or by generating metabolites that inhibit it. Has no activity toward DHEA (dehydroepiandrosterone), or A-dione (4-androste-3,17-dione), and only a slight activity toward testosterone to A-dione.
Belongs to the MICU1 family. MICU1 subfamily.
Homohexamer; in absence of calcium. Forms a homohexamer in absence of calcium and rearranges into a heterodimer in presence of calcium. Heterodimer; disulfide-linked; heterodimerizes with MICU2. The heterodimer formed with MICU2 associates with MCU at low calcium concentration and dissociates from MCU at high calcium level. Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1. Interacts (via polybasic region) with EMRE/SMDT1; the interaction is direct. Interacts (via polybasic region) with MCU (via coiled coil domains); the interaction is direct and precedes formation of the heterodimer with MICU2. Interacts with SLC25A23. Interacts with CHCHD4/MIA40; which introduces the interchain disulfide bond with MICU2.
Key regulator of mitochondrial calcium uniporter (MCU) that senses calcium level via its EF-hand domains. 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. Acts as a gatekeeper of MCU at low concentration of calcium, preventing channel opening. Enhances MCU opening at high calcium concentration, allowing a rapid response of mitochondria to calcium signals generated in the cytoplasm. Regulates glucose-dependent insulin secretion in pancreatic beta-cells by regulating mitochondrial calcium uptake. Induces T-helper 1-mediated autoreactivity, which is accompanied by the release of IFNG.
The C-helix is required for assembling the Ca(2+)-free homohexamer. It also plays a key role in mitochondrial calcium uptake, probably by mediating interaction with MICU2.
The EF-hand domains have high affinity for calcium and act as sensors of calcium levels.
Homodimer; disulfide-linked. 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. The IKK core complex seems to associate with regulatory or adapter proteins to form a IKK-signalosome holo-complex (By similarity). 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. Interacts with COPS3, CYLD, NALP2, TRPC4AP and PIDD1. Interacts with ATM; the complex is exported from the nucleus. Interacts with TRAF6. Interacts with IKBKE. Interacts with TANK; the interaction is enhanced by IKBKE and TBK1. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. Interacts with ZFAND5. Interacts with RIPK2. Interacts with TNIP1 and TNFAIP3; TNIP1 facilitates the TNFAIP3-mediated de-ubiquitination of IKBKG. Interacts with TNFAIP3; the interaction is induced by TNF stimulation and by polyubiquitin. Binds (via UBAN region) polyubiquitin; binds both 'Lys-63'-linked and linear polyubiquitin, with higher affinity for linear ubiquitin. Interacts with NLRP10. Interacts with TANK; this interaction increases in response to DNA damage. Interacts with USP10; this interaction increases in response to DNA damage. Interacts with ZC3H12A; this interaction increases in response to DNA damage. Interacts with IFIT5; the interaction synergizes the recruitment of IKK to MAP3K7 and enhances IKK phosphorylation. Interacts with TRIM29; this interaction induces IKBKG/NEMO ubiquitination and proteolytic degradation. Interacts with TRIM13; this interaction leads to IKBKG/NEMO ubiquitination. Interacts with ARFIP2 (By similarity). 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 (By similarity). Interacts with MARCHF2; during the late stages of macrophage viral and bacterial infection; the interaction leads to ubiquitination and degradation of IKBKG/NEMO (By similarity).
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-278 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-392 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-270 and Lys-302; 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-270, Lys-278, Lys-285, Lys-295, Lys-302 and Lys-319; 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 (By similarity). Ubiquitinated at Lys-319 by MARCHF2 following bacterial and viral infection which leads to its degradation (By similarity).
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. Its binding to scaffolding polyubiquitin plays a key role in IKK activation by multiple signaling receptor pathways. Can recognize and bind both 'Lys-63'-linked and linear polyubiquitin upon cell stimulation, with a much highr affinity for linear polyubiquitin. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination.
Sumoylated on Lys-270 and Lys-302 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.
Interacts with PIKFYVE; the interaction recruits RABEPK to the endosomal membrane. Interacts with RAB9 in its GTP-bound conformation.
Phosphorylated on Ser residues by PIKFYVE.
Rab9 effector required for endosome to trans-Golgi network (TGN) transport.
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 (By similarity). Plays a role in proper central nervous system (CNS) development in vertebrates (By similarity).
Forms functional homodimers and homooligomers. Can also form heterooligomers with PLPP1 and PLPP3.
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. Has no apparent extracellular phosphatase activity and therefore most probably acts intracellularly. Also acts on N-oleoyl ethanolamine phosphate/N-(9Z-octadecenoyl)-ethanolamine phosphate, a potential physiological compound. Through dephosphorylation of these bioactive lipid mediators produces new bioactive compounds and may regulate signal transduction in different cellular processes (By similarity). Indirectly regulates, for instance, cell cycle G1/S phase transition through its phospholipid phosphatase activity (PubMed:16467304).
Magnesium-independent phospholipid phosphatase. Insensitive to N-ethylmaleimide.
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 exclusively in brain. Abundant in telencephalon and expressed moderately in cerebellum, hypothalamus, thalamus, superior and inferior colliculi, and olfactory bulb. No expression detected in medulla oblongata, spinal cord or pituitary gland. Enriched in the neuropil rather than soma in the thalamus, corpus striatum and cerebral cortex. Detected in astrocytes.
In the embryo, expression increases dramatically between 14.5 dpc and 18.5 dpc (at protein level).
Interacts with BCAR1/p130Cas through its C-terminal domain and with CSK, CTTN and SRC (By similarity). Also interacts with MAPRE3/EB3, SORBS3/vinexin and the N-terminal coiled-coil region of SNAP25.
Tyrosine-phosphorylated in response to EGF and to cell adhesion to integrin ligands.
Interacts through its PDZ domains with NETO1 and APC. Interacts through its first two PDZ domains with ERBB4. Interacts through its third PDZ domain with NLGN1, and probably with NLGN2 and NLGN3 (By similarity). Interacts through its PDZ domains with GRIN2B and SYNGAP1. Interacts through its guanylate kinase-like domain with DLGAP1, DLGAP2, DLGAP3 and DLGAP4. Interacts with FRMPD4 (via C-terminus). Interacts with LRFN2. Interacts with LRFN1 and LRFN4. Interacts with FLTP (By similarity). Interacts with DGKI (via PDZ-binding motif) (PubMed:21119615).
Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling.
Belongs to the glycosyltransferase 8 family. Glycogenin subfamily.
Divalent metal ions. Required for self-glucosylation. Manganese is the most effective.
Homodimer. Interacts (via C-terminus) with glycogen synthase GYS1 (By similarity). 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.
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. Retinol uptake is enhanced by LRAT, an enzyme that converts retinol to all-trans retinyl esters, the storage forms of vitamin A. 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. Important for the homeostasis of vitamin A and its derivatives, such as retinoic acid. STRA6-mediated transport is particularly important in the eye, and under conditions of dietary vitamin A deficiency. Does not transport retinoic acid.
Homodimer (By similarity). Interacts with JAK2 and STAT5. Interacts (via extracellular domains) with RBP4. Interacts (via cytoplasmic domains) with RBP1 (By similarity).
Phosphorylated on tyrosine residues in response to RBP4 binding. 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.
Expressed in the brain, mainly in the perikarya and processes of astrocytes in the cerebellum, dentate gyrus and corpus callosum (at protein level). In the sciatic nerve, highly expressed in Schwann cells (at protein level). Isoforms are differentially expressed in testes, kidney, liver, heart, spleen and brain. Undetectable in skeletal muscle.
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 (By similarity).
Belongs to the complex I NDUFB5 subunit family.
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.
Found in certain neuronal populations of the CNS, including dorsal root ganglia, and in other non-neuronal tissues including mesenchymal tissue lining in the ribs.
Heterodimer with NRP1. Binds PLXNB1 (By similarity).
High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF.
Increased in dorsal root ganglia in response to injury caused by dorsal rhizotomy (PubMed:28270793). Increased in dorsal root ganglia in response to sciatic transection injury (PubMed:28270793). Transiently increased in dorsal root ganglia in response to sciatic nerve crush injury, returning to comparable levels 42 days post-injury (PubMed:28270793).
The tandem CUB domains mediate binding to semaphorin, while the tandem F5/8 domains are responsible for heparin and VEGF binding.
Could play a role in neuronal development.
Autophosphorylated on both serine/threonine and tyrosine residues (By similarity). Phosphorylated. Interaction with PPP2CA promotes dephosphorylation (By similarity).
Binds to RP9 (By similarity). Interacts with CDKN1B and FOXO3 (By similarity). Interacts (via N-terminal 96 residues) with CDC25A. Interacts with BAD (By similarity). Interacts with PPP2CA; this interaction promotes dephosphorylation of PIM1, ubiquitination and proteasomal degradation (By similarity). Interacts with HSP90, this interaction stabilizes PIM1 protein levels. Interacts (ubiquitinated form) with HSP70 and promotes its proteosomal degradation (By similarity). Interacts with CDKN1A (By similarity). Interacts with CDC25C (By similarity). Interacts (via N-terminal 96 residues) with CDC25A. Interacts with MAP3K5 (By similarity). Interacts with MYC (By similarity).
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). 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 protein 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. Promotes brown adipocyte differentiation (By similarity).
Belongs to the peptidase M24A family. Methionine aminopeptidase eukaryotic type 2 subfamily.
Binds EIF2S1 at low magnesium concentrations (By similarity). Interacts strongly with the eIF-2 gamma-subunit EIF2S3.
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.
Heat shock increases expression by more than 36-fold.
O-glycosylated; contains 12 O-linked GlcNAc.
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.
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. Tumor suppressor, the lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation. In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement (By similarity). Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. 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) (Ref.7). 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 (By similarity).
Constitutively phosphorylated by CK2 under normal conditions. 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 (By similarity). Phosphorylation by PLK3 promotes its stability and prevents its degradation by the proteasome. Phosphorylation by ROCK1 is essential for its stability and activity (By similarity).
Monomer. The unphosphorylated form interacts with the second PDZ domain of MAGI2 (By similarity). Interacts with MAGI2, MAGI3, MAST1 and MAST3, but neither with MAST4 nor with DLG5; interaction with MAGI2 increases protein stability (By similarity). Interacts with NEDD4 (By similarity). Interacts with NDFIP1 and NDFIP2; in the presence of NEDD4 or ITCH, this interaction promotes PTEN ubiquitination (By similarity). Interacts (via C2 domain) with FRK (By similarity). Interacts with USP7; the interaction is direct (By similarity). Interacts with ROCK1. Interacts with XIAP/BIRC4 (By similarity). Interacts with STK11; the interaction phosphorylates PTEN (By similarity). Interacts with PPP1R16B (By similarity). Interacts with NOP53; regulates PTEN phosphorylation and increases its stability (By similarity). Interacts (via PDZ domain-binding motif) with DLG4; the interaction is induced by NMDA and is required for PTEN location at postsynaptic density (PubMed:20628354).
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 (By similarity). Ubiquitinated by XIAP/BIRC4 (By similarity).
Interacts with the COPII coat components Sec23 (SEC23A and/or SEC23B) and Sec24 (SEC24A and/or SEC24B) (By similarity). Interacts with YIF1A (By similarity). May interact with RAB1A (By similarity). Interacts with YIPF3 and YIPF4 (By similarity).
Plays a role in transport between endoplasmic reticulum and Golgi. In pancreatic beta cells, required to transport proinsulin from endoplasmic reticulum into the Golgi (By similarity).
Binds EFNB1 and EFNB2. Binds the GNB1-GNG2 heterodimer (By similarity). Binds ESR1.
Detected in kidney, uterus, ovary, heart, brain, spleen, lung and testis.
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.
Has histone acetyltransferase activity in vitro, with specificity for histone H4.
Expressed predominantly in the striatum, hypothalamus, heart and liver and at lower levels in the cerebellum, hippocampus and pons.
Highly phosphorylated during mitosis. Phosphorylation is barely detectable during interphase (By similarity).
Homodimer. Interacts with RAB1A that has been activated by GTP-binding. 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.
Apical endosomal tubules of developing rat intestinal epithelial cells.
Probably involved in the sorting and selective transport of receptors and ligands across polarized epithelia.
Interacts with NINL. Interacts with OFD1. Interacts with FAM161A. Interacts with FAM161A. Interacts with components of the IFT complex B.
Involved in intraflagellar protein (IFT) transport in photoreceptor cilia.
Expressed in the brain, liver, kidney, lung and testis.
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.
Expressed in B and T-cells and peritoneal macrophages.
Co-expressed in the small diameter neurons with P2X3 and VR1 in dorsal root ganglia.
May regulate nociceptor function and/or development, including the sensation or modulation of pain. Functions as a specific membrane receptor for beta-alanine. The receptor couples with G-protein G(q) and G(i) (By similarity).
Catalyzes the conversion of gamma-aminobutyrate and L-beta-aminoisobutyrate to succinate semialdehyde and methylmalonate semialdehyde, respectively (PubMed:10447691). Can also convert delta-aminovalerate and beta-alanine (PubMed:10447691).
May act as a tumor suppressor. Inhibits tumor cell growth, when overexpressed (By similarity).
Expressed from days 14 to term of pregnancy.
Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form.
Contains 3 Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, which are usually required for the association with nuclear receptors.
Induced by combination of forskolin and dexamethasone in primary hepatocytes.
Interacts with estrogen receptor alpha/ESR1. Interacts with 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).
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 part of the pathways regulating the elevation of gluconeogenesis, beta-oxidation of fatty acids and ketogenesis during fasting. Stimulates SREBP-mediated lipogenic gene expression in the liver. Induces energy expenditure and antagonizes obesity when overexpressed. Induces also the expression of mitochondrial genes involved in oxidative metabolism. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner.
Ubiquitous with higher expression in heart, brown adipose tissue.
Belongs to the SOSS-B family. SOSS-B1 subfamily.
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 (By similarity).
Phosphorylated by ATM in response to DNA damage. Phosphorylation prevents degradation by the proteasome, hence stabilization of the protein and accumulation within cells (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.
Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions.
ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis. In vitro causes tubulation of endocytic membranes. Binding to phosphatidic acid induces its membrane tubulation activity. 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. Involved in the recycling of internalized D1 dopamine receptor (By similarity). Plays a role in cardiac protein trafficking probably implicating ANK2. 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. In conjunction with EHD4 may be involved in endocytic trafficking of KDR/VEGFR2 implicated in control of glomerular function. Involved in the rapid recycling of integrin beta-3 implicated in cell adhesion maintenance. 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. Plays a role in the formation of the ciliary vesicle, an early step in cilium biogenesis; possibly sharing redundant functions with Ehd1.
Homooligomer, and heterooligomer with EHD1, EHD2 and EHD4, ATP-binding is required for heterooligomerization (By similarity). Interacts with PACSIN1 (By similarity). Interacts with PACSIN2 (PubMed:15930129). Interacts (via EH domain) with MICALL1. Interacts (via EH domain) with RAB11FIP2 (By similarity). Interacts with ANK2 (By similarity). Interacts with CACNA1GG and CACNA1H (By similarity).
Abundantly expressed in the developing hippocampus.
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).
Monomer. Interacts with integrin (By similarity).
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 (By similarity).
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 (By similarity). Interacts with RIGI and RNF135; involved in RIGI ubiquitination and activation (By similarity).
Expressed at high levels in stomach and also in kidney and, at low levels, in heart (at protein level). In the stomach, highly expressed in foveolar cells, parietal cells and chief cells (at protein level). In kidney, expressed in endothelial cells, mesangial and epithelial cells (parietal and visceral epithelium) around glomerulus (at protein level).
May play a role in the regulation of cellular reactive oxygen species metabolism. May participate in cell growth regulation (By similarity).
Cation/chloride cotransporter that may play a role in the control of keratinocyte proliferation.
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.
Interacts (via C-terminus) with PLEKHM1; this interaction is weak but increased in a RAB7A-dependent manner.
Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts. Involved in bone resorption.
Belongs to the amiloride-sensitive sodium channel (TC 1.A.6) family. ASIC1 subfamily.
Blocked by Ca(2+). Mutagenesis of Asp-465 to Asn reduces Ca(2+) block.
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).
Expressed in dorsal root ganglia and sciatic nerve (at protein level). Widely distributed throughout the brain. Expressed in olfactory bulb, neo and allocortical regions, dentate granule cells, pyramidal cells of CA1-CA3 subfields of the hippocampal formation, habenula, basolateral amygdaloid nuclei, and in the Purkinje and granule cells of the cerebellum. Diffusely detected over most other regions of the basal ganglia, including thalamic nuclei, substantia nigra, striatum and globus pallidus, hypothalamus, midbrain, pons, medulla and choroid plexus. Isoform 3 is expressed only in dorsal root ganglion (DRG) while isoform 1 is expressed in DRG, spinal chord, trigeminal ganglia and the trigeminal mesencephalic nucleus.
Homotrimer or heterotrimer with other ASIC proteins (By similarity). Interacts with STOM and PRKCABP (By similarity). Interacts with ASIC2. Interacts with the spider venom Pi-hexatoxin-Hi1a (PubMed:28320941). Homotrimer of Asic1a interacts with the spider venom psalmotoxin-1 (PubMed:10829030, PubMed:26248594). Homotrimer of Asic1a (isoform 1) and Asic1b (isoform 3) and heterotrimer of Asic1a/Asic1b interact with the spider venom Pi-theraphotoxin-Hm3a (PubMed:28327374). Homotrimer of Asic1a (ASIC1 isoform 1) interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383, PubMed:24323786, PubMed:24695733, PubMed:26680001). Homotrimer of Asic1b (isoform 3) interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383, PubMed:24323786, PubMed:26680001). Heterotrimer of Asic1a-Asic1b (ASIC1 isoform 1-ASIC1 isoform 3) interacts with the snake venom mambalgin-1 and mambalgin-2 (PubMed:23034652). Heterotrimer of Asic1a-Asic2a interacts with the snake venom mambalgin-1, mambalgin-2 and mambalgin-3 (PubMed:23034652, PubMed:23624383, PubMed:26680001). Heterotrimer of Asic1a-Asic2b (ASIC1 isoform 1-ASIC2 isoform 2) interacts with the snake venom mambalgin-1 and mambalgin-2 (PubMed:23034652).
Phosphorylation by PKA regulates interaction with PRKCABP and subcellular location. Phosphorylation by PKC may regulate the channel (By similarity).
Potentiated by Ca(2+), Mg(2+), Ba(2+), multivalent cations and potentiated by FMRFamide-related neuropeptides. pH dependence may be regulated by serine proteases. Inhibited by anti-inflammatory drugs like salicylic acid. Isoform 1 homomultimeric channel is specifically and reversibly inhibited by psalmotoxin-1, a spider venom toxin, while isoform 2 and other ASICs are insensitive.
Proton-gated sodium channel; it is activated by a drop of the extracellular pH and then becomes rapidly desensitized. 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. Can also transport potassium ions, but with lower efficiency. It is nearly impermeable to the larger rubidium and cesium ions. Isoform 3 discrimates stronger than isoform 1 between monovalent cations. Isoform 3 can flux Ca(2+) while isoform 1 cannot. Heteromeric channels composed of isoform 2 and isoform 3 are active but have a lower pH-sensitivity. 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.
In the developing neocortex, expression is detected at embryonic day 12 (12 dpc) and peaks at 14 dpc. Then expression levels decrease until postnatal day 5 (P5) and increase again at least until P30.
May play a role in neuronal migration during embryonic development.
RNAi-mediated knockdown of the protein, performed in utero by electroporation in lateral ventricle of 15 dpc embryos, results in a massive neuronal migration defect and in the development of heterotopic nodules along the walls of the lateral ventricles. At 20 dpc, a significant arrest of cells within the ventricular zone is observed, while, at this stage in control embryos, cells have reached the cortical plate.
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.
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.
Homohexamer. Interacts with GABARAP and GABARAPL2 (By similarity). 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.
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. Interaction with AMPAR subunit GRIA2 leads to influence GRIA2 membrane cycling.
Heterodimer 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 PIFO. Interacts with DIAPH1 (By similarity). 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 (By similarity).
Ubiquitously expressed with highest levels in spleen, thymus and immature brain.
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. May mediate 'Lys-48'-linked polyubiquitination of RIPK1 and its subsequent proteasomal degradation thereby indirectly regulating the tumor necrosis factor-mediated signaling pathway. 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. Mediates PPARGC1A proteasomal degradation probably through ubiquitination thereby indirectly regulating the metabolism of brown fat cells. Possibly involved in innate immunity, through 'Lys-48'-linked polyubiquitination of NOD1 and its subsequent proteasomal degradation.
Interacts with CASP8 and CASP10. Interacts with p53/TP53; involved in p53/TP53 ubiquitination. Interacts (via RING-type zinc finger) with MDM2; the interaction stabilizes MDM2. Interacts (via RING-type zinc finger) with PPARGC1A. Interacts with NOD1.
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.
Ubiquitous. Detected in brain, cerebellum, midbrain, hippocampus, striatum, heart, lung, kidney, muscle, spleen and testis.
By exposure to bacterial lipopolysaccharide (LPS).
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.
Not detected in the absence of exposure to lipopolysaccharide (LPS). Detected only after exposure to lipopolysaccharide (LPS) in the tissues examined: spleen, lung, brain, liver, heart, kidney, thymus and small intestine.
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:15901796, PubMed:17082223, PubMed:18985798, PubMed:9545351). 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 (PubMed:15159385). 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 52.9 uM (PubMed:16332456). Pravastatin competitively inhibits the transport of taurocholic acid (PubMed:15901796, PubMed:18985798). Cyclosporin A, glibenclamide, rifampicin and troglitazonestrongly competitively inhibit the transport activity of taurocholate (PubMed:18985798). The canalicular transport activity of taurocholate is strongly dependent on canalicular membrane cholesterol content. The uptake of taurocholate is increased by short- and medium-chain fatty acids. Cholesterol increases transport capacity of taurocholate without affecting the affinity for the substrate (By similarity).
Ubiquitinated; short-chain ubiquitination regulates cell-Surface expression of ABCB11.
Forms homodimers and heterodimers with FOXP2 and FOXP4. Dimerization is required for DNA-binding. Self-associates. Interacts with CTBP1. Interacts with NCOR2 and AR. Interacts with FOXP2 (By similarity). Interacts with TBR1 (By similarity). Interacts with AURKA; this interaction facilitates the phosphorylation of FOXP1, which suppresses the expression of FBXL7 (By similarity). Interacts with ZMYM2 (By similarity).
Transcriptional repressor. Can act with CTBP1 to synergistically repress transcription but CTPBP1 is not essential. Plays an important role in the specification and differentiation of lung epithelium. Acts cooperatively with FOXP4 to regulate lung secretory epithelial cell fate and regeneration by restricting the goblet cell lineage program; the function may involve regulation of AGR2. Essential transcriptional regulator of B-cell development. Involved in regulation of cardiac muscle cell proliferation. Involved in the columnar organization of spinal motor neurons. Promotes the formation of the lateral motor neuron column (LMC) and the preganglionic motor column (PGC) and is required for respective appropriate motor axon projections. The segment-appropriate generation of spinal cord motor columns requires cooperation with other Hox proteins. Can regulate PITX3 promoter activity; may promote midbrain identity in embryonic stem cell-derived dopamine neurons by regulating PITX3. Negatively regulates the differentiation of T follicular helper cells T(FH)s. Involved in maintenance of hair follicle stem cell quiescence; the function probably involves regulation of FGF18. Represses transcription of various pro-apoptotic genes and cooperates with NF-kappa B-signaling in promoting B-cell expansion by inhibition of caspase-dependent apoptosis. Binds to CSF1R promoter elements and is involved in regulation of monocyte differentiation and macrophage functions; repression of CSF1R in monocytes seems to involve NCOR2 as corepressor. Involved in endothelial cell proliferation, tube formation and migration indicative for a role in angiogenesis; the role in neovascularization seems to implicate suppression of SEMA5B. Can negatively regulate androgen receptor signaling (By similarity). Acts as a transcriptional activator of the FBXL7 promoter; this activity is regulated by AURKA (By similarity).
Accessory component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. The beta subunit may assist in binding of the phospholipid substrate. Required for the proper folding, assembly and ER to Golgi exit of the ATP8A2:TMEM30A flippase complex. ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth, and, reconstituted to liposomes, predomiminantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). The ATP8A1:TMEM30A flippase complex seems to play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the plasma membrane. Required for the formation of the ATP8A2, ATP8B1 and ATP8B2 P-type ATPAse intermediate phosphoenzymes. Involved in uptake of platelet-activating factor (PAF). Can also mediate the export of alpha subunits ATP8A1, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B and ATP11C from ER to other membrane localizations (By similarity).
Component of various P4-ATPase flippase complexes which consists of a catalytic alpha subunit and an accessory beta subunit. Interacts with ATP8A1 to form a flippase complex; this complex forms an intermediate phosphoenzyme. Interacts with ATP8A2 to form a flippase complex (By similarity). TP8B1:TMEM30A and ATP8B2:TMEM30A flippase complexes have been shown to form intermediate phosphoenzymes in vitro. Interacts with alpha subunits ATP8A1, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B and ATP11C.
N-glycosylated. Contains high mannose-type oligosaccharides (By similarity).
The N-terminal domain seems to play a role in the reaction cycle of the catalytic subunit such as ATP8A2.
Probable component of the Arp2/3 complex in which it may replace ARPC1B.
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 (By similarity). 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).
3 different light chains, LC1, LC2 and LC3, can associate with MAP1A and MAP1B proteins. Interacts with guanylate kinase-like domain of DLG1, DLG2 and DLG4. Binds to CSNK1D. Interacts with TIAM2 (By similarity). MAP1 light chain LC2: Interacts with ELAVL4 (By similarity).
Expressed late during neuronal development appearing when axons and dendrites begin to solidify and stabilize their morphology.
LC2 is generated from MAP1A by proteolytic processing. It is free to associate with both MAP1A and MAP1B.
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.
Interacts with DTNA. Interacts with TRIM28.
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 (By similarity).
Highly expressed in intestine, kidney, ovary and placenta, moderately expressed in liver, lung, stomach, thymus, brain, and testis and slightly expressed in control thyroid and retina. Strongly expressed in pancreas (acinar cells) during acute pancreatitis.
Interacts with BECN1 (PubMed:17940279). Interacts with TJP1. Interacts with TP53INP2. Interacts with TMEM41B. Interacts with ATP2A2, PLN and SLN; competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2. Interacts with ATG2A (By similarity).
Overexpressed only in pancreas during acute pancreatitis. Up-regulated by starvation. Up-regulated following MTOR-inhibition by rapamycin.
Phospholipid scramblase involved in lipid homeostasis and membrane dynamics processes (By similarity). Has phospholipid scramblase activity toward cholesterol and phosphatidylserine, as well as phosphatidylethanolamine and phosphatidylcholine (By similarity). 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 (By similarity). Regulates ATP2A2 activity to control ER-isolation membrane contacts for autophagosome formation (PubMed:17940279). In addition to autophagy, involved in other processes in which phospholipid scramblase activity is required (By similarity). Modulates ER contacts with lipid droplets, mitochondria and endosomes (By similarity). Plays an essential role in formation of cell junctions (By similarity). Upon stress such as bacterial and viral infection, promotes formation of cytoplasmic vacuoles followed by cell death (PubMed:11785947, PubMed:12649568, PubMed:15367889). Involved in the cytoplasmic vacuolization of acinar cells during the early stage of acute pancreatitis (PubMed:11785947, PubMed:12649568, PubMed:15367889).
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.
ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis (By similarity). 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 (By similarity). 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 (By similarity). Upon elevated cytosolic copper concentrations, it relocalizes to the plasma membrane where it is responsible for the export of excess Cu(+) ions (By similarity). 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 (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 1479-Leu-Leu-1480 motif mediates endocytosis at the plasma membrane, whereas the di-leucine 1459-Leu-Leu-1460 motif is a sorting signal for retrograde trafficking to TGN via early endosomes.
Expressed in hippocampal neuron (at protein level) (PubMed:15634787). Expressed in anterior pituitary gland (at protein level) (PubMed:12488345).
Monomer. Interacts with PDZD11. Interacts with ATOX1 and COMMD1 (By similarity). Interacts with TYRP1 (By similarity). Directly interacts with SOD3; this interaction is copper-dependent and is required for SOD3 activity (By similarity).
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-1073 which forms an hydrogen bond with the adenine ring.
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. 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. Client proteins that cannot be properly delivered to the endoplasmic reticulum are ubiquitinated and sorted to the proteasome. 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. 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.
Component of the BAG6/BAT3 complex, at least composed of BAG6, UBL4A and GET4/TRC35. Interacts with BAG6; the interaction is direct and required for UBL4A protein stability. Interacts with USP13; may be indirect via BAG6.
Polyubiquitinated. Ubiquitination by AMFR and deubiquitination by USP13 may regulate the interaction between the BAG6/BAT complex and SGTA and therefore may regulate client proteins fate.
May be required for stable YIPF1 and YIPF2 protein expression.
Predominantly interacts with YIPF1 or YIPF2, but may also form a ternary complex with YIPF1 and YIPF2. This interaction may stabilize YIPF1 and YIPF2.
Part of prostatein which is the major secretory glycoprotein of ventral prostate gland. Steroid-binding protein; can bind non-polar steroids, cholesterol and a group of small proline-rich peptides.
Prostatein is composed of three different peptides called C1, C2 and C3. These form covalent C1:C3 (F) and C2:C3 (S) heterodimers whose non-covalent association forms tetrameric (C1:C3/C3:C2) prostatein molecules.
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 (By similarity).
Interacts with GNAQ. Interacts with TULP1.
High expression in heart and lung, low in small intestines, colon, kidney, liver, uterus and brain.
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. 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 (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 (By similarity).
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:9299394, PubMed:9790682, PubMed:10526230, PubMed:11128635, PubMed:15533037, PubMed:17649977). Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (PubMed:9122178, PubMed:11128635). It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:10526230, PubMed:15533037, PubMed:17649977). 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).
Found in neuronal cells throughout the CNS. Expressed in liver and brain, and to a lesser extent in spleen, lung, kidney and testes.
In the CNS it accumulates progressively between embryonic day 14 and postnatal day 10, remains high until postnatal day 30, then decreases into adulthood.
Homodimer; disulfide-linked. Interacts with tyrosine kinase LCK.
Ligand binding may be calcium dependent.
Plays a stimulatory role on natural killer (NK) cell cytotoxicity.
Associated with the EvC complex composed of EFCAB7, IQCE, EVC2 and EVC.
Participates positively in the ciliary Hedgehog (Hh) signaling.
Does not function as a ligand for either NMUR1 or NMUR2 (PubMed:28874765). Indirectly induces prolactin release although its potency is much lower than that of neuromedin precursor-related peptide 36 (PubMed:28874765).
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 gastrointestinal tract with highest levels in the duodenum and jejunum (PubMed:7916966). Low levels in spinal cord, hypothalamus, and stomach (PubMed:7916966). Neuromedin-U-23: Expressed in the small intestine and the pituitary gland (at protein level) (PubMed:28874765). Neuromedin precursor-related peptides: Expressed in pituitary gland and small intestine (at protein level) (PubMed:28874765).
Ligand for receptors NMUR1 and NMUR2 (PubMed:28874765). Receptor-binding is very tight if not irreversible and triggers an increase in the cytosolic Ca(2+) concentration (PubMed:28874765). Stimulates muscle contractions of specific regions of the gastrointestinal tract. In rat, NMU stimulates contractions of stomach circular muscle.
Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes. Promotes membrane remodeling and ER scission via its membrane bending capacity and targets the fragments into autophagosomes via interaction with ATG8 family proteins. Active under basal conditions. Required for collagen quality control in a LIR motif-dependent manner. Required for long-term survival of nociceptive and autonomic ganglion neurons.
Homooligomer; oligomerization is enhanced following endoplasmic reticulum stress and is mediated by the reticulon homology domain (By similarity). Interacts with ATG8 family modifier proteins MAP1LC3A, MAP1LC3B, GABARAP, GABARAPL1 and GABARAPL2.
Phosphorylation at Ser-134 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 lysosomal degradation.
The reticulon homology domain provides capacity to bend the membrane and promotes ER scission (By similarity). It is required for homooligomerization (By similarity). This domain does not show relevant similarities with reticulon domains, preventing any domain predictions within the protein sequence.
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. Involved in peroxisome biogenesis. Regulates the transport of peroxisomal biogenesis factors PEX3 and PEX16 from the ER to peroxisomes.
SEC16A and SEC16B are each present in multiple copies in a heteromeric complex. Interacts with TFG. Interacts with SEC13.
Stimulated by intracellular signaling factors.
Catalyzes the reduction of N-oxygenated molecules, acting as a counterpart of cytochrome P450 and flavin-containing monooxygenases in metabolic cycles. As a component of prodrug-converting system, reduces a multitude of N-hydroxylated prodrugs particularly amidoximes, leading to increased drug bioavailability. May be involved in mitochondrial N(omega)-hydroxy-L-arginine (NOHA) reduction, regulating endogenous nitric oxide levels and biosynthesis. 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.
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 (By similarity).
Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding 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. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (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). 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. Interacts with BRD4; to target chromatin binding. Interacts with JMJD6. Interacts with activated nuclear STAT3 and RELA/p65. Binds to AR and MYOD1. Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (By similarity). 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 (By similarity). Interacts with TBX21 (By similarity). 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 (By similarity).
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. The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation. Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.
Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD (By similarity).
Protein kinase involved in the regulation of transcription. 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. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE. 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). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. 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. 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. 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. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation. Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity.
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.
Activated by limited proteolysis with trypsin.
Autophosphorylated; preferably on serine. Phosphorylated during mitosis.
Interacts with ZFAND6 (By similarity). Interacts with ANDR. Interacts with PRKCB. Interacts (via REM 1 and REM 2 repeats) with RAC1. Interacts (via REM 1 repeat) with RHOA. Interacts with RHOB. Interacts (via C-terminus) with PDPK1. Interacts with CCNT2; enhances MYOD1-dependent transcription. 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 (By similarity).
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-778 (activation loop of the kinase domain) and Ser-920 (turn motif), need to be phosphorylated for its full activation (By similarity).
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 (PubMed:8051089, PubMed:15375078). Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14 (By similarity). 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 (ANDR)-dependent transcription, by being recruited to ANDR 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 (By similarity).
Highly expressed in bone marrow, spleen and white blood cells. Also detected at low levels in thymus, lung, trachea, white adipose tissue, nasal respiratory epithelium, colon, small intestine, kidney, liver, and heart.
Probable hormone (Probable). Promotes chemotaxis in myeloid cells (By similarity).
Heterodimer (via NTF2 domain) with NXT1. The formation of NXF1-NXT1 heterodimers is required for the NXF1-mediated nuclear mRNA export. Forms a complex with RANBP2/NUP358, NXT1 and RANGAP1. Associates with the exon junction complex (EJC). Associates with the transcription/export (TREX) complex. Found in a mRNA complex with UPF3A and UPF3B. Found in a post-splicing complex with RBM8A, UPF1, UPF2, UPF3A, UPF3B and RNPS1. 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. Interacts with FYTTD1/UIF. Interacts with EIF4A3. Interacts with NUP42. Interacts with ALYREF/THOC4. Interacts with CHTOP. Interacts with FRG1 (via N-terminus). Interacts with LUZP4. Interacts with FMR1; the interaction occurs in a mRNA-dependent and polyribosomes-independent manner in the nucleus. Interacts with CPSF6 (via N-terminus); this interaction is direct. Interacts with RBM15. Interacts with RBM15B. Interacts with MCM3AP; this interaction is not mediated by RNA (By similarity). Interacts with DDX3X (via C-terminus); this interaction may be partly involved in DDX3X nuclear export and in NXF1 localization to stress granules. Interacts with PABPC1/PABP1 (By similarity).
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). The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5 components of the TREX complex. ALYREF/THOC4-bound mRNA is thought to be transferred to the NXF1-NXT1 heterodimer for export. 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.
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 RNA-binding domain is a non-canonical RNP-type domain.
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.
Heterodimer with RPLP1 at the lateral ribosomal stalk of the large ribosomal subunit.
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 (By similarity).
Expressed in auditory hair cells at P10 (at protein level).
Monomer (By similarity). Homodimer (By similarity). Interacts with WHRN and MYO7A (By similarity). Interacts with ITGA2B (via C-terminus cytoplasmic tail region); the interactions are stabilized/increased in a calcium and magnesium-dependent manner (By similarity). Interacts with ITGA7 (via C-terminus cytoplasmic tail region); the interactions are stabilized/increased in a calcium and magnesium-dependent manner (By similarity). Interacts with TMC1 (By similarity). Interacts with TMC2 (By similarity).
Belongs to the calcium channel alpha-1 subunit (TC 1.A.1.11) family. CACNA1H subfamily.
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:11073957). 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. In the adrenal zona glomerulosa, participates in the signaling pathway leading to aldosterone production in response to either AGT/angiotensin II, or hyperkalemia (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIA1 subfamily.
Both variants Ser-710 and Thr-710 are phosphorylated at this position.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits (PubMed:21639859). Tetramers may be formed by the dimerization of dimers (By similarity). Found in a complex with GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (PubMed:16793768, PubMed:19265014). Interacts with HIP1 and RASGRF2. Interacts with SYNDIG1 and GRIA2 (By similarity). Interacts with DLG1 (via C-terminus) (PubMed:12070168, PubMed:17069616, PubMed:9677374). Interacts with LRFN1 (PubMed:16630835). Interacts with PRKG2 (PubMed:18031684). Interacts with CNIH2 and CACNG2 (PubMed:20805473). Interacts with CACNG5 (PubMed:18817736, PubMed:19234459). 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 (PubMed:15456832). 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 (PubMed:7877986). Phosphorylated at Ser-710 by PKC (PubMed:8848293). Phosphorylated at Ser-849 by PKC, PKA and CAMK2 (PubMed:9405465). Phosphorylated at Ser-863 by PKC, PKA and PRKG2 (PubMed:18031684, PubMed:9405465). Phosphorylation of Ser-863 is reduced by induction of long-term depression and increased by induction of long-term potentiation (By similarity).
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 (By similarity).
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 (By similarity).
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 (By similarity). Interacts (via ZRF1-UBD region) with ID1 (By similarity).
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.
Homodimer. Interacts with IL10RA and IL10RB.
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. In turn, STAT3 translocates to the nucleus where it drives expression of anti-inflammatory mediators. 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. 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 (By similarity). In addition, controls the inflammatory response of macrophages by reprogramming essential metabolic pathways including mTOR signaling (By similarity).
Detected in granulosa and thecal cells of adult ovaries and in spermatogonia, spermatocytes, round spermatids, and Sertoli cells of adult testes.
Negatively regulates TGF-beta signaling.
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 PPP1R15A and PPP1R15B; the interactions mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with PPP1R7. Forms a complex with ILF2, ILF3, YLPM1, KHDRBS1, RBMX and NCOA5. Interacts with NOM1 and PPP1R8. Interacts with PPP1R16B. Interacts with RPSA only in the presence of PPP1R16B. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R10/PNUTS and PPP1R8. Interacts with WDR82 in the presence of PPP1R10/PNUTS. Interacts with PPP1R39. Interacts with TRIM28; the interaction dephosphorylates TRIM28 on 'Ser-824' and forms a complex at the p21 promoter site (By similarity). Interacts with PPP1R9A, PPP1R9B and YLPM1. Interacts with NEK2. Interacts with PHACTR4; which acts as an activator of PP1 activity. Interacts with FER; this promotes phosphorylation at Thr-320 (By similarity). Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts with FOXP3 (By similarity). Interacts with CENPA (By similarity). Interacts with ATG16L1 (By similarity). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (By similarity). Interacts with tensin TNS1 (By similarity).
Phosphorylated. Dephosphorylated at Thr-320 in the presence of ionizing radiation (By similarity).
Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E (By similarity). Dephosphorylates CENPA (By similarity). Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy (By similarity).
Microtubule-binding protein that negatively regulates centriole duplication. Binds to and stabilizes microtubules.
Expressed in the central nervous system. Expressed in Schwann cells from newborn sciatic nerve.
Interacts with OMP (By similarity). Interacts with neurotrophin receptor p75NTR/NGFR.
Oscillates during the cell cycle, being lowest at G1 and highest at S phase (at protein level).
Phosphorylated. Phosphorylation of Ser-105 protects it from the proteasome.
Signaling adapter molecule involved in p75NTR/NGFR signaling. Plays a role in cell cycle progression and neuronal differentiation. Inhibits neuronal differentiation in response to nerve growth factor (NGF). May act as a link between the cell cycle and neurotrophic factor signaling, possibly by functioning as an upstream modulator of receptor signaling, coordinating biological responses to external signals with internal cellular states.
Ubiquitinated (Probable). Degraded by the proteasome (By similarity).
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 (By similarity). Modulates (PtdIns(4)P) levels by regulating the ER-to-Golgi trafficking of the phosphatidylinositide phosphatase SACM1L (By similarity).
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 (By similarity).
Homodimer. Interacts with AGTR2. Interacts with PTPN6 (By similarity).
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 isoform 2.
Phosphorylated by LCK. Phosphorylation at Tyr-132 increases its phosphatase activity.
Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity. May be involved in synaptogenesis.
Specifically expressed in the nervous system. Not expressed in heart, spleen, lung, liver, kidney or skeletal muscle. In the hippocampus, it is highly expressed in CA1 pyramidal cells and weakly expressed in other regions of the hippocampus.
Prenyltransferase that mediates the formation of menaquinone-4 (MK-4) and coenzyme Q10. MK-4 is a vitamin K2 isoform required for endothelial cell development. 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. 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. Mediates biosynthesis of coenzyme Q10 in the Golgi membrane, leading to protect cardiovascular tissues from NOS3/eNOS-dependent oxidative stress.
Homodecamer; composed of 5 homodimers. Interacts with LTO1.
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 (By similarity). Involved in cellular response to oxidative stress (By similarity).
Core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (By similarity). 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 (By similarity). Component of the U1 snRNP (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity).
Heart, and less in brain, pituitary and liver.
Methylated by PRMT5 (By similarity). Arg-108 and Arg-112 are dimethylated, probably to asymmetric dimethylarginine (By similarity).
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 (By similarity). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (By similarity). Is also a component of the minor U12 spliceosome (By similarity). As part of the U7 snRNP it is involved in histone pre-mRNA 3'-end processing (By similarity).
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.
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. Acts together with SPATA5, C1orf109 ortholog and CINP.
Associates with pre-60S ribosomal particles. Interacts with C1orf109 ortholog.
Belongs to the AAA ATPase family. AFG2 subfamily.
Expressed in neurons; also expressed at lower level in astrocytes, oligodendrocytes and microglia.
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.
Shared alpha chain of the active heterodimeric glycoprotein hormones thyrotropin/thyroid stimulating hormone/TSH, lutropin/luteinizing hormone/LH and follitropin/follicle stimulating hormone/FSH. These hormones bind specific receptors on target cells that in turn activate downstream signaling pathways.
Belongs to the homogentisate dioxygenase family.
The laminin G-like domain 2 binds to NXPH1. Isoforms alpha 4B bind to alpha-dystroglycan. The cytoplasmic C-terminal region binds to CASK.
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.
O-linked glycans are Glc-Gal disaccharides typically found as secondary modifications of hydroxylated lysines in collagen-like domains.
Proline residues in the collagen-like domain motif, GXPG, are typically 4-hydroxylated.
Found in a ternary complex with CX3CL1 and ITGAV:ITGB3 or ITGA4:ITGB1.
Most abundant in adult spinal cord, brain, kidney, gut, uterus and testes.
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. CX3CR1-CX3CL1 signaling mediates cell migratory functions. Responsible for the recruitment of natural killer (NK) cells to inflamed tissues. Acts as a regulator of inflammation process leading to atherogenesis by mediating macrophage and monocyte recruitment to inflamed atherosclerotic plaques, promoting cell survival. Involved in airway inflammation by promoting interleukin 2-producing T helper (Th2) cell survival in inflamed lung. Involved in the migration of circulating monocytes to non-inflamed tissues, where they differentiate into macrophages and dendritic cells. Acts as a negative regulator of angiogenesis, probably by promoting macrophage chemotaxis. Plays a key role in brain microglia by regulating inflammatory response in the central nervous system (CNS) and regulating synapse maturation. Required to restrain the microglial inflammatory response in the CNS and the resulting parenchymal damage in response to pathological stimuli. Involved in brain development by participating in synaptic pruning, a natural process during which brain microglia eliminates extra synapses during postnatal development. Synaptic pruning by microglia is required to promote the maturation of circuit connectivity during brain development. Acts as an important regulator of the gut microbiota by controlling immunity to intestinal bacteria and fungi. 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. 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 (By similarity). Also acts as a receptor for C-C motif chemokine CCL26, inducing cell chemotaxis (By similarity).
This protein is not N-glycosylated which is unusual for G-protein-coupled receptors.
Expressed in kidney; in the proximal tubule, glomerulus and cortical collecting duct.
Sodium-dependent, pyrimidine- and purine-selective. Involved in the homeostasis of endogenous nucleosides. Exhibits the transport characteristics of the nucleoside transport system cib or N3 subtype (N3/cib) (with marked transport of both thymidine and inosine). Employs a 2:1 sodium/nucleoside ratio. Also able to transport gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazauridine.
Catalyzes the dehalogenation of halotyrosines such as 3-bromo-L-tyrosine, 3-chloro-L-tyrosine, 3-iodo-L-tyrosine and 3,5-diiodo-L-tyrosine. During thyroid hormone biosynthesis, facilitates iodide salvage by catalysing the oxidative NADPH-dependent deiodination of the halogenated by-products of thyroid hormone production, monoiodotyrosine (L-MIT) and diiodotyrosine (L-DIT). The scavanged iodide can then reenter the hormone-producing pathways. Acts more efficiently on 3-iodo-L-tyrosine than 3,5-diiodo-L-tyrosine.
Binds to orexin receptor HCRTR2/OX2R only (PubMed:9491897). Stimulates food intake (PubMed:9491897). Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner (PubMed:9879756).
Binds to orexin receptors HCRTR1/OX1R and HCRTR2/OX2R with a high affinity (PubMed:9491897). Stimulates food intake (PubMed:9491897). Modulates pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner (PubMed:9879756).
By nutritional state, up-regulated by fasting, fluid deprivation and insulin-induced hypoglycemia. Orexin-A immunoreactivity varies diurnally and peaks during the dark phase, in the pons and the location of locus coeruleus.
Detected in the brain as early as embryonic day 18, but expression increases dramatically after the third postnatal week.
Mainly expressed in the brain, with expression in neurons in the dorsal lateral hypothalamic area (at protein level) (PubMed:9419374). Produced by a small group of neurons restricted to the lateral and posterior hypothalamus and perifornical areas (PubMed:9491897). Positive neurons project widely throughout the entire neuroaxis (PubMed:9491897). Particularly abundant projections in the cerebral cortex, olfactory bulb, hippocampus, amygdala, septum, diagonal band of Broca, bed nucleus of the stria terminalis, thalamus, anterior and posterior hypothalamus, midbrain, brainstem, and spinal cord (PubMed:9491897). Also expressed in the enteric nervous system and pancreas (PubMed:9491897). In small amount, also detected in the testis (PubMed:9491897).
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 (PubMed:9491897, PubMed:11340621, PubMed:11283317). A broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids, is also suggested (PubMed:9491897). A modulation effect on luteinizing hormone-releasing hormone (LHRH) secretion also suggests a more minor contribution to the regulation of reproductive function (PubMed:9879756, PubMed:11340621).
Specific enzymatic cleavages at paired basic residues yield the different active peptides.
In the retina, mainly expressed in vessels, but also diffuse expression in the inner and outer plexiform layers and in the inner nuclear layer.
May act as a scaffolding protein within caveolar membranes. Interacts directly with G-protein alpha subunits and can functionally regulate their activity. Acts as an accessory protein in conjunction with CAV1 in targeting to lipid rafts and driving caveolae formation. The Ser-36 phosphorylated form has a role in modulating mitosis in endothelial cells. Positive regulator of cellular mitogenesis of the MAPK signaling pathway. Required for the insulin-stimulated nuclear translocation and activation of MAPK1 and STAT3, and the subsequent regulation of cell cycle progression.
Monomer or homodimer (By similarity). Interacts with CAV1; the interaction forms a stable heterooligomeric complex that is required for targeting to lipid rafts and for caveolae formation. Tyrosine phosphorylated forms do not form heterooligomers with the Tyr-19-phosphorylated form existing as a monomer or dimer and the Tyr-27-form as a monomer only. Interacts (tyrosine phosphorylated form) with the SH2 domain-containing proteins, RASA1, NCK1 and SRC. Interacts (tyrosine phosphorylated form) with INSR; the interaction (Tyr-27-phosphorylated form) is increased on insulin stimulation. Interacts (Tyr-19-phosphorylated form) with MAPK1 (phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation. Interacts with STAT3; the interaction is increased on insulin-induced tyrosine phosphorylation leading to STAT activation.
Phosphorylated on serine and tyrosine residues. CAV1 promotes phosphorylation on Ser-23 which targets the complex to the plasma membrane, lipid rafts and caveolae. Phosphorylation on Ser-36 appears to modulate mitosis in endothelial cells (By similarity). Phosphorylation on both Tyr-19 and Tyr-27 is required for insulin-induced 'Ser-727' phosphorylation of STAT3 and its activation. Phosphorylation on Tyr-19 is required for insulin-induced phosphorylation of MAPK1 and DNA binding of STAT3. Tyrosine phosphorylation is induced by both EGF and insulin.
Converts retinaldehyde to retinoic acid. 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.
Found in testis and less abundantly in lung, brain, heart, liver and kidney.
Catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group in an ATP hydrolysis-dependent manner. May be involved in maintaining the translation efficiency of at least some genes through preventing degradation of their mRNAs. Prefers RNA molecules that are adenosine-rich close to 3'-end. In addition, may inhibit cell proliferation and cell cycle progression through ubiquitination of beta-catenin/CTNNB1.
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 (By similarity). Interacts with SGO1 (By similarity). Interacts with RAF1 (By similarity).
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.
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 (By similarity). Can also demethylate N(6)-methyladenosine in single-stranded DNA (in vitro). Requires molecular oxygen, alpha-ketoglutarate and iron. Demethylation of m6A mRNA affects mRNA processing and export (By similarity). 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).
Expressed in kidney and gastrointestinal tract. In kidney, it is highly expressed in the cortex, expressed at intermediate level in the outer medulla and not expressed in the inner medulla. It is expressed in the cecum, while it is absent in other segments of gastrointestinal tract.
Probable apical anion exchanger of the alpha-intercalated cells of kidney. May participate in HCO3(-) absorption.
Component of the SWI5-SFR1 complex, a complex required for double-strand break repair via homologous recombination.
Component of the SWI5-SFR1 complex. Interacts with RAD51 (By similarity).
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 (By similarity).
A putative trans-splicing which involves HDC and SHBG gene regions produces a fusion protein expressed in fetal liver.
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 (By similarity).
In the fetal liver, expressed from day 14 to day 17 after conception.
Isoform 2 is only expressed in the liver.
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 (By similarity).
(Microbial infection) Cleavage by B.anthracis lethal toxin (LT) endopeptidase 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 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome.
Activated by cleavage by B.anthracis lethal toxin (LT) endopeptidase (PubMed:20502689). Cleavage by LT 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 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome (By similarity). Nlrp1a inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) in a ternary complex, thereby preventing Nlrp1a oligomerization and activation (PubMed:33731929). Nlrp1a inflammasome is weakly activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:31383852). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by promoting disruption of the ternary complex, releasing its C-terminal part from autoinhibition (By similarity). Weakly activated by Toxoplasma gondii (PubMed:31383852).
Acts as the sensor component of the Nlrp1a inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:33731929). 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 (By similarity). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as B.anthracis lethal toxin (LT) or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex (PubMed:20502689, PubMed:31383852, PubMed:33731929). In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the 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 (By similarity). In the absence of GSDMD expression, the Nlrp1a inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (By similarity).
Autocatalytically cleaved. Autocatalytic cleavage in FIIND region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal parts remain associated non-covalently.
Constitutes the active part of the Nlrp1a inflammasome (PubMed:33731929). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing this form, which polymerizes to form the Nlrp1a inflammasome complex: the Nlrp1a inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis.
Interacts (via LRR repeats) with BCL2 and BCL2L1 (via the loop between motifs BH4 and BH3) (By similarity). Interacts with NOD2; this interaction is enhanced in the presence of muramyl dipeptide (MDP) and increases IL1B release (By similarity). Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to danger-associated signals (By similarity). Interacts with MEFV; this interaction targets Nlrp1a to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (By similarity). Interacts with DPP9; leading to inhibit activation of the inflammasome (PubMed:33731929). DPP9 acts via formation of a ternary complex, composed of a DPP9 homodimer, one full-length NLRP1 protein, and one cleaved C-terminus of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus) (PubMed:33731929). Interacts with DPP8; leading to inhibit activation of the inflammasome, probably via formation of a ternary complex with DPP8 (By similarity).
Interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus) in absence of pathogens and other damage-associated signals (By similarity). Homomultimer; forms the Nlrp1a inflammasome polymeric complex, a filament composed of homopolymers of this form in response to pathogens and other damage-associated signals (By similarity). The Nlrp1a inflammasome polymeric complex directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC (By similarity). Interacts (via CARD domain) with CASP1 (via CARD domain); leading to CASP1 activation (By similarity).
Nlrp1a gene is extremely polymorphic. 5 alleles have been described: 1 (this entry), 2 (AC D9I2G3), 3 (AC D9I2H0), 4 (AC D9I2G1) and 5 (AC D9I2G4).
The C-terminal part of Nlrp1a oligomerizes to form the core of the Nlrp1a 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. The UPA region reduces the threshold needed for filament formation and signaling.
The FIIND (domain with function to find) region is involved in homomerization, but not in CASP1-binding. Autocatalytic cleavage in this region occurs constitutively, prior to activation signals, and is required for inflammasome activity (IL1B release), possibly by facilitating CASP1 binding. Both N- and C-terminal fragments remain associated.
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.
Ubiquitinated 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 1a, C-terminus), which polymerizes and forms the Nlrp1a inflammasome.
Binding of unsaturated fatty acid molecules (via FZ domain) promotes homodimerization (via FZ domain). Interacts with WNT2B (By similarity). Interacts with WNT7A. Interacts with GOPC (By similarity).
Receptor for Wnt proteins (PubMed:20530549). Can activate WNT2, WNT10B, WNT5A, but not WNT2B or WNT4 (in vitro); the in vivo situation may be different since not all of these are known to be coexpressed (By similarity). In neurons, activation of WNT7A promotes formation of synapses (PubMed:20530549). Functions in the canonical Wnt/beta-catenin signaling pathway. The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes (By similarity). A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable). Plays a role in yolk sac angiogenesis and in placental vascularization (By similarity).
Ubiquitinated by RNF43 and ZNRF3, leading to its degradation by the proteasome.
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:22216341, PubMed:23873268). 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 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:9368071). 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:23723439). 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 (By similarity).
In myogenic progenitors, it is ubiquitously expressed.
Has antibacterial activity against the Gram-negative bacteria E.coli. May play a role in sperm maturation and fertilization.
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).
Binds to PDZK1. Interaction with PDZK1 is required for expression on hepatocyte surface.
Highly expressed in liver and kidney, and at lower levels in brain, lung, skeletal muscle and proximal colon.
Mediates the Na(+)-independent transport of organic anions such as steroid sulfate conjugates (dehydroepiandrosterone sulfate (DHEAS), 17-beta-glucuronosyl estradiol, estrone-3-sulfate), conjugated (taurocholate) and unconjugated (cholate) bile acids, prostaglandin E2 (PGE2) and L-thyroxine T4 (PubMed:19129463). Also capable of transporting sulfobromophthalein (BSP), ouabain and gadoxetate (By similarity). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463).
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.
Involved in cytokinesis and spindle organization. May play a role in actin cytoskeleton organization and microtubule stabilization and hence required for proper cell adhesion and migration (By similarity).
May interact with both microtubules and actin cytoskeleton.
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:8444196, PubMed:8117750, PubMed:15123652, PubMed:23382512). 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:8444196, PubMed:8117750, PubMed:15123652, PubMed:23382512). It may then act on 12-HPETE to produce hepoxilins, which may show pro-inflammatory properties (PubMed:15123652, PubMed:23382512). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate. 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. Can convert epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides (By similarity). 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 (By similarity).
May have the capacity to recognize and bind specific classes of odorants. May act as a carrier molecule, transporting odorants across the mucus layer to access receptor sites. May serve as a primary defense mechanism by recognizing and removing potentially harmful odorants or pathogenic microorganisms from the mucosa or clearing excess odorant from mucus to enable new odorant stimuli to be received.
Acts as a cargo receptor for glycogen. Delivers its cargo to an autophagic pathway called glycophagy, resulting in the transport of glycogen to lysosomes.
Interacts with the ATG8 family proteins GABARAP and GABARAPL1 (By similarity). Interacts with several glycogen-associated proteins, such as GYS2 (liver glycogen synthase), GDE (glycogen debranching enzyme), GBE1 (glycogen branching enzyme 1) and EPM2A (Laforin) (By similarity).
The C-terminal CBM20 domain is required for the interaction with glycogen.
The LIR motif (LC3-interacting region) is required for the interaction with the ATG8 family protein GABARAPL1.
Ubiquitinated, which leads to proteasomal degradation.
Belongs to the G-protein coupled receptor 1 family. Neurotensin receptor subfamily. NTSR1 sub-subfamily.
G-protein coupled receptor for the tridecapeptide neurotensin (NTS) (PubMed:23051748, PubMed:24453215, PubMed:26205105). 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 (By similarity).
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.
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 (By similarity).
Belongs to the strictosidine synthase family.
Exhibits strong arylesterase activity with beta-naphthyl acetate and phenyl acetate. May play a role in adipocyte differentiation (By similarity).
Antiparallel homodimer; disulfide-linked (PubMed:1560460). Interaction with LMBR1L is controversial (By similarity).
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).
Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin. This enzyme has a vasoconstrictor activity. KLK-9 has both a chymotrypsin-like and a trypsin-like properties.
Catalyzes 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.
Expressed in cerebral cortex, cerebellum, pituitary gland, mostly in anterior pituitary gland, and pineal gland, as well as in brown adipose tissue (BAT).
In the pineal gland, exhibits night/day variations with a 9-fold increased expression at night. Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway. In BAT, up-regulated in animals exposed to cold.
Interacts with USP20 and USP33. Interacts with MARCHF6 (By similarity).
Ubiquitinated by MARCHF6, leading to its degradation by the proteasome. Deubiquitinated by USP20 and USP33 (By similarity).
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.
Belongs to the WD repeat WDR12/YTM1 family.
Component of the PeBoW complex, composed of BOP1, PES1 and WDR12. 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. Interacts (via UBL domain) with MDN1 (via VWFA/MIDAS domain).
Belongs to the complex I NDUFA4 subunit family.
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:28209804, PubMed:23766516, PubMed:9096315). Preferentially activates arachidonate and eicosapentaenoate as substrates (PubMed:9096315). Preferentially activates 8,9-EET > 14,15-EET > 5,6-EET > 11,12-EET (PubMed:23766516). Modulates glucose-stimulated insulin secretion by regulating the levels of unesterified EETs (PubMed:23766516). Modulates prostaglandin E2 secretion (By similarity).
Expression is decreased by polyunsaturated fatty acid (PUFA).
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.
In the brain, it is detected in the medial habenula. In the peripheral nervous system, it is found at least in the adrenal gland.
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 (By similarity). Interacts with LYPD6 (By similarity). The pentamer alpha3-beta-4 interacts with the conotoxin BuIA (PubMed:16964981). The heteropentamer composed of alpha-3 and beta-4 subunits interacts with the alpha-conotoxin ImI (By similarity).
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. GRIK2 subfamily.
Cold receptor activity activated by temperatures between 10-19 degrees Celsius.
Highest expression is found in the olfactory lobe, piriform cortex, dentate gyrus, hippocampus, granular cell layer of the cerebellum, and in caudate-putamen.
Homotetramer or heterotetramer of pore-forming glutamate receptor subunits. Tetramers may be formed by the dimerization of dimers. Assembles into a kainate-gated homomeric channel that does not bind AMPA (By similarity). GRIK2 associated to GRIK5 forms functional channels that can be gated by AMPA. Interacts with DLG4. Interacts with NETO2. Interacts (via C-terminus) with KLHL17 (via kelch repeats); the interaction targets GRIK2 for degradation via ubiquitin-proteasome pathway.
Independent of its ionotropic glutamate receptor activity, acts as a thermoreceptor conferring sensitivity to cold temperatures (By similarity). Functions in dorsal root ganglion neurons (By similarity).
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist (PubMed:17115050, PubMed:17486098). Modulates cell surface expression of NETO2 (By similarity).
Partially edited. The presence of Gln at position 621 (non-edited) determines channels with low calcium permeability, whereas an arginine residue (edited) determines a higher calcium permeability especially if the preceding sites are fully edited. This receptor is nearly completely edited in all gray matter structures (90% of the receptors).
Phosphorylated by PKC at Ser-868 upon agonist activation, this directly enhance sumoylation.
Sumoylation mediates kainate receptor-mediated endocytosis and regulates synaptic transmission. Sumoylation is enhanced by PIAS3 and desumoylated by SENP1.
The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate > quisqualate > glutamate. It does not bind AMPA without coexpression with GRIK5.
Ubiquitinated. Ubiquitination regulates the GRIK2 levels at the synapse by leading kainate receptor degradation through proteasome.
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 (By similarity).
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.
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.
Plays a role in alternative splicing of pre-mRNAs, possibly by contributing to the selection of non-consensus donor sites.
Cell surface proteoglycan that bears heparan sulfate (By similarity). 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 (By similarity). 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 (By similarity). 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. This processing is essential for its role in inhibition of hedgehog signaling. 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.
Heterodimer; disulfide-linked (By similarity). Cleavage by a furin-like convertase results in production of alpha and beta chains which form a disulfide-linked heterodimer (By similarity). Interacts with DPP4 (By similarity). Interacts with FGF2 (PubMed:9065409). Interacts with WNT5A (By similarity). Also interacts with WNT3A and WNT7B (By similarity). 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 (By similarity).
In the intestine, expression decreases gradually from 20 dpc and finally becomes undetectable after weaning around 24 days after birth.
O-glycosylated; contains heparan sulfate.
As part of the spliceosome, plays a role in pre-mRNA splicing. Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity.
Despite the fact that it belongs to the cyclophilin-type PPIase family, it has probably no peptidyl-prolyl cis-trans isomerase activity.
Part of the activated spliceosome B/catalytic step 1 spliceosome, one of the forms of the spliceosome which has a well-formed active site but still cannot catalyze the branching reaction and is composed at least of 52 proteins, the U2, U5 and U6 snRNAs and the pre-mRNA. Recruited during early steps of activated spliceosome B maturation, it is probably one of the first proteins released from this complex as he matures to the spliceosome C complex.
Involved in the maintenance of the Golgi structure.
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. Inhibits EGF stimulated MAPK1 activation. Promotes ubiquitination of SRC phosphorylated at 'Tyr-419', has the highest ubiquitin ligase activity among CBL family proteins. 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.
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. 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.
Phosphorylation at Tyr-341 is necessary and sufficient for the activation of E3 activity.
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.
Binds a calmodulin chain via each of the two IQ domains (PubMed:12719468, PubMed:15853803). 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+) (PubMed:8034741, PubMed:15853803).
Contrary to the situation in zebrafish, xenopus and drosophila, rat Myo1d defects have no effects on left-right body asymmetry.
Detected on tracheal epithelial cells, and on epithelial cells and brush border cells in duodenum, jejunum and ileum (PubMed:26446290). Detected on myelinated white matter in the cerebellum, and the myelinated part of the optic nerve. Detected on mature oligodendrocites. Detected on the outside of the myelin sheet that surrounds axons (at protein level) (PubMed:24903835). Ubiquitous. Highest levels in adult brain, and spinal chord. Moderate levels in lung, kidney, liver and spleen. Low levels in testis and heart (at protein level).
Interacts (via the two IQ motifs) with calmodulin (PubMed:8034741, PubMed:12719468, PubMed:15853803). Binds an additional calmodulin chain via a third, C-terminal region (PubMed:8034741). Interacts with F-actin (PubMed:12719468, PubMed:15853803).
Mutants display no defects in body left-right asymmetry, no obvious motor defects, and normal kidney and liver morphology. Tracheal epithelial cells display aberrant ciliary bending angles and disordered ciliary bending patterns. Likewise, planar cell polarity is disrupted in ependymal epithelial cells.
Not detected in brain one week after birth, prior to the onset of myelination, and levels are low two weeks after birth. Expressed at high and constant levels in brain after three weeks and later (at protein level) (PubMed:24903835). Expression is developmentally regulated during brain ontogeny, rising 2-3 week postnatally, and is maximal in adult brain (PubMed:8034741, PubMed:24903835).
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 (PubMed:12719468, PubMed:15853803). 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 (PubMed:26446290).
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 (By similarity).
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.
Can form homooligomers (monomers, dimers and tetramers). Interacts with FKBP8; may negatively regulate ZFYVE27 phosphorylation. Interacts with VAPA (via MSP domain); may regulate ZFYVE27 retention in the endoplasmic reticulum and its function in cell projections formation. Interacts with VAPB (via MSP domain) (By similarity). Interacts with RAB11A (GDP-bound form); regulates RAB11A (PubMed:17082457). Interacts with RAB11B (GDP-bound form), REEP1, REEP5, ATL1, ATL2, ATL3, SPAST, SURF4, KIF5A, KIF5B, KIF5C and RTN3 (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. Involved in nerve growth factor-induced neurite formation in VAPA-dependent manner. Contributes to both the formation and stabilization of the tubular ER network. Involved in ER morphogenesis by regulating the sheet-to-tubule balance and possibly the density of tubule interconnections. Acts as an adapter protein that 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 (By similarity).
Phosphorylated. Phosphorylation is induced by NGF through the MAPK/ERK pathway and modulates interaction with RAB11A (By similarity).
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'.
Izumo is the name of a Japanese shrine to marriage.
Monomer, homodimer and homooligomer; depending on the context. Interacts with IZUMO1R/JUNO (By similarity). IZUMO1 and IZUMO1R/JUNO form a complex with 1:1 stoichiometry (By similarity). In gamete recognition, IZUMO1R/JUNO first binds to monomeric IZUMO1. The weak, but specific interaction with IZUMO1R/JUNO induces IZUMO1 homodimerization. The process follows a tight binding phase where IZUMO1 bends the entire structure towards the sperm membrane side through a thiol-disulfide exchange reaction. The molecule no longer binds to IZUMO1R/JUNO and instead binds to a putative second oocyte receptor. 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.
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. Interaction with IZUMO1R/JUNO triggers a conformation change, so that the IZUMO1 extracellular domain assumes an upright conformation.
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 signal (BSS) are required to direct SLC16A8 to the basolateral membrane.
Cleavage by MME initiates degradation of the factor and thereby regulates its activity (PubMed:2966343). Degradation by IDE results in reduced activation of NPR1 (in vitro) (By similarity). During IDE degradation, the resulting products can temporarily stimulate NPR2 to produce cGMP, before the fragments are completely degraded and inactivated by IDE (in vitro) (By similarity).
High levels of expression in the atria compared to the ventricles (PubMed:1837590). Very low levels of expression detected in extracardiac tissues such as the brain, hypothalamus, pituitary, lung and aorta (PubMed:1837590).
High levels of expression in the atria with very low levels of expression in the ventricles (at protein level) (PubMed:2525379). Relatively low levels of expression detected in the brain compared to the atria (at protein level) (PubMed:2525379).
Homodimer; disulfide-linked antiparallel dimer.
Hormone produced in the kidneys that appears to be important for maintaining cardio-renal homeostasis. Mediates vasodilation, natriuresis and diuresis primarily in the renal system, in order to maintain the extracellular fluid volume and control the fluid-electrolyte balance. Specifically binds and stimulates cGMP production by renal transmembrane receptors, likely NPR1. Urodilatin not ANP, may be the natriuretic peptide responsible for the regulation of sodium and water homeostasis in the kidney.
Hormone that plays a key role in mediating cardio-renal homeostasis, and is involved in vascular remodeling and regulating energy metabolism (By similarity). Acts by specifically binding and stimulating NPR1 to produce cGMP, which in turn activates effector proteins, such as PRKG1, that drive various biological responses (PubMed:15117952). Regulates vasodilation, natriuresis, diuresis and aldosterone synthesis and is therefore essential for regulating blood pressure, controlling the extracellular fluid volume and maintaining the fluid-electrolyte balance (PubMed:7831500). Also involved in inhibiting cardiac remodeling and cardiac hypertrophy by inducing cardiomyocyte apoptosis and attenuating the growth of cardiomyocytes and fibroblasts (By similarity). Plays a role in female pregnancy by promoting trophoblast invasion and spiral artery remodeling in uterus, and thus prevents pregnancy-induced hypertension (By similarity). In adipose tissue, acts in various cGMP- and PKG-dependent pathways to regulate lipid metabolism and energy homeostasis (By similarity). This includes up-regulating lipid metabolism and mitochondrial oxygen utilization by activating the AMP-activated protein kinase (AMPK), and increasing energy expenditure by acting via MAPK11 to promote the UCP1-dependent thermogenesis of brown adipose tissue (By similarity). Binds the clearance receptor NPR3 which removes the hormone from circulation (By similarity).
May have a role in cardio-renal homeostasis through regulation of diuresis and inhibiting aldosterone synthesis. In vitro, promotes the production of cGMP and induces vasodilation. May promote natriuresis, at least in part, by enhancing prostaglandin E2 synthesis resulting in the inhibition of renal Na+-K+-ATPase. May have a role in potassium excretion but not sodium excretion (natriuresis). Possibly enhances protein excretion in urine by decreasing proximal tubular protein reabsorption.
May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis and in vitro, vasodilates renal artery strips.
May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis. In vitro, selectively vasodilates intestinal and vascular smooth muscle strips.
May have a role in cardio-renal homeostasis through regulation of natriuresis and vasodilation. In vivo promotes natriuresis. In vitro, selectively vasodilates intestinal smooth muscle but not vascular smooth muscle strips.
May have a role in cardio-renal homeostasis through regulation of natriuresis, diuresis, and vasodilation (By similarity). In vitro, promotes the production of cGMP and induces vasodilation (By similarity). May promote natriuresis, at least in part, by enhancing prostaglandin E2 synthesis resulting in the inhibition of renal Na+-K+-ATPase (By similarity). However reports on the involvement of this peptide in mammal blood volume and blood pressure homeostasis are conflicting; according to a report, in vivo it is not sufficient to activate cGMP and does not inhibit collecting duct transport nor effect diuresis and natriuresis (PubMed:7831500). Appears to bind to specific receptors that are distinct from the receptors bound by the atrial natriuretic and long-acting natriuretic peptides (By similarity). Possibly functions in protein excretion in urine by maintaining the integrity of the proximal tubules and enhancing protein excretion by decreasing proximal tubular protein reabsorption (By similarity).
May have a role in cardio-renal homeostasis through regulation of natriuresis, diuresis, vasodilation, and inhibiting aldosterone synthesis (By similarity). In vitro, promotes the production of cGMP and induces vasodilation (By similarity). May promote natriuresis, at least in part, by enhancing prostaglandin E2 synthesis resulting in the inhibition of renal Na+-K+-ATPase (By similarity). However reports on the involvement of this peptide in mammal blood volume and blood pressure homeostasis are conflicting; according to a report, in vivo it is not sufficient to activate cGMP and does not inhibit collecting duct transport nor effect diuresis and natriuresis (PubMed:7831500). Appears to bind to specific receptors that are distinct from the receptors bound by atrial natriuretic peptide and vessel dilator. Possibly enhances protein excretion in urine by decreasing proximal tubular protein reabsorption (By similarity).
May have a role in cardio-renal homeostasis through regulation of regulation of natriuresis and vasodilation. In vivo promotes natriuresis. In vitro, vasodilates intestinal smooth muscle but not smooth muscle strips.
Phosphorylation on Ser-128 decreases vasorelaxant activity.
Results concerning the involvement of this peptide in blood volume and blood pressure homeostasis are conflicting. Several studies utilising in vitro and heterologous expression systems show that it is able to activate cGMP and promote vasodilation and natriuresis (By similarity). However, an in vivo study found that it is not sufficient to induce any diuretic, natriuretic, nor hypotensive responses, and is unable to bind NPR1 nor increase guanylyl cyclase activity (PubMed:7831500).
The precursor molecule is proteolytically cleaved by CORIN at Arg-122 to produce the atrial natriuretic peptide. Undergoes further proteolytic cleavage by unknown proteases to give rise to long-acting natriuretic peptide, vessel dilator and kaliuretic peptide (By similarity). Additional processing gives rise to the auriculin and atriopeptin peptides (PubMed:6233494, PubMed:6419347, PubMed:6232612, PubMed:3160114). In the kidneys, alternative processing by an unknown protease results in the peptide urodilatin (By similarity).
Receptor on natural killer (NK) cells. Inhibits the activity of NK cells thus preventing cell lysis.
Belongs to the glutamate-gated ion channel (TC 1.A.10.1) family. NR3B/GRIN3B subfamily.
Expressed in the hippocampus, the corpus callosum, in the facial and trigeminal nuclei of the brainstem and the ventral horn of the spinal cord.
Forms heteromeric channel of a zeta subunit (GRIN1), a epsilon subunit (GRIN2A, GRIN2B, GRIN2C or GRIN2D) and a third subunit (GRIN3A or GRIN3B). Does not form functional homomeric channels. Found in a complex containing GRIN1 and GRIN2A (By similarity).
NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine.
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. Interacts with NDUFAF3. Interacts with NDUFAF7 (By similarity). 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). Essential for the catalytic activity of complex I (PubMed:30922174). 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.
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-421 and allows the kinase domain to adopt an active structure (By similarity).
Detected at high levels in the brain and at low levels in the testis.
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. Interacts with ARHGEF6 and ARHGEF7 (By similarity). Interacts with GIT1 and GIT2 (By similarity).
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 (PubMed:12890786). 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).
Component C2 which is part of the classical pathway of the complement system is cleaved by activated factor C1 into two fragments: C2b and C2a. C2a, a serine protease, then combines with complement factor C4b to generate the C3 or C5 convertase.
As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity. Known to inhibit cathepsin B, H, and L.
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).
Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histone H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), and have reduced activity toward histone H4. Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity.
Component of the NuA4 histone acetyltransferase complex. Component of the hbo1 complex. Component of the moz/morf complex.
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). 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 (By similarity). Isoform 1 interacts through its C-terminus with the PDZ domains of RIMS1 and RIMS2. Interacts with ERC2/CAST1. Interacts with SDCCAG8.
Isoform 1 is specifically expressed in brain. A further probable isoform is widely expressed outside of brain It is referred to as ERC1a by PubMed:12391317 and characterized by a C-terminus identical to that of isoforms 1 in human and mouse.
Regulatory subunit of the IKK complex. Probably recruits IkappaBalpha/NFKBIA to the complex (By similarity). 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.
Expressed in both embryonic, fetal and adult heart. Also expressed in lung, skeletal muscle and adrenal glands.
Expressed in cardiomyocytes from 14 dpc.
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.
Up-regulated by activation of alpha1-adrenergic receptors.
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.
Increases the transcriptional activity of NFKB1 by facilitating its nuclear translocation, DNA-binding and associated apoptotic response, when overexpressed.
Essential component of the mitotic spindle required for faithful chromosome segregation and progression into anaphase. Promotes the metaphase-to-anaphase transition and is required for chromosome alignment, normal timing of sister chromatid segregation, and maintenance of spindle pole architecture. The astrin (SPAG5)-kinastrin (SKAP) complex promotes stable microtubule-kinetochore attachments. 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.
Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2 (By similarity). Interacts with SPAG5 (By similarity). Directly binds to microtubules, although at relatively low affinity (By similarity). Interacts with CENPE; this interaction greatly favors microtubule-binding (By similarity). Interacts with DSN1/MIS13; leading to localization to kinetochores (By similarity). Interacts with MAPRE1/EB1; leading to localization to the microtubule plus ends (By similarity). Interacts with PRPF19 (By similarity). Interacts with DYNLL1 (By similarity). Interacts with MAP4 (By similarity).
The coiled coil regions mediate binding to kinetochores.
Acts as a transcriptional repressor. Increases DNMT3B-mediated repressive transcriptional activity when DNMT3B is tethered to DNA. May link molecule between DNMT3B and other co-repressor proteins (By similarity).
Forms homodimers. Heterodimer (via HD1 domain) with ZHX2 (via HD1 domain). Also forms a heterodimer with ZHX3 which is a prerequisite for repressor activity. Interacts with ATF7IP and NFYA. Interacts (via homeobox domains) with DNMT3B (via PWWP domain) (By similarity).
Inhibits SNARE complex formation by absorbing free syntaxin-1.
Component of the KMT2 family MLL2/MLL3 complex, at least composed of the histone methyltransferases 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 (By similarity). Forms a constitutive complex with PAXIP1/PTIP independently of the MLL2/MLL3 complex. Interacts with NCOA1, ESR1, NR3C1, AR.
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. However, its function in DNA damage has been questioned. 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. Involved in both estrogen receptor-regulated gene transcription and estrogen-stimulated G1/S cell-cycle transition. 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.
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.
Exhibits night/day variations with a 9-fold increased expression at night in the pineal gland (at protein level). A light pulse of 1 hour is sufficient to decrease mRNA levels. Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway.
Expressed in the cerebellum, pineal gland and skeletal muscle. In the pineal gland, expressed in pinealocytes, not in perivascular spaces (at protein level).
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) (By similarity).
Neuroendocrine tissues. Predominantly expressed in the hypothalamus, pituitary, and longitudinal muscle-myenteric plexus. Abundant expression is also seen in the midbrain/thalamus and eye. A lower level expression is seen in the other brain regions and adrenal.
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.
Activated by factor XIa, which excises the activation peptide. The propeptide can also be removed by snake venom protease.
Calcium binds to the gamma-carboxyglutamic acid (Gla) residues in the Gla domain. Calcium can also bind, with stronger affinity, to another site beyond the Gla domain. Under physiological ion concentrations, Ca(2+) is displaced by Mg(2+) from some of the gammaglutamate residues in the N-terminal Gla domain. This leads to a subtle conformation change that may affect the interaction with its binding protein.
Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
Heterodimer of a light chain and a heavy chain; disulfide-linked. Interacts with SERPINC1.
Predominantly O-glucosylated at Ser-92 by POGLUT1 in vitro.
Belongs to the dTDP-4-dehydrorhamnose reductase family. MAT2B subfamily.
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.
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.
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. Can bind NADP (in vitro).
Belongs to the RNA cytidine acetyltransferase family. NAT10 subfamily.
RNA cytidine acetyltransferase with specificity toward both 18S rRNA and tRNAs. Catalyzes the formation of N(4)-acetylcytidine (ac4C) in 18S rRNA. Required for early nucleolar cleavages of precursor rRNA at sites A0, A1 and A2 during 18S rRNA synthesis. Catalyzes the formation of ac4C in serine and leucine tRNAs. Requires the tRNA-binding adapter protein THUMPD1 for full tRNA acetyltransferase activity but not for 18S rRNA acetylation.
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 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 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.
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 (PubMed:10448933). 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).
Strongly expressed in eye and gastrointestinal tract (GIT), moderately in the brain and oviduct and weakly in the epididymis. In the eye, expressed in the epithelium of the iris and ciliary body and in photoreceptor cells of the retina. In the brain, expressed in leptomeninges, choroid plexus and spinal cord (sensory and motor neurons of the dorsal and ventral horns). In the stomach, expressed in the mucous-secreting goblet cells and the columnar epithelium. Expressed in platelets.
Does not have 2'-5'-OAS activity, but can bind double-stranded RNA. Displays antiviral activity against viruses via an alternative antiviral pathway independent of RNase L (By similarity).
Highly expressed in the brain, liver, spleen and heart.
Belongs to the SSU72 phosphatase family.
Interacts with GTF2B (via C-terminus); this interaction is inhibited by SYMPK. Interacts with RB1. Interacts with CD226. Interacts with SYMPK.
Protein phosphatase that catalyzes the dephosphorylation of the C-terminal domain of RNA polymerase II. Plays a role in RNA processing and termination. Plays a role in pre-mRNA polyadenylation via its interaction with SYMPK (By similarity).
Detected at low levels in newborn brain. Levels increase steadily during postnatal development up to adulthood.
Detected in brain, with highest expression in brain cortex, caudate putamen, cerebellum and hippocampus. Detected in neuropil (at protein level). Detected in brain and kidney.
Interacts (via C-terminus) with SHANK3 (via PDZ domain) (PubMed:16522626). Interacts (via coiled coil) with SIPA1L1 (PubMed:16522626). Can form homooligomers (PubMed:16522626).
May be involved in promoting the maturation of dendritic spines, probably via regulating SIPA1L1 levels at the postsynaptic density of synapses(PubMed:27252646).
May play a role in regulation of gastrulation.
Belongs to the mitochondrion-specific ribosomal protein mS33 family.
Polyubiquitinated by RNF128 with 'Lys-63'-linked chains, leading to proteasomal degradation.
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.
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. The PAMPs include alpha-mannans on C.albicans hypheas and mycobacterial trehalose 6,6'-dimycolate (TDM) (By similarity). Interacts with signaling adapter Fc receptor gamma chain/FCER1G, likely via CLEC4E, to form a functional complex in myeloid cells (PubMed:23921530). 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. The heterodimer formed with CLEC6A is active against fungal infection. Functions as an endocytic receptor. 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 (By similarity).
Expressed in myeloid cells (dendritic cells, macrophages and neutrophils) and B-cells.
Heterodimer with CLEC4E; disulfide-linked (PubMed:23921530). CLEC4E acts as a bridge for interaction between CLEC4D and FCER1G to form a functional complex (PubMed:23921530). Heterodimer with CLEC6A; this heterodimer forms a pattern recognition receptor (PRR) against fungal infection (By similarity).
Interacts with MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK9/JNK2, PPP1R9B/NEURABIN-2 and actin (By similarity). Binds to and stabilizes microtubules; binding affinity is strongly reduced by autophosphorylation.
Protein kinase with a significantly reduced Ca(2+)+/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 binding to microtubules.
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. About 20 C9 chains oligomerize to give rise to a huge beta-barrel that forms a 100 Angstrom diameter pore in target membranes.
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. C9 is the pore-forming subunit of the MAC.
Detected at low levels in neonate blood serum. Levels increase throughout the first three weeks after birth.
The structure of the human polymeric form indicates the existence of an additional disulfide bond compared to the mouse monomeric form.
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 (By similarity).
The YXXL motif mediates the interaction with MAP1 LC3 family proteins MAP1LC3A, MAP1LC3B and GABARAP.
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.
A connexon is composed of a hexamer of connexins (PubMed:1371548). Interacts with SGSM3 (By similarity). Interacts with RIC1/CIP150 (By similarity). Interacts with CNST and CSNK1D (By similarity). Interacts (via C-terminus) with TJP1 (PubMed:15492000, PubMed:18636092). Interacts (via C-terminus) with SRC (via SH3 domain) (PubMed:15492000). Interacts (not ubiquitinated) with UBQLN4 (via UBA domain) (PubMed:20127391). Interacts with NOV (PubMed:15181016, PubMed:15213231). Interacts with TMEM65 (By similarity).
Acetylated in the developing cortex; leading to delocalization from the cell membrane.
Contains at least one intramolecular disulfide bond.
Detected in ventricle and atrium (at protein level).
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. 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 (PubMed:15181016). Plays an essential role in gap junction communication in the ventricles (By similarity).
In bladder smooth muscle cells, exhibits night/day variations with low levels during the sleep phase, at circadian time (CT) 4-8 (at protein level). Expression starts to increase around CT12 and forms a plateau during the active phase (CT16-24) (at protein level).
Phosphorylation at Ser-325, Ser-328 and Ser-330 by CK1 modulates gap junction assembly. Phosphorylated at Ser-368 by PRKCG; phosphorylation induces disassembly of gap junction plaques and inhibition of gap junction activity (By similarity). Phosphorylation at Ser-368 by PRKCD triggers its internalization into small vesicles leading to proteasome-mediated degradation (PubMed:24500718).
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 (By similarity).
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 (By similarity).
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.
Probable transporter, its substrate specificity is unknown.
Belongs to the metallo-dependent hydrolases superfamily. Phosphotriesterase family.
Binds resiniferotoxin, a vanilloid that desensitizes nociceptive neurons.
Expressed primarily in proximal tubules of the kidney.
Was reported to promote CD8+ T cell immunity through effects on mitochondrial respiration. However, the corresponding article has been retracted.
Component of the small ribosomal subunit (By similarity). Required for proper rRNA processing and maturation of 18S rRNAs (By similarity).
Component of the small ribosomal subunit.
Expressed in the striatum, cerebellum, hippocampus, hypothalamus, pons, heart and liver.
Removes 5-oxoproline from various penultimate amino acid residues except L-proline.
Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SETD6 subfamily.
Monomer, homodimer and homotrimer; these structures are stabilized in the presence of S-adenosyl-L-methionine (SAM).
Protein-lysine N-methyltransferase. Monomethylates 'Lys-310' of the RELA subunit of NF-kappa-B complex, leading to down-regulation of NF-kappa-B transcription factor activity. Monomethylates 'Lys-8' of H2AZ (H2AZK8me1) (By similarity). Required for the maintenance of embryonic stem cell self-renewal (By similarity). Methylates PAK4.
Expressed in lung, spleen, kidney, thymus and macrophages.
In animals in which experimental allergic encephalomyelitis (EAE) has been induced.
Interacts with ARRB1 (By similarity). Interacts (via extracellular N-terminal region) with beta-defensin DEFB106A/DEFB106B; this interaction may preferentially require specific tyrosine sulfation on CCR2 (By similarity). Interacts with NUP85; the interaction is required for CCR2 clusters formation on the cell membrane and CCR2 signaling (By similarity).
Key functional receptor for CCL2 but can also bind CCL7 and CCL12 (By similarity). Its binding with CCL2 on monocytes and macrophages mediates chemotaxis and migration induction through the activation of the PI3K cascade, the small G protein Rac and lamellipodium protrusion (By similarity). Also acts as a receptor for the beta-defensin DEFB106A/DEFB106B (By similarity). Regulates the expression of T-cell inflammatory cytokines and T-cell differentiation, promoting the differentiation of T-cells into T-helper 17 cells (Th17) during inflammation (By similarity). Facilitates the export of mature thymocytes by enhancing directional movement of thymocytes to sphingosine-1-phosphate stimulation and up-regulation of S1P1R expression; signals through the JAK-STAT pathway to regulate FOXO1 activity leading to an increased expression of S1P1R (By similarity). Plays an important role in mediating peripheral nerve injury-induced neuropathic pain (By similarity). Increases NMDA-mediated synaptic transmission in both dopamine D1 and D2 receptor-containing neurons, which may be caused by MAPK/ERK-dependent phosphorylation of GRIN2B/NMDAR2B (By similarity). Mediates the recruitment of macrophages and monocytes to the injury site following brain injury (By similarity).
Sulfation increases the affinity for both monomeric and dimeric CCL2 with stronger binding to the monomeric form (By similarity). Binding of sulfated CCR2 to CCL2 promotes conversion of CCL2 from dimer to monomer (By similarity).
Vascular smooth muscle and prostate. Periacinar ring.
Transports dicarboxylates across the inner membranes of mitochondria by a counter-exchange mechanism. 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. 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.
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).
Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein BCL2.
Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein BCL2. Interacts with PLEKHN1.
Induces caspase activation and apoptosis (By similarity). Allows the release of cytochrome c (By similarity).
Induces caspases and apoptosis. Counters the protective effect of BCL2.
Interacts with ITCH (By similarity). Interacts with MTCH2 (By similarity).
TNF-alpha induces caspase-mediated cleavage into a major p15 and minor p13 and p11 products (By similarity). Cleaved by CASP6 into a major p15 and minor p13 products, leading to release of cytochrome c and subsequent nonalcoholic steatohepatitis (By similarity).
Ubiquitinated by ITCH; ubiquitination results in proteasome-dependent degradation.
Belongs to the mitochondrion-specific ribosomal protein mL54 family.
Expressed in lung, brain, heart, testis.
Expressed in lung, brain, heart, testis. Diffuse cytoplasmic distribution and some modest association with the Golgi apparatus.
Expressed in lung, brain, heart, testis. Localized to vesicular-like punctate spots, neither at the plasma membrane nor the Golgi area.
Isoform-specific expression in germ-cell-depleted testis (Sertoli cells), brain (peripheral sensory neurons), lung and heart.
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.
Up-regulated expression throughout development.
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.
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.
Found in several complexes of 140-500 kDa. Interacts with YME1L1. Interacts with COX4I1. Interacts with COX5A. Interacts with TP53; mediates mitochondrial translocation of TP53 in response to genotoxic stress such as mitomycin C treatment.
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. Mediates mitochondrial translocation of TP53 and its transcription-independent apoptosis in response to genotoxic stress.
In the brain, especially in the olfactory bulb and in the brain stem. No detectable expression in peripheral tissues such as lung, testis, spleen, and small intestine.
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. Isoform A but not isoform B 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.
Self-associates. Interacts with HTT/huntingtin; enhanced by an expanded polyglutamine repeat within HTT. Isoform A interacts with DCTN1; decreased in presence of HTT with expanded polyglutamine repeat; decreased by phosphorylation of Hap1 isoform A at Thr-598. Isoform A interacts with KLC2; decreased by phosphorylation of Hap1 isoform A at Thr-598. Isoform A interacts with ITPR1 and APP. Isoform A interacts with AR; decreased by an expanded polyglutamine repeat within AR. Isoform A interacts with YWHAZ; enhanced by phosphorylation of Hap1 isoform A at Thr-598. Isoform A 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. Interacts with NTRK2; HAP1 stabilizes association of NTRK2 with SORT1 preventing NTRK2 degradation. Interacts with CCDC113.
Transcription elongation factor which increases mitochondrial RNA polymerase processivity. Regulates transcription of the mitochondrial genome, including genes important for the oxidative phosphorylation machinery (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 (By similarity).
Disintegrin domain binds to integrin alphaV-beta3.
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 (By similarity). Interacts with ITAG9-ITGB1. 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 (By similarity).
Phosphorylation increases association with PTKs.
Predominantly expressed in brain, spinal cord, sciatic nerve and lung. Expressed at lower levels in all other tissues. In the peripheral nervous system, expressed predominantly by Schwann cells. In the central nervous system, preferentially expressed by neuronal cells.
The cytoplasmic domain is required for SH3GL2- and SNX9-binding.
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. Can also elongate RNA oligos ending with uridine molecule, provided that the sequence is adenosine-rich. Mainly targets mRNAs encoding endoplasmic reticulum-targeted protein.
Interacts with BCCIP and PABPC1; the interaction has no effect on TENT5C poly(A) polymerase function. Interacts with PLK4; this interaction leads to the TENT5C recruitment into the centrosome.
Allosterically activated by phosphatidylinositol 5-phosphate (PI5P).
Heterodimer with MTMR12. Interacts with KMT2A/MLL1 (via SET domain). Interacts with DES in skeletal muscle but not in cardiac muscle. Interacts with SPEG.
Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2). Has also been shown to dephosphorylate phosphotyrosine- and phosphoserine-containing peptides. Negatively regulates EGFR degradation through regulation of EGFR trafficking from the late endosome to the lysosome. Plays a role in vacuolar formation and morphology. Regulates desmin intermediate filament assembly and architecture. Plays a role in mitochondrial morphology and positioning. Required for skeletal muscle maintenance but not for myogenesis. In skeletal muscles, stabilizes MTMR12 protein levels.
The GRAM domain mediates binding to PI(3,5)P2 and, with lower affinity, to other phosphoinositides.
By PDGF and angiotensin II in aortic smooth muscle cells. By deprivation of NGF in neuronal cell cultures. Induced during coronary heart ligation.
Highly expressed in vascular smooth muscle. Moderately expressed in esophagus, stomach, small bowel and aorta. Low levels in tail and kidney. Expression also in pheochromocytoma cell line PC-12.
Interacts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex (By similarity). Interacts with PAX2; the interaction targets PAX2 for destruction (By similarity). Interacts with PKM; the interaction hydroxylates PKM in hypoxia (By similarity). Interacts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity (PubMed:16407229). Interacts with BCL2 (via its BH4 domain); the interaction disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of BCL2 (By similarity).
Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as PKM, TELO2, ATF4 and HIF1A (By similarity). Target proteins are preferentially recognized via a LXXLAP motif (By similarity). Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184). Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (By similarity). Also hydroxylates HIF2A (By similarity). Has a preference for the CODD site for both HIF1A and HIF2A (By similarity). Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site (By similarity). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (By similarity). 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 (By similarity). ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia (By similarity). Also hydroxylates PKM in hypoxia, limiting glycolysis (By similarity). Under normoxia, hydroxylates and regulates the stability of ADRB2 (By similarity). Regulator of cardiomyocyte and neuronal apoptosis (By similarity). In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex (PubMed:20849813). In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity (PubMed:10386996, PubMed:11060309). Also essential for hypoxic regulation of neutrophilic inflammation (By similarity). Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway (By similarity). Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (By similarity).
Has both NAD(+) glycohydrolase and ADP-ribosyltransferase activity (to a lesser extent).
Component of the uniplex complex. Interacts (via the transmembrane region) with MCU (via the first transmembrane region); the interaction is direct.
Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria.
Belongs to the peroxiredoxin family. Prx6 subfamily.
Homodimer (By similarity). Interacts with GSTP1; mediates PRDX6 glutathionylation and regeneration (Probable). Interacts with APEX1. Interacts with STH. May interact with FAM168B (By similarity). May interact with HTR2A (By similarity).
Irreversibly inactivated by overoxidation of Cys-47 to sulfinic acid (Cys-SO(2)H) and sulfonic acid (Cys-SO(3)H) forms upon oxidative stress.
Phosphorylation at Thr-177 by MAP kinases increases the phospholipase activity of the enzyme (PubMed:19140803). Phosphorylated form exhibits a greater lysophosphatidylcholine acyltransferase activity compared to the non-phosphorylated form (PubMed:26830860).
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this 1-Cys peroxiredoxin, no C(R) is present and C(P) instead forms a disulfide with a cysteine from another protein or with a small thiol molecule. C(P) is reactivated by glutathionylation mediated by glutathione S-transferase Pi, followed by spontaneous reduction of the enzyme with glutathione.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively (PubMed:15004285). Can reduce H(2)O(2) and short chain organic, fatty acid, and phospholipid hydroperoxides (By similarity). Also has phospholipase activity, can therefore either reduce the oxidized sn-2 fatty acyl group of phospholipids (peroxidase activity) or hydrolyze the sn-2 ester bond of phospholipids (phospholipase activity) (PubMed:8999971, PubMed:15004285, PubMed:17652308). These activities are dependent on binding to phospholipids at acidic pH and to oxidized phospholipds at cytosolic pH (By similarity). Plays a role in cell protection against oxidative stress by detoxifying peroxides and in phospholipid homeostasis (By similarity). Exhibits acyl-CoA-dependent lysophospholipid acyltransferase which mediates the conversion of lysophosphatidylcholine (1-acyl-sn-glycero-3-phosphocholine or LPC) into phosphatidylcholine (1,2-diacyl-sn-glycero-3-phosphocholine or PC) (PubMed:26830860). Shows a clear preference for LPC as the lysophospholipid and for palmitoyl CoA as the fatty acyl substrate (By similarity).
Belongs to the PIGG/PIGN/PIGO family. PIGG subfamily.
Homodimer. The homodimer is not disulfide-linked. Interacts with ERO1A and CLGN (By similarity).
Probable redox-inactive chaperone involved in spermatogenesis.
Testis-specific. Expressed exclusively in postmeiotic male germ cells (at protein level).
The thioredoxin domain lacks the conserved redox-active Cys at position 414 which is replaced by a Ser residue, suggesting that it lacks thioredoxin activity.
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 (By similarity). Found in a complex with VAMP8 and STX1A (By similarity). 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 (PubMed:14993220). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (By similarity).
Cell surface proteoglycan that may bear heparan sulfate. 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 (By similarity).
High levels in neonatal brain, heart, and Schwann cells, barely detectable in neonatal or adult liver, or adult brain.
Interacts with TIAM1 (By similarity). Interacts (via heparan sulfate chains) with PTN; this interaction mediates the neurite outgrowth-promoting signal from PTN to the cytoskeleton of growing neurites; this interaction mediates osteoblast recruitment (PubMed:8175719, PubMed:9817766). Interacts with MDK; this interaction induces SDC3 clustering; this interaction induces neuronal cell adhesion and neurite outgrowth (PubMed:9089390).
O-glycosylated within the Thr/Ser-rich region which could interact with lectin domains on other molecules.
Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT).
Belongs to the steroid 5-alpha reductase family. Polyprenol reductase subfamily.
Expressed in the 2 tissues tested i.e. testis and liver.
Plays a key role in early steps of protein N-linked glycosylation by being required for the conversion of polyprenol into dolichol (PubMed:8486680). Dolichols are required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-glycosylation (PubMed:8486680). Acts as a polyprenol reductase that promotes the reduction of the alpha-isoprene unit of polyprenols into dolichols in a NADP-dependent mechanism (PubMed:8486680). Also able to convert testosterone (T) into 5-alpha-dihydrotestosterone (DHT) (By similarity).
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.
Broadly expressed in brain (at protein level).
Interacts with Chrna4 (By similarity). 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 (By similarity).
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).
Highly expressed in aorta, bladder, and kidney with much lower levels in all other tissues analyzed. Expression in kidney is restricted to proximal convoluted tubules.
May be involved in vascular wall and kidney homeostasis.
Interacts with APBA1 (via PDZ 1 and 2 domains).
Transcriptional repressor that down-regulates the expression of the fibrinogen gamma chain. Represses transcription of GSK3B gene promoter via its interaction with APBA1 (By similarity).
Belongs to the dihydropyrimidine dehydrogenase family.
Binds 4 [4Fe-4S] clusters. Contains approximately 16 iron atoms per subunit.
Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil.
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.
Heterodimer of an alpha chain and a beta chain. Beta-2-microglobulin is the beta-chain of major histocompatibility complex class I molecules. Forms a heterotrimer with MR1 and a metabolite antigen.
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).
Forms heterooligomers with AFG3L1 and AFG3L2. Component of the mitochondrial permeability transition pore complex (mPTPC), at least composed of SPG7, VDAC1 and PPIF. Interacts with AFG3L2; the interaction is required for the efficient assembly of mitochondrial complex I. Interacts with AFG3L1. Interacts with MAIP1. Interacts with VDAC1 and PPIF.
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.
Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump (PubMed:32165585). Interacts (via N-terminus) with ATP6AP2 (via N-terminus) (PubMed:32165585). Interacts with RNASEK (By similarity). Interacts with TMEM106B (via C-terminus) (By similarity).
Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles (PubMed:32165585). Guides the V-type ATPase into specialized subcellular compartments, such as neuroendocrine regulated secretory vesicles or the ruffled border of the osteoclast, thereby regulating its activity. Involved in membrane trafficking and Ca(2+)-dependent membrane fusion. May play a role in the assembly of the V-type ATPase complex. 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 (By similarity). In islets of Langerhans cells, may regulate the acidification of dense-core secretory granules (By similarity).
Brain specific (PubMed:11182241). Highly expressed in frontal cortex, hippocampus, olfactory bulb, caudate-putamen and cerebellum (at protein level) (PubMed:11182241).
Interacts with CAMK2B; the presence of Ca(2+)/calmodulin increases the interaction but is not essential (PubMed:11182241). Interacts with CAMK2A; this interaction requires CAMK2A activation by Ca(2+) (PubMed:11182241).
Knockout in a spontaneously hypertensive rat model results in decreased blood pressure and vascular reactivity to N-omega-Nitro-L-arginine methyl ester hydrochloride (PubMed:31327268). Increased renal and serum endothelial nitric oxide synthase and serum nitrate levels (PubMed:31327268). Reduced fasting plasma glucose concentrations and a 23% decrease in visceral and brown adipose tissue relative mass, resulting from a decrease in adipocyte number (PubMed:31327268).
Potent and specific inhibitor of CaM-kinase II (CAMK2) (PubMed:11182241). 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 (PubMed:31327268). 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 (PubMed:31327268).
Aminooxyacetic acid (AOAA) blocks its activity in both cytoplasm and mitochondria.
Catalyzes the synthesis of N-acetylaspartate acid (NAA) from L-aspartate and acetyl-CoA (PubMed:18621030). Promotes dopamine uptake by regulating TNF-alpha expression (By similarity). Attenuates methamphetamine-induced inhibition of dopamine uptake (By similarity).
Expressed in brain, including in mesencephalic dopaminergic neurons of the substantia nigra and ventral tegmental area and oligodendrocytes. Expressed in cortical pyramidal neurons and granule cells of the hippocampus (at protein level).
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 isobutyrate among fatty acids with 2-6 carbon atoms (By similarity).
Expressed at low levels in brain cortex, hippocampus, striatum, hypothalamus, cerebellum and brainstem (at protein level).
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 (PubMed:9826657). Interacts with, and phosphorylates chemokine-stimulated CCR5 (By similarity). Interacts with ARRB1 (By similarity). Interacts with LPAR1 and LPAR2 (By similarity). Interacts with RALA in response to LPAR1 activation (By similarity). ADRBK1 and RALA mutually inhibit each other's binding to LPAR1 (By similarity). Interacts with ADRB2 (By similarity).
Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them (PubMed:1403099). Key regulator of LPAR1 signaling (By similarity). Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor (By similarity). Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner (By similarity). 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 (By similarity).
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.
Component of activated spliceosome complexes. 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. 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.
Belongs to the complex I NDUFB11 subunit family.
During a Nippostrongylus brasiliensis parasite infection. The expression is a transient event, with a maximum at day 6 of the 13-day-long infection.
Posseses strong A transferase activity and a weak B transferase activity.
Tongue, esophagus, large intestine, stomach, caecum, pancreas, uterus, seminal vesicle, submaxillary gland, parotid gland, thyroid gland, parathyroid gland, salivary gland and thymus (at protein level). Esophagus, large intestine, stomach, kidney, urinary bladder, uterus and thymus.
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. 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 (By similarity). May regulate the cellular storage of triacylglycerol through activation of the phospholipase PNPLA2 (By similarity). Involved in keratinocyte differentiation (By similarity). Regulates lipid droplet fusion (By similarity).
Increased in the early stage of adipocyte differentiation.
Interacts with ADRP and PLIN. Interacts with PNPLA2 (By similarity). Interacts with PLIN5; promotes interaction with PNPLA2.
Detected in a variety of tissues. High levels are found in the lymphoid organs, central nervous system, mammary gland and uterus.
May be involved in the regulation of feeding, neuroendocrine system, memory and learning. May be involved in the afferent pain pathway (By similarity).
Plays a role in the regulation of Wnt signaling pathway during early development.
Abundantly expressed in cerebrum and cerebellum. Localized in secretory epithelial cells in the brain and the eye including choroid plexus epithelial cells, ciliary epithelial cells, iris pigment epithelial cells, and retinal pigment cells.
Hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids (PubMed:12633853, PubMed:29259743, PubMed:27660691, PubMed:27268273, PubMed:27075612, PubMed:12354767). Major substrate is lysophosphatidylcholine (PubMed:12119361, PubMed:27660691, PubMed:27268273, PubMed:27075612, PubMed:12176993). Can also act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility (PubMed:12119361). Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP (PubMed:12633853, PubMed:27268273). 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. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor (By similarity). 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 (By similarity). Shows a preference for the sn-1 to the sn-2 isomer of 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) (By similarity).
Inhibited by vanadate (PubMed:27268273). Inhibited by micromolar levels of bile salts, such as tauroursodeoxycholate. Not inhibited by taurodeoxycholate. Not inhibited by hydroxysterols, such as 7-hydroxycholesterol, testosterone, dexamethasone and prednisolone (PubMed:27075612). Inhibited by EDTA and EGTA (PubMed:12354767).
N-glycosylation, but not furin-cleavage, plays a critical role on secretion and on lysoPLD activity.
The interdomain disulfide bond between Cys-413 and Cys-830 is essential for catalytic activity.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. EngB GTPase family.
Expressed in pancreas, kidney, brain, submandibular gland, and lung.
Interacts with ADRA2B. Interacts with RIMS1 (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. 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 (By similarity). Plays a role in the secretion of amylase from acinar granules in the parotid gland.
ADP-ribosylated by PARP1 or PARP2 on Ser-7 (H2BS6ADPr) in response to DNA damage (By similarity). H2BS6ADPr promotes recruitment of CHD1L (By similarity). Mono-ADP-ribosylated on Glu-3 (H2BE2ADPr) by PARP3 in response to single-strand breaks (By similarity). 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-112 promotes monoubiquitination of Lys-120. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).
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 (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-120 (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 (By similarity).
Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination. Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity).
Expressed in osteoclasts and in neurons.
Interacts with NTRK1/TRKA (PubMed:16306406). Interacts with RILP (By similarity). Interacts with PSMA7 (By similarity). Interacts with RNF115 (By similarity). Interacts with and FYCO1 (By similarity). Interacts with the PIK3C3/VPS34-PIK3R4 complex (By similarity). The GTP-bound form interacts with OSBPL1A (By similarity). The GTP-bound form interacts with RAC1 (PubMed:16040606). Interacts with CLN3 (By similarity). Interacts with CHM, the substrate-binding subunit of the Rab geranylgeranyltransferase complex (PubMed:18756270, PubMed:15186776). Interacts with C9orf72 (By similarity). Does not interact with HPS4 and the BLOC-3 complex (heterodimer of HPS1 and HPS4). Interacts with CLN5 (By similarity). Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with PRPH; the interaction is direct (By similarity). Interacts with VPS13A (By similarity). The GDP-bound form interacts with RIMOC1 (By similarity). Interacts with the MON1A-CCZ1B complex and this interaction is enhanced in the presence of RIMOC1 (By similarity).
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 (By similarity). 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-transporter-mediated nutrient uptake, neurotrophin transport in the axons of neurons and lipid metabolism (By similarity). Also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes, pathogen-induced phagosomes (or vacuoles) and autophagosomes (By similarity). Plays a role in the maturation and acidification of phagosomes that engulf pathogens, such as S.aureus and Mycobacteria (By similarity). Plays a role in the fusion of phagosomes with lysosomes (By similarity). Plays important roles in microbial pathogen infection and survival, as well as in participating in the life cycle of viruses (By similarity). 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) (By similarity). In concert with RAC1, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:16040606). Controls the endosomal trafficking and neurite outgrowth signaling of NTRK1/TRKA (PubMed:16306406). Regulates the endocytic trafficking of the EGF-EGFR complex by regulating its lysosomal degradation (By similarity). Involved in the ADRB2-stimulated lipolysis through lipophagy, a cytosolic lipase-independent autophagic pathway. Required for the exosomal release of SDCBP, CD63 and syndecan (By similarity). Required for vesicular trafficking and cell surface expression of ACE2 (By similarity). May play a role in PRPH neuronal intermediate filament assembly (By similarity).
Abundant in the islets of Langerhans but is not present in the brain or seven other tissues examined.
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, but contrary to the human protein, it does not easily form fibrillar aggregates.
ATP dependent phosphorylation of adenosine and other related nucleoside analogs to monophosphate derivatives.
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.
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.
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. As part of the BORC complex may play a role in lysosomes movement and localization at the cell periphery. The BORC complex is most probably associated with the cytosolic face of lysosomes, may recruit ARL8B and couple lysosomes to microtubule plus-end-directed kinesin motor.
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. Component of the BLOC-one-related complex (BORC) which is composed of BLOC1S1, BLOC1S2, BORCS5, BORCS6, BORCS7, BORCS8, KXD1 and SNAPIN. Interacts with ATP5F1A and NDUFA9; involved in their acetylation on lysine residues. Interacts with KXD1.
May negatively regulate aerobic respiration through mitochondrial protein lysine-acetylation. May counteract the action of the deacetylase SIRT3 by acetylating and regulating proteins of the mitochondrial respiratory chain including ATP5F1A and NDUFA9.
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).
Binds 1 [4Fe-4S] cluster per subunit. [4Fe-4S]-binding affects RNA-binding activity, thereby inhibiting activity of the protein.
Interacts with RBCK1 only in iron-rich conditions. Interacts (when associated with the 4Fe-4S) with FBXL5 (By similarity). Interacts with CIAO1 and CIAO2A (By similarity).
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 (By similarity).
Ubiquitously expressed in rat tissues, the highest amounts present in skeletal muscle and heart.
During ontogenesis, there is a transition from the alpha/alpha homodimer to the alpha/beta heterodimer in striated muscle cells.
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 (By similarity).
Thyroid hormones up-regulate expression during hindleg muscle development and down-regulate during cardiac muscle development. Decrease in ENO3 levels with aortic stenosis.
Belongs to the CND3 (condensin subunit 3) family.
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).
Acts as a regulator of tubulin stability.
Belongs to the acetyltransferase family. MAK3 subfamily.
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.
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.
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 (By similarity).
Orphan receptor activated by neuropeptides terminating in Arg-Phe or Arg-Phe-amide. 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. May regulate the function of nociceptive neurons by modulation of pain perception (By similarity).
Uniquely localized in a subset of small dorsal root and trigeminal sensory neurons. Associated preferentially with IB4 class of small-diameter somatosensory afferents (also known as nociceptors).
High affinity receptor that binds to the Fc region of immunoglobulins epsilon. Aggregation of FCER1 by multivalent antigens is required for the full mast cell response, including the release of preformed mediators (such as histamine) by degranulation and de novo production of lipid mediators and cytokines. Also mediates the secretion of important lymphokines. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators responsible for the manifestations of allergy.
Phosphorylated on tyrosine residues by LYN.
Tetramer of an alpha chain, a beta chain, and two disulfide linked gamma chains. Binds LILRB1. Interacts with FES/FPS and LYN (By similarity). Interacts with FGR.
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.
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.
Can degrade fibronectin, gelatins of type I, III, IV, and V; weakly collagens III, IV, and V. Activates procollagenase.
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. CPSF2/YSH1 subfamily.
Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3L and EIF3K. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Interacts with EIF4G1. Also interacts with KRT7 and PIWIL2.
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination.
Interacts with GORASP2 (PubMed:11739401). 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.
Was initially thought to be a potential transcription factor, localized in the nucleus.
Liver, exhibiting a sex-dependent spatial localization in the lobule of the liver.
Oligomer consisting of several isoelectric variants with the same molecular mass. Relative contents of these isoelectic variants are different in weanling (20 days) than in young adults (110 days).
The ST activities display gender- and age-dependent alterations and are known to be under the regulation of gonadal, adrenal and growth hormones.
There is a marked sex difference (female >> male) in the cytosolic level of this protein. Its activity increases after birth in parallel in both sexes until the weanling stage. Thereafter the activity decreases in males, whereas it declines temporarily in females and increases again to a maximum level in adult females.
Coordinated expression with SEPTIN2 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 (By similarity). 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 (By similarity).
Septins polymerize into heterooligomeric protein complexes that form filaments, and associate with cellular membranes, actin filaments and microtubules (By similarity). GTPase activity is required for filament formation (By similarity). Septin filaments are assembled from asymmetrical heterotrimers, composed of SEPTIN2, SEPTIN6 and SEPTIN7 that associate head-to-head to form a hexameric unit (By similarity). Interaction between SEPTIN2 and SEPTIN7 seems indirect (PubMed:15485874). Interacts also with SEPTIN9 and SEPTIN5 (By similarity). Interaction with SEPTIN4 not detected (By similarity). 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 (By similarity). Interacts with MAP4 (By similarity). Interacts with DZIP1L (By similarity).
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 NUPL2 (By similarity).
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) (By similarity).
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).
Monomer. Interacts with SARS1/SerRS; interaction is mediated via tRNA(Ser) and is required for N(3)-methylcytidine methylation.
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). Interaction with SARS1/SerRS is required for N(3)-methylcytidine methylation.
Highly expressed in heart, skeletal muscle, brain and lung (at protein level).
Interacts (when S-nitrosylated) with GAPDH (PubMed:19607794). Interacts with RAB8A; interaction is dependent on the phosphorylation of 'Thr-72' of RAB8A (By similarity). Interacts with RAB10 and RAB12; the interaction is dependent on the phosphorylation of 'Thr-73' of RAB10, and 'Ser-105' of RAB12 (By similarity).
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 (PubMed:19607794). Competes with SIAH1 for binding GAPDH (PubMed:19607794). Does not regulate lysosomal morphology and distribution (By similarity). Binds to RAB10 following LRRK2-mediated RAB10 phosphorylation which leads to inhibition of ciliogenesis (By similarity).
S-nitrosylation is required for the interaction with GAPDH.
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). 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 (By similarity). 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 (By similarity).
Expressed in the heart (PubMed:19219384).
Interacts with KCNB1 (PubMed:19219384). Associates with KCNH2/ERG1 (By similarity). May associate with KCNQ2 and KCNQ3 (By similarity). Associates with HCN1 and probably HCN2 (PubMed:11420311). Heteromultimer with KCNC2. Interacts with KCNC2 (PubMed:14679187). 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 (By similarity).
Interacts with YIPF6; this interaction may stabilize YIPF2. May also form a ternary complex with YIPF1 and YIPF6.
Essential acyltransferase that catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Required for synthesis and storage of intracellular triglycerides (By similarity). Probably plays a central role in cytosolic lipid accumulation. In liver, is primarily responsible for incorporating endogenously synthesized fatty acids into triglycerides (By similarity). Functions also as an acyl-CoA retinol acyltransferase (ARAT) (By similarity). Also able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG) (By similarity).
Forms multimeric complexes consisting of several DGAT2 subunits (By similarity). Interacts with SLC27A1 and this interaction is enhanced in the presence of ZFYVE1 (By similarity).
Epithelium of the tongue; including the taste buds.
Detected in kidney distal convoluted tubules (at protein level).
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 PDZ domain) with ARHGEF16. Interacts (via PDZ domain) with KCNJ4 (via C-terminus). Competes with LIN7A for KCNJ4 binding (By similarity). Interacts (via its PDZ domain) with CTNNB1; this interaction inhibits the transcriptional activity of CTNNB1 (By similarity). Interacts with ADGRB2.
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 (By similarity).
Acetylation stimulates DNA-binding. Enhanced under stress conditions such as DNA damage and inhibited by retinoblastoma protein RB1. Regulated by KAP1/TRIM28 which recruits HDAC1 to E2F1 resulting in deacetylation (By similarity).
BIRC2/c-IAP1 stimulates its transcriptional activity.
Component of the DRTF1/E2F transcription factor complex. Forms heterodimers with DP family members. The E2F1 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. Interacts with TRRAP, which probably mediates its interaction with histone acetyltransferase complexes, leading to transcription activation. Binds TOPBP1 and EAPP. Interacts with ARID3A. Interacts with TRIM28; the interaction inhibits E2F1 acetylation through recruiting HDAC1 and represses its transcriptional activity. Interaction with KAT2B; the interaction acetylates E2F1 enhancing its DNA-binding and transcriptional activity. Interacts with BIRC2/c-IAP1 (via BIR domains). The complex TFDP1:E2F1 interacts with CEBPA; the interaction prevents CEBPA binding to target genes promoters and represses its transcriptional activity. Interacts with RRP1B. Interacts with HCFC1. Interacts with KMT2E; the interaction is probably indirect and is mediated via HCFC1.
Phosphorylated by CDK2 and cyclin A-CDK2 in the S-phase. Phosphorylation by CHEK2 stabilizes E2F1 upon DNA damage and regulates its effect on transcription and apoptosis. Phosphorylation at Ser-398 by GSK3B promotes interaction with USP11, leading to its deubiquitination and stabilization.
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. E2F1 binds preferentially RB1 in a cell-cycle dependent manner. It can mediate both cell proliferation and TP53/p53-dependent apoptosis. Blocks adipocyte differentiation by binding to specific promoters repressing CEBPA binding to its target gene promoters. Directly activates transcription of PEG10. Positively regulates transcription of RRP1B.
Ubiquitinated via 'Lys-63'-linked ubiquitin, leading to its degradation. Deubiquitinated by USP11 follwong phosphorylation by GSK3B, promoting its stability.
Expressed in all developing tissues with highest levels detected in primitive, transformed cells. Relative abundance: lung > kidney = skin = gut > spleen > brain > liver.
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P) (PubMed:10383399). S1P is a bioactive lysophospholipid that elicits diverse physiological effects on most types of cells and tissues (PubMed:10383399). Receptor for the chemokine-like protein FAM19A5 (PubMed:29453251). Mediates the inhibitory effect of FAM19A5 on vascular smooth muscle cell proliferation and migration (PubMed:29453251).
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ11 subfamily.
Interacts with ABCC9/SUR2 (By similarity). Interacts with ABCC8/SUR.
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. Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (By similarity).
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. 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.
Homoheptamer arranged in a ring structure. 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 (By similarity). Interacts with HRAS (By similarity). Interacts with ATAD3A. Interacts with ETFBKMT and EEF1AKMT3 (By similarity). Interacts with MFHAS1 (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 (By similarity). Interacts with ALKBH4, IFIT1 and IFIT2 (By similarity). Interacts with BZW2/5MP1 (By similarity).
Interacts with activated GNAQ and GNA11. Interacts with RHOA, CDC42 and RAC1. Interacts (via the DH domain) with BVES (via the C-terminus cytoplasmic tail) (By similarity).
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.
Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy. 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. The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and modulating its protein kinase activity. As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro (By similarity). Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ULK1/ATG1 kinase complex to the phagophore which leads to autophagosome formation. Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates. Plays a role in endosomal trafficking. May be involved in regulating the maturation of phagosomes to lysosomes. Promotes the lysosomal localization and lysosome-mediated degradation of CARM1 which leads to inhibition of starvation-induced lipid metabolism (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation. This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of CFL1/cofilin, leading to cofilin activation. Positively regulates axon extension and axon growth cone size in spinal motor neurons. Required for SMCR8 protein expression and localization at pre- and post-synaptic compartments in the forebrain, also regulates protein abundance of RAB3A and GRIA1/GLUR1 in post-synaptic compartments in the forebrain and hippocampus (By similarity). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity.
Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41 (By similarity). The complex is formed of two protomers, each individually consisting of one molecule each of C9orf72, SMCR8 and WDR41 (By similarity). The protomers homodimerize via an interaction between C9orf72 (via C-terminus) and SMCR8 (via N-terminus) (By similarity). 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) (By similarity). The C9orf72-SMCR8 complex associates with the ULK1/ATG1 kinase complex. Interacts with ULK1/ATG1 kinase complex members ULK1, ATG13 and RB1CC1. Interacts with SMCR8; the interaction is direct (By similarity). Interacts with HNRNPA1, HNRNPA2B1 and UBQLN2. Interacts with small Rab GTPase RAB1A; the interaction mediates recruitment of RAB1A to the ULK1/ATG1 kinase complex. Also interacts with small Rab GTPase RAB7A. Interacts with cofilin (By similarity). Interacts with GTP-binding proteins ARF1 and ARF6. Interacts with the DLG4/PSD-95 (By similarity). Interacts with CARM1 (via PH domain-like fold) (By similarity).
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) (PubMed:17575325, PubMed:9736690). CF(0) has three main subunits: a, b and c (PubMed:17575325). Interacts with ATPAF2. Interacts with HRG; the interaction occurs on the surface of T-cells and alters the cell morphology when associated with concanavalin (in vitro). Interacts with PLG (angiostatin peptide); the interaction inhibits most of the angiogenic properties of angiostatin (By similarity). 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 ATP5MPL (By similarity). Interacts with BLOC1S1 (By similarity). 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 (PubMed:21926988). 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 (PubMed:31511561).
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 (By similarity).
The siderophore enterobactin (Ent) produced by enteric bacteria binds Fe(3+) and helps bacteria scavenge iron ions from the environment. 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.
Calmodulin-dependent kinase that phosphorylates MYL2 in vitro. Promotes sarcomere formation in cardiomyocytes. Increases cardiomyocyte contractility.
Expressed in cardiomyocytes (at protein level). Up-regulated in heart after experimental myocardial infarction at the mRNA level.
Up-regulated in the heart from 1 week after birth through adulthood.
AMP and XMP inhibit AICAR formyltransferase activity.
Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis. 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). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction. Also catalyzes the cyclization of FAICAR to IMP (By similarity). Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571).
Homodimer (By similarity). 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).
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.
50% of the mature protein that was isolated had Leu-39 as its N-terminal residue and 50% had Ser-40 suggesting two adjacent processing sites. However, the possibility of proteolytic removal of Leu-39 during the isolation of the enzyme cannot be excluded. Undergoes proteolytic cleavage in the C-terminal region corresponding to the loss of approximately 12 AA residues from the C-terminus (PubMed:23649895).
Can form homooligomers (monomers as predominant form and dimers).
Glutarylated. Glutarylation levels increase during fasting. Deglutarylated by SIRT5 at Lys-55, Lys-219, Lys-412, Lys-889, Lys-892, Lys-915, Lys-1360 and Lys-1486, leading to activation.
Involved in the urea cycle of ureotelic animals where the enzyme plays an important role in removing excess ammonia from the cell.
Primarily in the liver and small intestine.
Requires N-acetyl-L-glutamate (NAG) as an allosteric activator. N-acetyl-L-beta-phenylglutamate (Phe-NAG) can also activate CPSase I, but with an activation constant that is 2-fold higher than that for NAG.
Succinylated at Lys-287 and Lys-1291. Desuccinylated at Lys-1291 by SIRT5, leading to activation (By similarity).
The type-1 glutamine amidotransferase domain is defective.
Binds 5 Ca(2+) ions per subunit. Two of the Ca(2+) ions are bound to the C2 domain.
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:16000311). Essential for trophoblast and placental development (By similarity). Binds phosphatidylinositol 4,5-bisphosphate (By similarity).
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 (By similarity).
Interacts with the C-terminal of STOM (By similarity). Interacts with the EPS8 SH3 domain. Interaction with EPS8 is inhibited by glutathione binding (By similarity).
Strongly expressed in the brain, testis and skeletal muscle. Expressed in the neurons of the cerebellum, the germinal cells of the seminiferous tubules in testis, in liver hepoatocytes and in cardiac myocytes.
Component of a CRL2 E3 ubiquitin-protein ligase complex, also named ECS (Elongin BC-CUL2/5-SOCS-box protein) complex, composed of CUL2, Elongin BC (ELOB and ELOC), RBX1 and substrate-specific adapter KLHDC10. Interacts (via the 6 Kelch repeats) with PPP5C.
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. 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. The CRL2(KLHDC10) complex specifically recognizes proteins with a proline-glycine (Pro-Gly) at the C-terminus, leading to their ubiquitination and degradation (By similarity). Participates in the oxidative stress-induced cell death through MAP3K5 activation. Inhibits PPP5C phosphatase activity on MAP3K5. Acts as a regulator of necroptosis (By similarity).
Expressed in the retina. Strongly expressed by the mitral and tufted cells in the main and accessory olfactory bulbs. Also expressed in the septum and olfactory cortex. Weakly expressed in the triangular septal nucleus and piriform cortex.
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.
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.
Belongs to the TDD superfamily. DTWD1 family.
Catalyzes the formation of 3-(3-amino-3-carboxypropyl)uridine (acp3U) at position 20 in the D-loop of several cytoplasmic tRNAs (acp3U(20)).
Brain and osteoblastic cells (at protein level) (PubMed:21076856). Highly expressed in brain (PubMed:7475896, PubMed:21076856).
Deoxyglucose transport is inhibit by D-glucose, D-galactose and maltose. Galactose transport is inhibited by D-glucose and maltose.
Facilitative glucose transporter that can also mediate the uptake of various other monosaccharides across the cell membrane. Mediates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose and fucose, and probably also dehydroascorbate. Does not mediate fructose transport.
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.
Interacts directly with activated HRAS; a RASSF5-STK4/MST1 complex probably associates with activated HRAS. Interacts with KRAS. Probably interacts with Ras-like GTPases RRAS, MRAS, RAP1B, RAP2A and RALA (By similarity). Interacts with RRAS2 (By similarity). Can self-associate. Interacts with RSSF1 isoform A. 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. Binds STK4/MST1, inhibiting STK4/MST1 autoactivation (By similarity).
Potential tumor suppressor. Seems to be involved in lymphocyte adhesion by linking RAP1A activation upon T-cell receptor or chemokine stimulation to integrin activation. 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 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 (By similarity).
Found in several tissues including central nervous system, liver and kidney. A high level of expression was found in the hippocampus.
Interacts with EPHA3 (phosphorylated); dephosphorylates EPHA3 and may regulate its trafficking and function. Interacts with MET.
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 (By similarity).
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 (By similarity).
Has no tyrosine-protein phosphatase activity at mild acidic conditions (pH 5.5). The in vivo relevance of the low PPase activity for the human protein 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.
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). Required to maintain normal levels of renin expression and renin release. 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, phosphatidylinositol 5-phosphate and phosphatidylinositol 3-phosphate (PubMed:20097759). 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 (By similarity).
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) (PubMed:15882444). Interacts with MYO5A (PubMed:25744490).
Subject to proteolytic cleavage at multiple sites.
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.
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.
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.
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 (By similarity).
Interacts with the cytoplasmic domain of the autophosphorylated insulin receptor, through the SH2 domain. Interacts with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop on INSR from dephosphorylation (By similarity). 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) (By similarity).
Phosphorylated on serine residues. Phosphorylated on tyrosine residues by TEK/TIE2 (By similarity).
The PH domain binds relatively non-specifically and with low affinity to several phosphoinositides, the best binder being PI(3,4,5)P3.
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. Both, PI3KC3-C1 and PI3KC3-C2, can associate with further regulatory subunits, such as RUBCN, SH3GLB1/Bif-1, AMBRA1 and NRBF2. PI3KC3-C1 probably associates with PIK3CB. Interacts with RAB7A in the presence of PIK3C3/VPS34. Interacts with NRBF2 (By similarity).
Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2 (By similarity).
Component of 250-400 kDa complexes called cytochrome oxidase assembly intermediates or COA complexes.
Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both translation of mitochondrial encoded components and assembly of nuclear-encoded components imported in mitochondrion. Required for efficient translation of MT-CO1 and mitochondrial respiratory chain complex IV assembly.
Required for assembly of cytochrome c oxidase (complex IV).
Belongs to the peroxiredoxin-like PRXL2 family. PRXL2A subfamily.
Expressed by the principal cells of the epididymis. Detected in the head region of epididymal sperm (at protein level). Expressed in bone marrow.
Involved in redox regulation of the cell. Acts as an antioxidant. Inhibits TNFSF11-induced NFKB1 and JUN activation and osteoclast differentiation. May affect bone resorption and help to maintain bone mass. Acts as a negative regulator of macrophage-mediated inflammation by inhibiting macrophage production of inflammatory cytokines, probably through suppression of the MAPK signaling pathway.
The active site cysteines correspond to the redox-active cysteines of peroxiredoxins.
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 ATP5MPL (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.
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. 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.
Ubiquitous. Highly expressed in skeletal and cardiac muscle. Moderately expressed in brain, thymus, stomach and testis. Lowest expression levels were detected in lung, liver, kidney, adrenal gland, spleen, small intestine and adipose tissue. In streptozotocin-induced diabetes, the insulin-sensitive tissues skeletal and cardiac muscle were down-regulated.
Expressed in brain, lung, heart, kidney, stomach, small intestine, colon, and testis, and at a much lower levels in thymus, liver and muscle.
Function as phospholipase selective for phosphatidylcholine (By similarity) (PubMed:15282299, PubMed:9111050). May have a role in signal-induced cytoskeletal regulation and/or endocytosis (By similarity) (PubMed:15282299).
Interacts with PIP5K1B (By similarity). Interacts with EGFR (By similarity).
Phosphorylated by FGR (PubMed:15282299). Phosphorylated on Tyr-11; most likely by EGFR (By similarity).
Stimulated by phosphatidylinositol 4,5-bisphosphate and phosphatidylethanolamine. Inhibited by phosphatidylserine and by oleate. Is not responsive to ADP-ribosylation factor 1 (ARF1), nor to GTP-binding protein RhoA.
G-protein coupled receptor for Big LEN, a 16-amino acid neuropeptide produced from the precursor protein, proSAAS (encoded by PCSK1N) (PubMed:24043826). 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. Acts as a negative regulator T cell function (By similarity).
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 (By similarity).
Belongs to the ligand-gated ion channel (TC 1.A.9) family. Glycine receptor (TC 1.A.9.3) subfamily. GLRB sub-subfamily.
Detected in spinal cord and brain stem (at protein level) (PubMed:22592841). Detected in spinal cord, cerebellum and brain cortex (PubMed:2163264).
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:15574743, PubMed:14551753). Heteropentameric channels composed of GLRB and GLRA1 are activated by lower glycine levels than homopentameric GLRA1. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents (By similarity).
Heteropentamer composed of GLRB and GLRA1 (PubMed:15574743, PubMed:8581315, PubMed:14551753). Heteropentamer composed of GLRB and GLRA2 (PubMed:8581315). Heteropentamer composed of GLRB and GLRA3 (PubMed:8581315). Heteropentamer composed of two GLRA1 and three GLRB subunits. Heteropentamer composed of three GLRA1 and two GLRB subunits (By similarity). Interacts with GPHN (PubMed:8581315, PubMed:15201864, PubMed:16511563).
Belongs to the MoaE family. MOCS2B subfamily.
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.
This protein is produced by a bicistronic gene which also produces the small subunit (MOCS2A) from an overlapping reading frame.
Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-alpha-induced necroptosis. Negatively regulates NF-kappa-B activation by deubiquitinating upstream signaling factors. Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation. Negative regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules. Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis. Required for normal cell cycle progress and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B. Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation (By similarity). Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells. Negatively regulates TNFRSF11A signaling and osteoclastogenesis. Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation (By similarity). Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins. Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (By similarity). Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity). Negatively regulates intestinal inflammation by removing 'Lys-63' linked polyubiquitin chain of NLRP6, thereby reducing the interaction between NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (By similarity).
Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region). Interacts with TRAF2 and TRIP. Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and RIGI. Interacts (via CAP-Gly domain) with microtubules. Interacts with HDAC6 and BCL3 (By similarity). Interacts with MAP3K7. Identified in a complex with TRAF6 and SQSTM1 (By similarity). Interacts with OPTN and SQSTM1 (By similarity). Interacts with CEP350. Interacts with RNF31; the interaction is indirect and is mediated via SPATA2. Interacts with SPATA2 (via the PUB domain); the interaction is direct and recruits CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis (By similarity).
Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B (By similarity).
Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation.
Involved in the cell-cell adhesion. Has calcium- and magnesium-independent cell-cell adhesion activity. May have tumor-suppressor activity (By similarity).
Receptor for brain injury-derived neurotrophic peptide (BINP), a synthetic 13-mer peptide.
Acetylated. Autoacetylated; autoacetylation at Lys-238 stimulates transcription activation.
Found in a ternary complex with TATA box-bound TBP. 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. Associates with TFIID-TFIIA (DA complex) to form TFIID-TFIIA-TFIIB (DAB complex), which is then recognized by RNA polymerase II (Pol II). Found in a RNA polymerase II initiation complex. Interacts (via C-terminus) with TBP; this interaction with TATA box-bound TBP guides Pol II into the PIC. Interacts (via N-terminus) with Pol II. Interacts (via C-terminus) with SSU72; this interaction is inhibited by SYMPK. Interacts with NR2F1; this interaction is direct. Interacts with PGR. Interacts with ESR1. Interacts with GTF2F1 (via C-terminus and preferentially via acetylated form); this interaction prevents binding of GTF2B to GTF2F2. Interacts with GTF2F2 (via N-terminus); this interaction is inhibited in presence of GTF2F1. Interacts with the transcription elongation factor TCEA2. Interacts with HSF1 (via transactivation domain) (By similarity). 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. Together with the TATA box-bound TBP forms the core initiation complex and provides a bridge between TBP and the Pol II-TFIIF complex. 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. Associates with chromatin to core promoter-specific regions. 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. Modulates transcription start site selection. Exhibits also autoacetyltransferase activity that contributes to the activated transcription.
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. The C-terminus is necessary and sufficient for interaction with the TATA box-bound TBP complex and for the formation of PIC.
A cytochrome P450 monooxygenase with a key role in vitamin D catabolism and calcium homeostasis. Via C24-oxidation pathway, 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:2026586, PubMed:16617161, PubMed:10231362). 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:10231362, PubMed:16617161). Hydroxylates at C-24 or 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:2026586).
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 (By similarity). 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: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. Plays a key role in bile acid metabolism (By similarity). In addition, catalyzes the metabolic activation of potent carcinogenic polycyclic arylmethanols (PubMed:7854148).
There is a marked sex difference (female >> male) in the expressed level of mRNA for this protein.
Can mediate aggregation most likely through a homophilic molecular interaction.
Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity (PubMed:12445492). 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 (By similarity).
Homotrimer. Interacts with ALOX5AP and ALOX5.
Phosphorylation at Ser-36 by RPS6KB1 inhibits the leukotriene-C4 synthase activity.
Up-regulated by all-trans retinoic acid.
Interacts with NOTCH4 (By similarity). Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains) (PubMed:25700513).
Involved in the Notch signaling pathway as Notch ligand. Activates NOTCH1 and NOTCH4 (PubMed:25700513). Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. 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. During spinal cord neurogenesis, inhibits V2a interneuron fate (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.
Tightly associated with the RNA polymerase II complex (By similarity). Component of the R2TP complex composed at least of RUVBL1, RUVBL2, RPAP3 and PIHD1 (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 (By similarity). Interacts with PIH1D1 (By similarity). Interacts with TSC1 and TSC2 (By similarity). Interacts with PRPF8 and EFTUD2 in a ZNHIT2-dependent manner (By similarity).
Interacts with USP25 (isoform USP25m only); the interaction prevents proteasomal degradation of MYBPC1.
Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands. Slow skeletal protein that binds to both myosin and actin. In vitro, binds to native thin filaments and modifies the activity of actin-activated myosin ATPase. May modulate muscle contraction or may play a more structural role.
Forms a water-specific channel; mercury-sensitive. It may have an important role in spermatogenesis, in fertilization, and in the secretion of pancreatic juice and saliva.
Highly expressed in sperm, pancreas and liver. Some expression has been found in salivary gland and absorptive colonic epithelial cells.
The N-terminal and the C-terminal half of the protein have a very similar 3D-structure, suggesting they arose from duplication. Requires a bound zinc ion for normal folding and solubility.
Associates with the 60S ribosomal subunit. Interacts with NPM1, RPA1 and PRKDC. May interact with NIP7. Found in a complex consisting of 60S ribosomal subunit, SBDS and EFL1. Interacts with CLN3 (By similarity).
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 (By similarity).
Expressed in heart, kidney, liver, spleen, and to a lesser extent in brain.
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:32165585). 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:32165585). 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:32165585). 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:32165585). 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:32165585). Interacts with SPAAR (By similarity).
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 (By similarity). 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).
Homodimer; dimerization promotes enzymatic activity. Forms heterodimer with HAS3. Forms heterodimer with HAS1.
O-GlcNAcylation at Ser-221 increases the stability of HAS2 and plasma membrane localization.
Phosphorylation at Thr-328 is essential for hyaluronan synthase activity.
Ubiquitination at Lys-190; this ubiquitination is essential for hyaluronan synthase activity and homo- or hetero-oligomerization. Can also be poly-ubiquitinated. Deubiquitinated by USP17L22/USP17 and USP4. USP17L22/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.
Protects cells and enzymes from oxidative damage, by catalyzing the reduction of hydrogen peroxide, lipid peroxides and organic hydroperoxide, by glutathione.
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. Nascent tubulin polypeptide interacts (via beta-tubulin MREC motif) with TTC5/STRAP; this interaction may result in tubulin mRNA-targeted degradation.
The MREC motif mediates interaction with TTC5/STRAP and may be critical for tubulin autoregulation.
At 6 weeks of age, detected in mesenteric and retroperitoneal fat pads. Expression prominently increases in mesenteric and subdermal adipose tissues at 30 weeks and is barely detectable at 50 weeks.
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 (By similarity).
Predominantly expressed in the white adipose tissue.
Up-regulated in mature adipocytes and adipocyte tissue of obese animals.
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 (By similarity). Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation (PubMed:23576431).
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 BORCS5. Interacts with ZFYVE27. Interacts with VAPA, VAPB, SURF4, RAB11A (GDP-bound form), RAB11B (GDP-bound form) and RTN3 in a ZFYVE27-dependent manner. Interacts with BICD2. Interacts with DTNB (PubMed:14600269).
Inhibitor of serine proteases. The primary target is elastase, but also has a moderate affinity for plasmin and thrombin.
Interacts with CELA2A (By similarity). Interacts with ERGIC3 and LMAN1/ERGIC53 (By similarity). Interacts with PRSS1/Trypsin (By similarity).
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 (By similarity).
Activated by the AGRIN-induced phosphorylation which is mediated by MUSK.
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).
Autoproteolytic cleavage at pH 4.5 gives rise to the alpha and beta subunit. 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.
Degrades bioactive fatty acid amides to their corresponding acids, with the following preference: N-palmitoylethanolamine > N-myristoylethanolamine > N-stearoylethanolamine > N-oleoylethanolamine > N-linoleoylethanolamine > N-arachidonoylethanolamine.
Expressed in brain, cecum, colon, heart, ileum, kidney, liver, lung, spleen, stomach, submaxillary gland, testis and thymus.
Heterodimer of an alpha and a beta subunit, produced by autocatalytic cleavage.
N-glycosylated. Tunicamycin treatment causes a reduction in specific activity against N-palmitoylethanolamine.
Stimulated by DTT (PubMed:11463796, PubMed:22860206). Stimulated by nonionic detergent of the polyoxyethylenep-t-octylphenylether type (Triton X-100 or Nonidet P-40) whereas 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate (CHAPS) and octyl alpha-D-glucopyranoside decrease the N-(long-chain-acyl)ethanolamine deacylase activity (PubMed:22860206). Polysorbate 20 (Tween 20) is inhibitory (PubMed:11463796). Stimulated by endogenous phospholipids such as choline- or ethanolamine-containing phospholipids, and dihydrolipoic acid (PubMed:22860206).
Directly interacts with TJP1/ZO-1, TJP2/ZO-2 and TJP3/ZO-3 (By similarity). Interacts with MPDZ.
Auxillary component of the N-terminal acetyltransferase C (NatC) complex which catalyzes acetylation of N-terminal methionine residues. Involved in regulation of apoptosis and proliferation of smooth muscle cells.
Expressed in primary spermatocytes, basal epidermis, interstitial fibroblasts of skeletal muscle, and intestinal crypts.
In carotid arteries, after mechanic injury.
Widely expressed in the embryo. Expressed in embryonic aorta and pulmonary arteries from 12 dpc to 19 dpc.
Belongs to the tRNA nucleotidyltransferase/poly(A) polymerase family.
Acts as a transcriptional repressor for zinc finger transcription factors EGR1 and EGR2. Also represses multiple types of non-EGR1 activation domains (in vitro).
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.
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (By similarity). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By similarity). In addition to its ADP:ATP antiporter activity, also involved in mitochondrial uncoupling and mitochondrial permeability transition pore (mPTP) activity (By similarity). Plays a role in mitochondrial uncoupling by acting as a proton transporter: proton transport uncouples the proton flows via the electron transport chain and ATP synthase to reduce the efficiency of ATP production and cause mitochondrial thermogenesis. Proton transporter activity is inhibited by ADP:ATP antiporter activity, suggesting that SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output by maintaining a delicate balance between ATP production (ADP:ATP antiporter activity) and thermogenesis (proton transporter activity). 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 SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates it (By similarity). Acts as a regulator of mitophagy independently of ADP:ATP antiporter activity: promotes mitophagy via interaction with TIMM44, leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
Catalyzes the exchange of ADP and ATP across the membrane.
Monomer (By similarity). Found in a complex with ARL2, ARL2BP and SLC25A4/ANT1. Interacts with ARL2BP. Interacts with TIMM44; leading to inhibit the presequence translocase TIMM23, thereby promoting stabilization of PINK1 (By similarity).
The matrix-open state (m-state) is inhibited by the membrane-permeable bongkrekic acid (BKA) (By similarity). The cytoplasmic-open state (c-state) is inhibited by the membrane-impermeable toxic inhibitor carboxyatractyloside (CATR) (By similarity). Proton transporter activity is inhibited by ADP:ATP antiporter activity (By similarity).
Under cell death induction, transglutaminated by TGM2. Transglutamination leads to formation of covalent cross-links between a glutamine and the epsilon-amino group of a lysine residue, forming polymers.
Highly expressed in the liver, brain, kidney and intestine (at protein level).
Interacts with adapter protein complex 1 (AP-1) and AP-2, but not AP-3 and AP-4 (By similarity). Interacts with LAMP2 (By similarity).
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. Involved in the uptake of single-stranded oligonucleotides by living cells, a process called gymnosis (By similarity). 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).
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 (By similarity).
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.
E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated (PARsylated) proteins and mediates their ubiquitination and subsequent degradation. May regulate many important biological processes, such as cell survival and DNA damage response. 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. Acts in cooperation with tankyrase proteins (TNKS and TNKS2), which mediate PARsylation of target proteins AXIN1, AXIN2, BLZF1, CASC3, TNKS and TNKS2. Recognizes and binds tankyrase-dependent PARsylated proteins via its WWE domain and mediates their ubiquitination, leading to their degradation. Different ubiquitin linkage types have been observed: TNKS2 undergoes ubiquitination at 'Lys-48' and 'Lys-63', while AXIN1 is only ubiquitinated at 'Lys-48'. May regulate TNKS and TNKS2 subcellular location, preventing aggregation at a centrosomal location. Neuroprotective protein (By similarity). 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. 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. Facilitates DNA repair (By similarity).
E3 ubiquitin-protein ligase that specifically binds poly-ADP-ribosylated proteins and mediates their ubiquitination and subsequent degradation.
The WWE domain mediates non-covalent poly(ADP-ribose)-binding.
Ubiquitinated; autoubiquitinated. Autoubiquitination is enhanced upon poly(ADP-ribose)-binding (By similarity).
Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:7689223, 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 a higher activity with long-chain diacylglycerols like 1,2-di-(9Z-octadecenoyl)-sn-glycerol compared to 1,2-didecanoyl-sn-glycerol (PubMed:7689223). Specifically expressed in brain, it regulates neuron-specific morphological changes including neurite branching and neurite spine formation (By similarity).
Highly expressed in brain where it is restricted to neuronal populations such as the caudate-putamen, the accumbens nucleus, and the olfactory tubercle (PubMed:7689223). Less abundantly expressed in adrenal gland, small intestine and heart (PubMed:7689223).
Detected in 13-day old embryos. Expression increases gradually in later embryos and markedly in neonates to adults.
Expressed at high levels in brain. Very little expression detected in other tissues (PubMed:9394004). Detected in Purkinje cells in the cerebellum (PubMed:12880183).
Regulates G protein-coupled receptor signaling cascades, including signaling via muscarinic acetylcholine receptor CHRM2 and dopamine receptor DRD2. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. Modulates the activity of potassium channels that are activated in response to DRD2 and CHRM2 signaling.
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 (By similarity). In addition, may also function as scaffolding protein (By similarity).
Expressed in muscle, brain and hepatoma cells.
Homotetramer. Interacts with SNX9 and WAS. Interacts with FBP2; the interaction blocks FBP2 inhibition by physiological concentrations of AMP and reduces inhibition by Ca(2+) (By similarity).
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 heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.
Uncompetitive inhibition by micromolar concentrations of lithium. Competitive inhibition by inositol 1,4-bisphosphate. Inhibited by calcium ions.
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. May be involved in the regulation of serine protease-dependent germ cell apoptosis. It also inhibits trypsin.
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 (By similarity).
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. 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.
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. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. 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. Interacts with PUF60. Interacts with ATF7IP. Interacts with KAT2A; leading to KAT2A recruitment to promoters and acetylation of histones.
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 (By similarity).
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).
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.
Interacts with AGTR1. Interacts with FLNA (via filamin repeat 21); increases PKA-mediated phosphorylation of FLNA.
Receptor for angiotensin 1-7 (By similarity). Acts specifically as a functional antagonist of AGTR1 (angiotensin-2 type 1 receptor), although it up-regulates AGTR1 receptor levels. Positive regulation of AGTR1 levels occurs through activation of the G-proteins GNA11 and GNAQ, and stimulation of the protein kinase C signaling cascade. The antagonist effect on AGTR1 function is probably due to AGTR1 being physically altered by MAS1 (By similarity).
Expressed in cerebral cortex and cerebellum, but not in other organs.
Homodimer (By similarity). Interacts with DYNLL1 and DYNLL2 (PubMed:16133941).
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-111, Lys-144 and Lys-174 capture Ser that is misactivated by AARS/AlaRS.
Heterotetramer of 2 alpha/HADHA and 2 beta/HADHB subunits; forms the mitochondrial trifunctional enzyme (By similarity). Also purified as higher order heterooligomers including a 4 alpha/HADHA and 4 beta/HADHB heterooligomer which physiological significance remains unclear (PubMed:1730633). The mitochondrial trifunctional enzyme interacts with MTLN (By similarity). Interacts with RSAD2/viperin (By similarity).
Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway. 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. Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids. 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.
Interacts with INHBA and INHBB. Interacts with FN1. Interacts with ADAM12. Interacts with MLLT10; the interaction enhances MLLT10 in vitro transcriptional activity and self-association. Interacts with MSTN (By similarity).
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 differentiation. 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. The nuclear form is probably involved in transcriptional regulation via interaction with MLLT10 (By similarity).
Binds DNA as a homodimer and as a heterodimer. Can form stable heterodimers with CEBPA, CEBPB 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:1714459). Important transcription factor regulating the expression of genes involved in immune and inflammatory responses. Transcriptional activator that enhances IL6 transcription alone and as heterodimer with CEBPB (By similarity).
Interacts with SCN8A; regulates SCN8A activity. Interacts with SCN1A; may regulate SCN1A activity. Interacts with SCN5A; the interaction is direct and may regulate SNC5A density at membranes and function. May also interact with SCN2A and SCN11A. Interacts with MAPK8IP2; may regulate the MAPK8IP2 scaffolding activity.
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 (By similarity). 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).
Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A18 subfamily.
Functions as a sodium and chloride-dependent neutral amino acid transporter in kidneys. Requires CLTRN for surface expression and for its amino acid transporter activity.
Interacts with CLTRN; this interaction regulates the trafficking of SLC6A18 to the cell membrane and its amino acid transporter activity.
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-748 and phosphorylation of Ser-744 by PKC relieves auto-inhibition by the PH domain. Phosphorylation on Tyr-469 by the SRC-ABL1 pathway in response to oxidative stress, is also required for activation. Activated by DAPK1 under oxidative stress (By similarity).
Interacts (via N-terminus) with ADAP1/CENTA1. Interacts with MAPK13. Interacts with DAPK1 in an oxidative stress-regulated manner. Interacts with USP28; the interaction induces phosphorylation of USP28 and activated KRAS-mediated stabilization of ZNF304 (By similarity). Interacts with AKAP13 (via C-terminal domain) (By similarity).
Phosphorylated at Ser-403 and Ser-407 by MAPK13 during regulation of insulin secretion in pancreatic beta cells. Phosphorylated by DAPK1. Phosphorylated at Tyr-93 and by ABL at Tyr-469, which primes the kinase in response to oxidative stress, and promotes a second step activating phosphorylation at Ser-744/Ser-748 by PKRD. Phosphorylated on Ser-916 upon S.enterica infection in macrophages.
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-469 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 (By similarity). Regulates nuclear translocation of transcription factor TFEB in macrophages upon live S.enterica infection (By similarity).
Histone methyltransferase that methylates 'Lys-4' and 'Lys-36' of histone H3, 2 specific tags for epigenetic transcriptional activation. Specifically mediates dimethylation of H3 'Lys-36'.
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.
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).
Forms homodimers and possibly oligomers (PubMed:12473661, PubMed:19136011). May form heterooligomers with GIT2 (Probable). Interacts with G protein-coupled receptor kinases, including GRK2, GRK3, GRK5 and GRK6 (PubMed:9826657). Interacts with PPFIA1, PPFIA2 and PPFIA4 (PubMed:12473661, PubMed:12629171). Interacts with GRIP1 and forms a ternary complex with PPFIA1 and GRIP1 (PubMed:12473661, PubMed:12629171). Directly interacts with ARHGEF7/beta-PIX, forming in vitro a heptameric complex made of a GIT1 dimer and an ARHGEF7 trimer (PubMed:10938112, PubMed:12473661, PubMed:12629171, PubMed:17310244, PubMed:19136011). Directly interacts with PXN/paxillin; this interaction is enhanced in the presence of ARHGEF7 (PubMed:10938112, PubMed:12153727, PubMed:12473661, PubMed:12629171). Directly interacts (via C-terminus) with TGFB1I1/Hic-5 (via LD motif 3) (PubMed:12153727). Directly interacts with PTK2/FAK1 (PubMed:10938112, PubMed:12473661, PubMed:12629171). May interact with PTK2B/PYK2; this interaction may be indirect (PubMed:12629171). Interacts with AMPA receptors GRIA2/3 (PubMed:12629171). Directly interacts with protein Piccolo/PCLO (PubMed:12473661). Forms a complex with Ephrin-B1/EFNB1 and NCK2/GRB4 (via SH2); this interaction is important for spine morphogenesis and synapse formation. Interaction with NCK2 is transient and depends upon GIT1 phosphorylation at Tyr-392 (PubMed:17310244). Interacts with GRIN3A/GluN3A (via C-terminus); this interaction competes with GIT1 interaction with ARHGEF7 and limits synaptic localization of GIT1 (PubMed:24297929). Interacts with IKBKG/NEMO in resting bone mesenchymal stem cells, as well as in TNF-stimulated cells; this interaction may increase IKBKG affinity for 'Lys-63'-linked polyubiquitin chains (By similarity). Interacts with GABA(A) receptors, including GABRB3 and GABRG2 (PubMed:25284783). Interacts with SCRIB (By similarity). Interacts (via N- and C-terminus) with ENTR1/SDCCAG3 (via N-terminus); this interaction is direct. May form a tripartite complex with ENTR1 and PTPN13 (By similarity). Interacts with YWHAZ (By similarity). Interacts with PAK1 and PAK3 (By similarity). Directly interacts (via N-terminus) with gamma-tubulin (By similarity). Interacts with MAPK1 and MAPK3; this interaction is required for MAPK1/3 recruitment to focal adhesions (PubMed:15923189).
GTPase-activating protein for ADP ribosylation factor family members, including ARF1 (PubMed:9826657). Multidomain scaffold protein that interacts with numerous proteins and therefore participates in many cellular functions, including receptor internalization, focal adhesion remodeling, and signaling by both G protein-coupled receptors and tyrosine kinase receptors (PubMed:9826657). Through PAK1 activation, positively regulates microtubule nucleation during interphase. Plays a role in the regulation of cytokinesis; for this function, may act in a pathway also involving ENTR1 and PTPN13 (By similarity). May promote cell motility both by regulating focal complex dynamics and by the activation of RAC1 (PubMed:10938112). May act as scaffold for MAPK1/3 signal transduction, recruiting MAPK1/3 to focal adhesions after EGF stimulation via a Src-dependent pathway, hence stimulating cell migration (PubMed:15923189). Plays a role in brain development and function. Involved in the regulation of spine density and synaptic plasticity that is required for processes involved in learning (By similarity). Plays an important role in dendritic spine morphogenesis and synapse formation (PubMed:12695502, PubMed:15800193, PubMed:17310244, PubMed:24297929, PubMed:25009255). In hippocampal neurons, recruits guanine nucleotide exchange factors (GEFs), such as ARHGEF7/beta-PIX, to the synaptic membrane. These in turn locally activate RAC1, which is an essential step for spine morphogenesis and synapse formation (PubMed:12473661). May contribute to the organization of presynaptic active zones through oligomerization and formation of a Piccolo/PCLO-based protein network, which includes ARHGEF7/beta-PIX and FAK1 (PubMed:12473661). In neurons, through its interaction with liprin-alpha family members, may be required for AMPA receptor (GRIA2/3) proper targeting to the cell membrane (PubMed:12629171). In complex with GABA(A) receptors and ARHGEF7, plays a crucial role in regulating GABA(A) receptor synaptic stability, maintaining GPHN/gephyrin scaffolds and hence GABAergic inhibitory synaptic transmission, by locally coordinating RAC1 and PAK1 downstream effector activity, leading to F-actin stabilization (PubMed:25284783). May also be important for RAC1 downstream signaling pathway through PAK3 and regulation of neuronal inhibitory transmission at presynaptic input (By similarity). Required for successful bone regeneration during fracture healing. The function in intramembranous ossification may, at least partly, exerted by macrophages in which GIT1 is a key negative regulator of redox homeostasis, IL1B production, and glycolysis, acting through the ERK1/2/NRF2/NFE2L2 axis (By similarity). May also play a role in angiogenesis during fracture healing (By similarity). In this process, may regulate activation of the canonical NF-kappa-B signal in bone mesenchymal stem cells by enhancing the interaction between NEMO and 'Lys-63'-ubiquitinated RIPK1/RIP1, eventually leading to enhanced production of VEGFA and others angiogenic factors (By similarity). Essential for VEGF signaling through the activation of phospholipase C-gamma and ERK1/2, hence may control endothelial cell proliferation and angiogenesis (By similarity).
In the brain cortex and in the hippocampus, continuously expressed from P0 to adult age (at protein level).
Phosphorylated on tyrosine residues by PTK2/FAK1 and SRC in growing fibroblasts (PubMed:10938112). Phosphorylation at Tyr-392 is induced by activation of Ephrin-B1/EFNB1 and catalyzed by SRC family kinases. It is required for the interaction with NCK2 and for GIT1 recruitment to synapses in hippocampal neurons (PubMed:17310244).
The coiled coil region mediates dimerization.
Widely expressed (PubMed:9826657). Expressed at high levels in testis (at protein level) (PubMed:10938112). Expressed in the brain, including in CA1 hippocampal neurons, in the amygdala, and thalamic nuclei (at protein level) (PubMed:10938112, PubMed:12473661, PubMed:12695502, PubMed:12629171, PubMed:15800193, PubMed:17310244, PubMed:24297929, PubMed:25284783).
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.
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. 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. ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan (By similarity).
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 (By similarity).
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).
Homodimer. Interacts (via the Fibrinogen C-terminal domain) with LAG3 (via Ig-like domains 1 and 2).
Immune suppressive molecule that inhibits antigen-specific T-cell activation by acting as a major ligand of LAG3. Responsible for LAG3 T-cell inhibitory function. Binds LAG3 independently from MHC class II (MHC-II). Secreted by, and promotes growth of, hepatocytes.
Highest expression in brain, lower in heart and kidney. Within the brain, highest expression in cerebellum.
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.
Preferentially expressed in the lens epithelial cells.
Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway.
Belongs to the twisted gastrulation protein family.
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, SLCO6C1, 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. 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 (By similarity).
Directly antagonizes activity of BMP2, BMP4, BMP6 and BMP7 in a dose-dependent manner (By similarity). 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.
Highly expressed in epidermis, dermis and the outermost periderm layer in the 17 day post-coitum (dpc).
Highly expressed within the maximally sensitized/receptive endometrium. Weakly expressed in brain, kidney and the female reproductive tract. Expressed in the dermal papilla (DP) and at high level in the precortex of both anagen vibrissae and pelage follicles. Dynymic expression during the hair cycle.
Interacts with BMP2, BMP4, BMP6 and BMP7 with high affinity.
Up-regulated at day 5 pregnant or pseudopregnant of the uterine glandular epithelial cells, at time of maximal sensitization for the decidual cell reaction. Down-regulated at day 6 refractory uterus.
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). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1. Interacts with the chaperonin-containing T-complex (TRiC) complex; which mediates the folding of WRAP53/TCAB1. Interacts with COIL. Interacts with SMN1. Interacts with RNF8. Interacts with histone H2AX.
Phosphorylated at Ser-61 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. Specifically recognizes and binds the Cajal body box (CAB box) present in both small Cajal body RNAs (scaRNAs) and telomerase RNA template component (TERC). Essential component of the telomerase holoenzyme complex, a ribonucleoprotein complex essential for the replication of chromosome termini that elongates telomeres in most eukaryotes. In the telomerase holoenzyme complex, required to stimulate the catalytic activity of the complex. 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. In addition, also controls telomerase holoenzyme complex localization to Cajal body. During S phase, required for delivery of TERC to telomeres during S phase and for telomerase activity. In addition to its role in telomere maintenance, also required for Cajal body formation, probably by mediating localization of scaRNAs to Cajal bodies. 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. Acts by recruiting the ubiquitin ligase RNF8 to DNA breaks and promote both homologous recombination (HR) and non-homologous end joining (NHEJ).
Homodimeric cytokine expressed predominantly by T-lymphocytes and NK cells that plays an important role in the survival, differentiation, and chemotaxis of eosinophils. Acts also on activated and resting B-cells to induce immunoglobulin production, growth, and differentiation. Mechanistically, exerts its biological effects through a receptor composed of IL5RA subunit and the cytokine receptor common subunit beta/CSF2RB. 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.
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 required for the association of CNOT10 with the CCR4-NOT complex. Seems not to be required for complex deadenylase function (By similarity).
Asn-335 is present instead of the conserved Asp which is expected to be an active site residue.
Binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional up-regulation and mRNA stabilization.
Interacts with MYD88. IL-1 stimulation leads to the formation of a signaling complex which dissociates from the IL-1 receptor following the binding of PELI1 (By similarity).
Required for cis-Golgi integrity and efficient ER to Golgi transport.
The B box-type and RING-type zinc fingers although degenerate play a central role in function of the protein.
Homotetramer. Interacts with TRPC1 and TRPC3 (By similarity). Interacts with TRPC4 (PubMed:11163362). Interacts with TRPV4 (By similarity). Interacts with SIGMAR1 (PubMed:11149946). Interacts with AKT1 and PML. Interacts with IRAG2 (via coiled-coil domain) (By similarity). Interacts with CABP1 (PubMed:12032348). Interacts with TMBIM4/LFG4 (By similarity). Interacts with CEMIP (By similarity). Interacts with TESPA1 (By similarity). Interacts with TMEM203 (By similarity). Interacts with BOK; regulates ITPR3 expression (PubMed:23884412). Interacts with BCL2L10 (By similarity).
Phosphorylated on tyrosine residues. Phosphorylated by AKT1 on serine and/or threonine residues (By similarity).
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.
Component of the BRCA1-A complex. Component of the BRISC complex. Both the BRCA1-A complex and the BRISC complex bind polyubiquitin.
Metalloprotease that specifically cleaves 'Lys-63'-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). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates. 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. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1.
E3 ubiquitin-protein ligase (Probable). E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates.
Hexamer. 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 (By similarity).
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 (By similarity). 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.
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 (By similarity). Modulates the expression of IL2 (By similarity). Involved in platelet activation (By similarity). Prevents the degradation of SKAP1 and SKAP2 (By similarity). May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells (PubMed:12681493).
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 (PubMed:12681493). Interacts with CLNK (via its SH2 domain) and FYN; 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 (By similarity). Interacts with LCP2 (By similarity). Interacts with SKAP1 (PubMed:12681493). Interacts with SKAP2 (By similarity). Interacts with FASLG (By similarity). Interacts with EVL (By similarity). Interacts with TMEM47 (By similarity). Interacts with LCK (By similarity).
T-cell receptor ligation leads to increased tyrosine phosphorylation.
Acts as a heparin receptor in vascular cells (PubMed:26769966). May be involved in vesicle transport in exocrine cells and Sertoli cells (By similarity).
Expressed in vascular cells (at protein level).
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 (By similarity).
In brain, kidney, intestine and at a much lower level, in fetal tissues.
May play a role in signal transduction cascades in terminally differentiated cells.
Belongs to the potassium channel family. H (Eag) (TC 1.A.1.20) subfamily. Kv12.2/KCNH3 sub-subfamily.
Highly expressed in adult and embryonic brain, in particular in cerebellum, brain stem, hippocampus, cortex and striatum. Detected at slightly lower levels in heart, spinal cord, olfactory bulb, pituitary and medulla. In the hippocampus expression is strongest in the pyramidal cell body layers of the dentate gyrus. Also found in pituitary.
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.
Mainly expressed in granulosa cells from preantral and small antral follicles.
Plays an important role in several reproductive functions. Induces Muellerian duct regression during male fetal sexual differentiation and plays a role in Leydig cell differentiation and function (By similarity). In female acts as a negative regulator of the primordial to primary follicle transition and decreases FSH sensitivity of growing follicles. AMH signals by binding to a specific type-II receptor, AMHR2, that heterodimerizes with type-I receptors (ACVR1 and BMPR1A), and recruiting SMAD proteins that are translocated to the nucleus to regulate target gene expression (By similarity).
Preproprotein is proteolytically processed to generate N- and C-terminal cleavage products that homodimerize and associate to form a biologically active non-covalent complex. Binding of the non-covalent complex to AMHR2 induces dissociation of the pro-region from the mature C-terminal dimer. The N-terminal portion of the protein, despite having no intrinsic activity, has the role of amplifying the activity of the C-terminus.
At 12 dpc, only isoform 1 is seen while at 16 dpc and 18 dpc, isoform 1 and isoform 2 are seen. In the adult brain expression of isoform 2 increases dramatically as compared with its expression in embryonic brain where as isoform 1 decreases to undetectable levels.
Binds to EPS15 (a clathrin coat-associated protein) via a C-terminal domain containing three Asn-Pro-Phe (NPF) repeats.
In the central section; belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2 and PACSIN3 (By similarity). Binds AMPH, SH3GL1, SH3GL2 and SH3GL3 (PubMed:9238017, PubMed:9341169). Interacts with MYO1E (via SH3 domain) (PubMed:17257598). Interacts with BIN1 and DNM1 (PubMed:9341169).
Isoform 1 is found in neonatal brain, and in a wide variety of adult non-neuronal tissues. Isoform 2 is expressed predominantly in the neurons, but is also found in all other tissues at much lower levels. Isoform 1 and isoform 2 are detected in the lung and heart. Isoform 1 is expressed at higher levels than isoform 2 in the testis and liver and both isoforms are not detected in the skeletal muscle. Isoform 3 with the 16-amino-acid insert is only found in the brain while isoform 3 without the 16-amino-acid insert is found in the lung.
Phosphatase that acts on various phosphoinositides, including phosphatidylinositol 4-phosphate, phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate (By similarity). Has a role in clathrin-mediated endocytosis (PubMed:9428629). Hydrolyzes PIP2 bound to actin regulatory proteins resulting in the rearrangement of actin filaments downstream of tyrosine kinase and ASH/GRB2 (By similarity).
Splicing of the SAC1 domain does not alter the catalytic activity of synaptojanin 1.
The C-terminal proline-rich region mediates binding to a variety of SH3 domain-containing proteins including AMPH, SH3GL1, SH3GL2, SH3GL3 and GRB2.
Homodimer; disulfide-linked. Interacts with GRB2 and GRB7 in a phosphorylation-dependent manner (By similarity).
May play a role in the downstream signal transduction pathways involving GRB2 and GRB7.
Binds both calcium and zinc. May be involved in calcium-dependent cuticle cell differentiation, hair shaft and hair cuticular barrier formation (By similarity).
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 (By similarity).
Interacts with SELPLG. 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 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:7334008). Identified in a complex that contains ETFA, ETFB and ETFRF1. Interaction with ETFRF1 promotes dissociation of the bound FAD and loss of electron transfer activity (By similarity). 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:7334008). It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase) (Probable). Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism.
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). AP-3 associates with the BLOC-1 complex (By similarity).
Component of the adaptor 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. Ap47 is a subunit of the plasma membrane adaptor. 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).
In adults, expressed in brain, testes, ovaries, and kidney. Expression in the adult liver is barely detectable.
Inhibits IGF-mediated growth and developmental rates (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.
Predominantly expressed at fetal stages with highest expression in fetal liver. Also expressed in fetal kidney, intestine and lung, as well as muscle, heart and stomach.
The C-terminus is required for IGF-binding and growth inhibition.
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:17934141, PubMed:15951807, PubMed:20972425). 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:17934141). Modulates the organization and assembly of the cytoskeleton. Facilitates the CHP1-dependent microtubule and membrane associations through its ability to stimulate the binding of CHP1 to microtubules (PubMed:15312048). 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 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 (By similarity). 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 (By similarity). Participates in nuclear events including transcription, RNA transport, DNA replication and apoptosis (PubMed:10424669, PubMed:15951807, PubMed:20972425). Nuclear functions are probably due to the nitrosylase activity that mediates cysteine S-nitrosylation of nuclear target proteins such as SIRT1, HDAC2 and PRKDC (PubMed:15951807, PubMed:20972425).
High levels in skeletal muscle and heart, low levels in liver, brain, and kidney.
Homotetramer (By similarity). Interacts with TPPP; the interaction is direct (By similarity). Interacts (when S-nitrosylated) with SIAH1; leading to nuclear translocation (PubMed:15951807, PubMed:19607794). Interacts with RILPL1/GOSPEL, leading to prevent the interaction between GAPDH and SIAH1 and prevent nuclear translocation (PubMed:19607794). Interacts with CHP1; the interaction increases the binding of CHP1 with microtubules (PubMed:15312048). Associates with microtubules (PubMed:15312048). Interacts with EIF1AD, USP25, PRKCI and WARS1. Interacts with phosphorylated RPL13A; inhibited by oxidatively-modified low-densitity lipoprotein (LDL(ox)). Component of the GAIT complex. Interacts with FKBP6; leading to inhibit GAPDH catalytic activity. Interacts with TRAF2, promoting TRAF2 ubiquitination. Interacts with TRAF3, promoting TRAF3 ubiquitination (By similarity).
Oxidative stress can promote the formation of high molecular weight disulfide-linked GAPDH aggregates, through a process called nucleocytoplasmic coagulation.
S-nitrosylation of Cys-150 leads to interaction with SIAH1, followed by translocation to the nucleus (PubMed:1281150, PubMed:15951807, PubMed:20972425, PubMed:8626764). The effect of S-nitrosylation on enzymatic activity is unclear: according to some authors, it inhibits enzymatic activity and increases endogenous ADP-ribosylation, inhibiting the enzyme in a non-reversible manner (PubMed:8626764). According to others, it does not affect glycolysis (PubMed:15951807). ADP-ribosylation is likely to be a pathophysiological event associated with inhibition of gluconeogenesis (PubMed:8626764). S-nitrosylation of Cys-245 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 (By similarity).
Succination of Cys-150 and Cys-245 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 rats. 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-150 increases catalytic activity.
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.
May play a role in regulated exocytosis (PubMed:10383386). Modulates the localization of synaptophysin/SYP into synaptic-like microvesicles and may therefore play a role in synaptic-like microvesicle formation and/or maturation (PubMed:15590695, PubMed:12928441). Involved in the regulation of short-term and long-term synaptic plasticity (By similarity).
Subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K(+) channels and insulin release.
Associates with GIRK1 or GIRK2 to form a G-protein-activated heteromultimer pore-forming unit. The resulting inward current is much larger.
Belongs to the inward rectifier-type potassium channel (TC 1.A.2.1) family. KCNJ5 subfamily.
Most abundant in heart tissue where it is found predominantly in atria. Also found in brain, kidney, liver, spleen, lung and thymus.
May play an important role in the sperm/egg interaction; released during the acrosome reaction.
There appears to be no human ortholog of this protein.
Component of the tRNA(Sec) complex composed at least of EEFSEC, SECISBP2, SEPHS1, SEPSECS, TRNAU1AP and tRNA(Sec). Associates with mRNP and/or polysomes (By similarity). Found in a complex with tRNA(Sec). Interacts with SEPSECS.
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).
Homooligomer; homooligomerizes following activation of Naip proteins by pathogenic proteins such as S.typhimurium (Salmonella) flagellin or PrgJ. Component of the NLRC4 inflammasome, at least composed of NLRC4, caspase-1 (CASP1) and some NAIP family member (By similarity). Interacts with EIF2AK2/PKR (By similarity).
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.
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. The NLRC4 inflammasome is activated as part of the innate immune response to a range of intracellular bacteria.
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.
Interacts with HTT (via C-terminus) (PubMed:16476778). Interacts with RAB5A (PubMed:16476778). Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A onto early endosomes (PubMed:16476778).
RAB5A effector molecule that is involved in vesicular trafficking of early endosomes. 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.
Expressed in adult but not at postnatal day 1. In the seminiferous tubule, expressed in first layer capped spermatids at stage VII and in spermatids closer to the lumen of the tubule at stage XII. Not detected in spermatogonia, first layer of spermatocytes or mature spermatozoa.
Highly expressed in adult retina and testis with lower levels in cerebral cortex, kidney and epididymis. In the retina, strongly expressed in the ganglion cell layer and throughout the inner nuclear layer in amacrine and bipolar cells. Not expressed in the outer nuclear layer. In the testis, detected in the seminiferous tubules.
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. 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.
Heterotetramer; composed of two copies of TRMT6 and two copies of TRMT61A.
Homodimer. Interacts with ARL1, ARL2 and ARL3. Directly interacts with FEZ1 and UVRAG. The interaction with UVRAG is reduced by amino acid starvation, but the complex is stabilized in the presence of FEZ1. Interacts with NRBF2.
Positive regulator of amino acid starvation-induced autophagy.
Is widely distributed in the CNS. Predominant expression is seen in the neuronal cells of the cerebral cortex, dentate gyrus, and glial cells throughout brain regions.
Expressed at high level in the brain embryo at 14.5 dpc. Expressed at lower level in the brain embryo at 10.5 dpc and 19.5 dpc.
Expressed in embryonic brain, mostly in the isthmus cerebellar neuroepithelium and septum neuroepithelium, and in all adult tissues.
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.
Highest expression in kidney proximal tubules and ileum enterocytes. High expression also detected in liver and pituitary. Lower levels in heart, adrenal gland and brain. Not detected in aorta, lung or spleen. In heart, higher levels in ventricle than in atrium. Also expressed in glomerular mesangial cells.
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.
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. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Plays a central role in the transcriptional activation of genes.
Can occur as a homodimer or as a heterodimer with RRAGC or RRAGD in a sequence-independent manner; heterodimerization stabilizes proteins of the heterodimer. In complex with RRAGC, but not with RRAGB, interacts with RPTOR. The GTP-bound form of RRAGA interacts with NOL8. 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. 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. The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor. Interacts (inactive GDP-bound form) with RNF152; stimulated by amino acid starvation. Interacts (polyubiquitinated) with the GATOR1 complex; inactivates RRAGA. Interacts (polyubiquitinated) with TSC2. Interacts with SESN1, SESN2 and SESN3 (By similarity). Interacts with PIP4P1 (By similarity). Interacts with GPR137B (By similarity). The Rag heterodimer interacts with the Ragulator complex (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. Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form. In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway. May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death.
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 RRAGA GTPase activity to turn it into its inactive GDP-bound form.
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.
Widely expressed as a 1.8 kb transcript. Highly expressed in adrenal gland and detected at lower levels in brain, skeletal muscle, fat cells, liver, spleen, testis, ovary, thymus, and lung.
Highest levels expressed in the kidney and spleen. Restricted to the basolateral membrane in renal epithelial cells and varies in its level of expression along the nephron.
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.
N-terminal region is required for phagocytosis of Gram negative bacterium.
A cytochrome P450 monooxygenase involved in corticoid and androgen biosynthesis. 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. 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. 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. 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).
Regulated predominantly by intracellular cAMP levels. The 17,20-lyase activity is stimulated by cytochrome b5, which acts as an allosteric effector increasing the Vmax of the lyase activity.
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.
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.
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.
Involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites. 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.
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 (By similarity).
Cleaved after Lys-176 by GZMA. The cleavage inhibits its nucleosome assembly activity and disrupts the inhibition on NME1 (By similarity).
Headphone-shaped homodimer. Isoform 1 and isoform 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 omponent 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 (By similarity).
Higher expression in neonatal kidney than in adult. In the neonatal kidney, expressed more strongly in primitive nephrons undergoing early morphogenesis than in more developed structures. In 1-day old rat kidney, restricted to the first recognizable primitive nephron structures. Up-regulated after partial hepatectomy, with a peak after 24 hours.
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 (By similarity).
N-terminus of isoform 1 is methylated by METTL11A/NTM1. Mainly trimethylated (By similarity).
Widely expressed, with higher expression in brain, thymus, spleen and bone marrow, and lower expression in heart, liver and muscle.
Homodimer (via the homeobox); binds DNA as homodimer. Interacts (via the homeobox) with TBX5 (via the T-box); this complex binds DNA. 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. Interacts with histone methyltransferase NSD2 (via HMG box) (By similarity). Interacts with NEDD9 (By similarity).
The homeobox domain binds to double-stranded DNA.
Transcription factor required for the development of the heart and the spleen (By similarity). 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. Together with PBX1, required for spleen development through a mechanism that involves CDKN2B repression (By similarity). Positively regulates transcription of genes such as COL3A1 and MMP2, resulting in increased pulmonary endothelial fibrosis in response to hypoxia (By similarity).
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 (By similarity). Preferentially acts on 6-oxopurine nucleosides including inosine and guanosine (By similarity).
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 (By similarity). 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) (By similarity). Interacts with TMEM107 (By similarity). Interacts with TCTN3, AHI1, TCTN1, TCTN2, CC2D2A (By similarity). Interacts with FLNA. Interacts with TMEM67 (By similarity). Interacts with B9D1 and B9D2 (By similarity).
Possible regulatory or functional link with the histocompatibility cluster.
Has low affinity for peptide hormones in the absence of bound chloride.
Homodimer; disulfide-linked. Interacts with OSTN.
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.
Does not interact with MKLN1 (PubMed:11006128).
Interacts (via C-terminus) with MKLN1 (PubMed:11006128).
Principally expressed in the tubules of the renal medulla. Specific expression is seen in medullary and cortical thick ascending limbs; lower levels are detected in cortical and inner medullary collecting ducts. Not detected significantly in the glomeruli (PubMed:8393672). In the brain, expressed in all types of glial cells (PubMed:8919306).
Receptor for prostaglandin E2 (PGE2) (PubMed:8393672, PubMed:11006128). 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).
Receptor for prostaglandin E2 (PGE2); ligand binding activates a signaling cascade via G(i) proteins that leads to the inhibition of adenylate cyclase.
Receptor for prostaglandin E2 (PGE2); ligand binding can activate several distinct signaling cascades, resulting in activation or inhibition of adenylate cyclase.
Belongs to the zinc-containing alcohol dehydrogenase family. Class-V subfamily.
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 (By similarity). Inhibits Notch signaling in postmitotic neurons of the brain. It may play a role in adult brain and in neurogenesis (PubMed:11165380). It may play a role in limb development (By similarity).
Most abundantly expressed in adult brain. Expressed in most neurons of the brain but not in glial cells. Also detected to a lower extent in adult lung and kidney.
Expressed predominantly in kidney, small intestine and stomach and moderately in thymus, lung, spleen, testis and skin. In the kidney, expressed mainly in collecting duct of renal medulla and cortex.
Inhibited by aprotinin, leupeptin, benzamidine and soybean trypsin inhibitor. Partially inhibited by PMSF and DFP.
Selectively cleaves synthetic peptide substrates of trypsin. Activates the epithelial sodium channel ENaC.
Homodimer; disulfide-linked. When phosphorylated, interacts with PTPN11/SHP2, GRB2 and CSK (By similarity).
Negatively regulates T-cell antigen receptor (TCR)-mediated signaling. Involved in positive selection of T-cells.
Phosphorylated on tyrosines upon TCR activation; which promotes recruitment of PTPN11, GRB2 and CSK.
Component of the SIN3-repressing complex. Enhances the ability of SIN3-HDAC1-mediated transcriptional repression. When tethered to the promoter, it can direct the formation of a repressive complex to core histone proteins. Auxiliary component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junction on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Component of the ASAP and PSAP complexes which bind RNA in a sequence-independent manner and are proposed to be recruited to the EJC prior to or during the splicing process and to regulate specific excision of introns in specific transcription subsets. The ASAP complex can inhibit mRNA processing during in vitro splicing reactions. The ASAP complex promotes apoptosis and is disassembled after induction of apoptosis. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits the formation of proapoptotic isoforms such as Bcl-X(S); the activity is different from the established EJC assembly and function.
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.
Expressed in intestine, lung, brain, kidney, epididymis and testis.
Interacts with BIK and STEAP3. Interacts (via C-terminal domain) with VCP. Interacts with ubiquitin and ubiquitinated proteins (By similarity).
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 (By similarity).
One study reported that the protein is not localized in the mitochondrion.
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 (By similarity).
Interacts with HCK. Interacts with SHC1; may mediate interaction with receptors (By similarity). Interacts with SYK (By similarity). Interacts with PI-3 kinase (By similarity). Interacts with GRB2 (via SH3 2 domain) (By similarity). Interacts (phosphorylated) with PTPN11 (By similarity). Interacts with TNFRSF11A (via cytoplasmic domain) (By similarity). Interacts (phosphorylated) with 14-3-3 family proteins SFN, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ and YWHAZ; prevents interaction with GRB2 and attenuates GAB2 signaling (By similarity).
Phosphorylated upon EGF stimulation. Phosphorylated on tyrosine residues by HCK upon IL6 signaling (By similarity). 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).
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.
Defects in Plp1 are the causee of the dysmyelinating disease MD.
This is the major myelin protein from the central nervous system. It plays an important role in the formation or maintenance of the multilamellar structure of myelin.
Cell-cycle arrest properties are inactivated by phosphorylation on Thr-332, Ser-640, Ser-959 and Ser-970 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. 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 AATF. Interacts with KDM5A (By similarity). Interacts with KMT5B and KMT5C. Interacts with USP4 (By similarity). Interacts with RBBP9 (PubMed:9697699).
Key regulator of entry into cell division (By similarity). 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 (By similarity). Potent inhibitor of E2F-mediated trans-activation. May act as a tumor suppressor (By similarity).
Belongs to the ornithine cyclodeaminase/mu-crystallin family.
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 (By similarity).
Component of the BCR(KLHL25) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL25 and RBX1.
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex involved in various processes, such as translation homeostasis and lipid synthesis. The BCR(KLHL25) ubiquitin ligase complex acts by mediating ubiquitination of hypophosphorylated EIF4EBP1 (4E-BP1): ubiquitination and subsequent degradation of hypophosphorylated EIF4EBP1 (4E-BP1) probably serves as a homeostatic mechanism to maintain translation and prevent eIF4E inhibition when eIF4E levels are low. The BCR(KLHL25) complex does not target EIF4EBP1 (4E-BP1) when it is hyperphosphorylated or associated with eIF4E. The BCR(KLHL25) complex also acts as a regulator of lipid synthesis by mediating ubiquitination and degradation of ACLY, thereby inhibiting lipid synthesis. BCR(KLHL25)-mediated degradation of ACLY promotes fatty acid oxidation and is required for differentiation of inducible regulatory T (iTreg) cells.
Belongs to the Nudix hydrolase family. NudF subfamily.
Hydrolyzes ADP-ribose (ADPR) to AMP and ribose 5'-phosphate.
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).
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:23793029). ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target it to the proximal ciliary axoneme (PubMed:23793029). Interacts with ANKS3 (By similarity).
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. Plays a role in organogenesis and is involved in the regulation of the Hippo signaling pathway (By similarity).
Interacts with VMP1. Interacts with COPA, COPB1, VDAC1 and ERLIN2. Interacts with ATG2A. Interacts with SURF4.
Phospholipid scramblase involved in lipid homeostasis and membrane dynamics processes. Has phospholipid scramblase activity toward cholesterol and phosphatidylserine, as well as phosphatidylethanolamine and phosphatidylcholine. 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. In addition to autophagy, involved in other processes in which phospholipid scramblase activity is required (By similarity). Required for normal motor neuron development (By similarity).
Belongs to the SelWTH family. Selenoprotein T subfamily.
May contain a selenide-sulfide bond between Cys-46 and Sec-49. This bond is speculated to serve as redox-active pair (By similarity).
Rapidly induced by ADCYAP1/PACAP neuropeptide and cAMP.
Selenoprotein with thioredoxin reductase-like oxidoreductase activity (PubMed:26866473). Protects dopaminergic neurons against oxidative stress and cell death (By similarity). Involved in ADCYAP1/PACAP-induced calcium mobilization and neuroendocrine secretion (PubMed:18198219). 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 (PubMed:26779623). In pancreatic islets, involved in the control of glucose homeostasis, contributes to prolonged ADCYAP1/PACAP-induced insulin secretion (By similarity).
Ubiquitous, detected in all tissues tested.
Ubiquitously expressed as early as 7 dpc.
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 (By similarity). 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 (By similarity).
Interacts with PTPN13/PTPL1. Interacts with RAP2A via its coiled coil domain (By similarity). Interacts with RASIP1 (By similarity).
Can be either O-glucosylated or O-xylosylated at Ser-93 by POGLUT1.
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 (By similarity).
By mechanical tensile force in periodontal ligament fibroblasts.
Expressed in brain, kidney and testis, and at lower levels in heart.
Involved in the cell surface expression of neuronal nicotinic receptors (PubMed:10980252). Binds RNA (PubMed:10980252).
Not present in the maxillary first molar tooth before 18 dpc. Present at high levels in ameloblasts and adjacent cells at P7. At P14, present in differentiating pre-cementoblasts and pre-osteoblasts along the developing root surface and alveolar bone. At P28, present in cementoblastic cells in the periodontal ligament and osteoblastic cells on the alveolar bone surface (at protein level).
Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane.
Interacts with tyrosine phosphorylated forms of SHC1 (PubMed:8910587). Interacts with tyrosine phosphorylated form of DOK1 (By similarity). Interacts with tyrosine phosphorylated form of DOK3 (By similarity). Interacts with tyrosine phosphorylated form of SLAMF1/CD150 (By similarity). Interacts with PTPN11/SHP-2 in response to IL-3 (By similarity). Interacts with receptor EPOR (By similarity). Interacts with receptors MS4A2/FCER1B and FCER1G (PubMed:8910587). 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:8910587). 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 (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:8910587). Also able to hydrolyze the 5-phosphate of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (By similarity). 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. 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 (By similarity).
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.
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:10854428). Also able to transfer galactose to galactosylceramide/beta-D-Gal-(1<->1')-Cer (By similarity). 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 (By similarity).
Ubiquitous. Highly expressed in kidney, mesenteric lymph node, spleen and brain.
E3 ubiquitin-protein ligase that cooperates with the microRNAs (miRNAs) machinery and promotes embryonic stem cells proliferation and maintenance (By similarity). 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 (By similarity). 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 (By similarity).
Interacts (via NHL repeats) with AGO2; the interaction increases in presence of RNA. Interacts with HSP90AA1. Interacts (via NHL repeats) with MOV10, PABPC1, PUM1, PUM2, STAU2, XRN1 and XRN2 in an RNA-dependent manner (By similarity). Interacts with SHCBP1; leading to enhance its stability (By similarity).
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.
Belongs to the PPP phosphatase family. PP-4 (PP-X) subfamily.
Methylation at the C-terminal Leu-307 is critical for interactions with regulatory subunits and functions in DNA repair.
Protein phosphatase that is involved in many processes such as microtubule organization at centrosomes, maturation of spliceosomal snRNPs, apoptosis, DNA repair, tumor necrosis factor (TNF)-alpha signaling, activation of c-Jun N-terminal kinase MAPK8, regulation of histone acetylation, DNA damage checkpoint signaling, NF-kappa-B activation and cell migration. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3. The PPP4C-PPP4R2-PPP4R3A PP4 complex specifically dephosphorylates H2AX phosphorylated on Ser-140 (gamma-H2AX) generated during DNA replication and required for DNA DSB repair. Dephosphorylates NDEL1 at CDK1 phosphorylation sites and negatively regulates CDK1 activity in interphase (By similarity). In response to DNA damage, catalyzes RPA2 dephosphorylation, an essential step for DNA repair since it allows the efficient RPA2-mediated recruitment of RAD51 to chromatin (By similarity).
Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complexes PPP4C-PPP4R1, PPP4C-PPP4R2, PPP4C-PPP4R2-PPP4R3A, PPP4C-PPP4R2-PPP4R3B and PPP4C-PPP4R4. The PPP4C-PPP4R2 complex appears to be a tetramer composed of 2 molecules of PPP4C and 2 molecules of PPP4R2. Interacts with REL, NFKB1/p50 and RELA. Interacts with SMN1 and GEMIN4. Interacts with IRS4 (phosphorylated). Interacts with SMEK1/PPP4R3A; the interaction requires PP4R2. Interacts with HDAC3 (By similarity).
Dioxygenase that can both act as a arginine demethylase and a lysyl-hydroxylase. 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. Hydroxylates its own N-terminus, which is required for homooligomerization. In addition to peptidyl-lysine 5-dioxygenase activity, may act as an RNA hydroxylase, as suggested by its ability to bind single strand RNA. Also acts as an arginine demethylase which preferentially demethylates asymmetric dimethylation. 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. However, histone arginine demethylation may not constitute the primary activity in vivo. 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. Demethylates other arginine methylated-proteins such as ESR1. Has no histone lysine demethylase activity (By similarity). 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 (By similarity).
Homooligomerizes; requires lysyl-hydroxylase activity. Interacts with LUC7L2, LUC7L3 and U2AF2/U2AF65 (By similarity). Interacts with LIAT1 (By similarity). Interacts with CDK9 and CCNT1; the interaction is direct with CDK9 and associates the P-TEFb complex when active. 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 (By similarity).
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.
Belongs to the eukaryotic ribosomal protein eL31 family.
Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling. Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel. Extraction by the PEX1-PEX6 AAA ATPase complex is accompanied by unfolding of the TPR repeats and release of bound cargo from PEX5.
Interacts with PEX1; forming the PEX1-PEX6 AAA ATPase complex, which is composed of a heterohexamer formed by a trimer of PEX1-PEX6 dimers. Interacts with PEX26; interaction is direct and promotes recruitment to peroxisomal membranes. Interacts with ZFAND6.
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) (By similarity). 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.
Expressed to a relatively high level in kidney, spleen, thymus and lung, and to a lower level in aorta, adrenals, and heart. Expression is not detected in liver or brain.
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.
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-120' (By similarity).
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 (By similarity).
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 (By similarity).
Involved in the synthesis of gangliosides GD1c, GT1a, GQ1b, GP1c and GT3 from GD1a, GT1b, GM1b and GD3 respectively.
'Lys-48'-linked polyubiquitination at Lys-72 is induced by TNFalpha, and leads to proteasomal degradation. Undergoes 'Lys-48'-linked polyubiquitination catalyzed by ITCH. 'Lys-63'-linked polyubiquitination at Lys-158 by TRIM8 does not lead to proteasomal degradation but contributes to autophosphorylation and activation. Deubiquitinated by CYLD, a protease that selectively cleaves 'Lys-63'-linked ubiquitin chains.
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.
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 (By similarity).
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 (By similarity).
Can form homodimer. Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts with TAB1/MAP3K7IP1, TAB2/MAP3K7IP2 and TAB3/MAP3K7IP3. Identified in the TRIKA2 complex composed of MAP3K7/TAK1, TAB1/MAP3K7IP1 and TAB2/MAP3K7IP2. Interacts with PPM1L and PPM1B/PP2CB. Interaction with PP2A and PPP6C leads to its repressed activity. Interacts with TRAF6 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with TAOK1 and TAOK2; interaction with TAOK2 interferes with MAP3K7 interaction with IKKA, thus preventing NF-kappa-B activation. Interacts with DYNC2I2 (via WD domains). Interacts with CYLD and RBCK1. Interacts with TGFBR1; induces MAP3K7/TAK1 activation by TRAF6. Interacts with MAPK8IP1 and SMAD6. Interacts with isoform 1 of VRK2. Interacts with DAB2; the interaction is induced by TGF-beta stimulation and may mediate TGF-beta stimulated JNK activation. Interacts with TRIM5. Part of a complex containing ITCH, NDFIP1 and MAP3K7. Interacts with PLEKHM1 (via N- and C-terminus). Found in a complex with SH3RF1, RAC2, MAP2K7/MKK7, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2. Interacts with SASH1 (By similarity). Interacts with RIPK1 (By similarity).
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 (By similarity). Promotes TRIM5 capsid-specific restriction activity (By similarity). 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).
Bidirectional proton-coupled monocarboxylate transporter. 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. The transport direction is determined by the proton motive force and the concentration gradient of the substrate monocarboxylate. MCT1 is a major lactate exporter (PubMed:9374487, PubMed:9639576, PubMed:10417314, PubMed:19473976, PubMed:8526936, PubMed:10564700, PubMed:11719518, PubMed:17127621). 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. Functions via alternate outward- and inward-open conformation states. Protonation and deprotonation of 302-Asp is essential for the conformational transition (By similarity).
Detected in erythrocytes (at protein level). Detected in brain, heart, kidney, lung, muscle, jejunum enterocytes and brain capillaries.
Inhibited by stilbene disulfonates, such as di-isothiocyanostilbene disulfonate(DIDS), a cross-linking reagent that forms covalent linkages with lysine groups.
Interacts with BSG. Interacts with EMB. Interaction with either BSG or EMB is required for expression at the cell membrane.
Belongs to the chloride channel (TC 2.A.49) family. ClC-2/CLCN2 subfamily.
Phosphorylated. Activated by dephosphorylation.
Voltage-gated chloride channel (PubMed:1311421, PubMed:12163466). Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport (PubMed:1311421). Involved in the regulation of aldosterone production. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated Ca2+ channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis (By similarity).
(Microbial infection) Binding to BoNT/B induces formation of an alpha-helix in the membrane-proximal extracytoplasmic domain (PubMed:17167421).
(Microbial infection) Receptor for C.botulinum neurotoxin type B (BoNT/B, botB); unlike the case with BoNT/B interaction is not improved in the presence of gangliosides (PubMed:17167421). The toxin binds to the vesicular domain of Syt2 (residues 1-61) (PubMed:15123599).
(Microbial infection) Receptor for C.botulinum neurotoxin type G (BoNT/G, botG); unlike the case with BoNT/B interaction is not improved in the presence of gangliosides (PubMed:15123599). The toxin binds to the vesicular domain of Syt2 (residues 1-61) (PubMed:15123599).
Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties. May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse. Plays a role in dendrite formation by melanocytes.
Homotetramer (Probable). Interacts with SCAMP5 (By similarity). Interacts with STON2 (By similarity). Interacts with PRRT2 (By similarity).
Predominantly expressed in brain regions such as the spinal cord, brain stem and cerebellum (PubMed:1856191).
The second C2 domain mediates interaction with Stonin 2. The second C2 domain mediates phospholipid and inositol polyphosphate binding in a calcium-independent manner.
Belongs to the 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).
Exhibits both phospholipase A1/2 and acyltransferase activities (PubMed:19047760). Shows phospholipase A1 (PLA1) and A2 (PLA2), ccatalyzing the calcium-independent release of fatty acids from the sn-1 or sn-2 position of glycerophospholipids (PubMed:19047760). For most substrates, PLA1 activity is much higher than PLA2 activity (By similarity). Shows O-acyltransferase activity,catalyzing the transfer of a fatty acyl group from glycerophospholipid to the hydroxyl group of lysophospholipid (By similarity). 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:17158102, PubMed:19047760). Exhibits high N-acyltransferase activity and low phospholipase A1/2 activity (By similarity). 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).
Induced during preadipocyte differentiation into adipocytes.
Interacts with PPP2R1A; this interaction might decrease PP2A activity.
Specifically expressed in H-ras resistant fibroblasts.
The C-terminal transmembrane domain is required for the targeting of the protein to damaged organelles.
Expressed in a subset of IB4-positive small diameter nociceptive dorsal root neurons.
Orphan receptor activated by a subset of RFamide-family neuropeptides such as FLRF-amide and FMRF-amide. 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. May regulate the function of nociceptive neurons by modulation of pain perception (By similarity).
Was originally thought to be an adenine receptor but PubMed:12397184 found no activation by adenine of the mouse ortholog.
High expression in heart, skeletal muscle and brown adipose tissue. Also expressed in white adipose tissue, but not in liver.
Placental lactogen II is expressed from days 12 to term of pregnancy.
Either Cys-2 or Cys-12 or both are palmitoylated.
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.
Mediates sodium-independent multispecific organic anion transport. Transport of ketoprofen, indomethacin, salicylate, acetylsalicylate, prostaglandin E2, 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), dicarboxylates and p-aminohippurate (PAH).
Positive regulator of Th1-type cytokine gene expression.
Acts as an atypical protein-lysine deacetylase in vitro. Catalyzes the deacetylation of lysine residues using CoA as substrate, generating acetyl-CoA and the free amine of protein-lysine residues. Additional experiments are however required to confirm the protein-lysine deacetylase activity in vivo. 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. May activate transcription.
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 (By similarity). Additional experiments are therefore required to confirm this activity in vivo (By similarity).
Catalyzes ghrelin acylation at 'Ser-3' using preferentially octanoyl-CoA, hexanoyl-CoA and decanoyl-CoA as acyl-CoA donors leading to ghrelin activity (By similarity) (PubMed:18443287). In vitro uses also acyl-CoA donors of different lengths from short-chain (C2) to long-chain fatty acids (C16) knowing that acyl-CoA donors from butanoyl-CoA (C4) to dodecanoyl-CoA (C12) are more efficient compared to longer acyl-CoA donors, such as myristoyl-CoA (C14) and palmitoyl-CoA (C16) that are not efficient (By similarity).
Specifically methylates the N1 position of guanosine-37 in various cytoplasmic and mitochondrial 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.
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 (By similarity).
Interacts with TMEM48/NDC1 (By similarity). Forms a complex with NUP93, NUP155, NUP205 and lamin B. The interaction with NUP93 is direct (By similarity).
Its interaction with PHYH suggests a role in the development of the central system.
Catalyzes the oxygenation of arachidonate 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. Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene. 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 (By similarity). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers. 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. 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. May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK. Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity).
Homodimer. Interacts with ALOX5AP and LTC4S. Interacts with COTL1, the interaction is required for stability and efficient catalytic activity. 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). 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.
Serine phosphorylation by MAPKAPK2 is stimulated by arachidonic acid. Phosphorylation on Ser-523 by PKA has an inhibitory effect. Phosphorylation on Ser-271 prevents export from the nucleus. Phosphorylation at Ser-523 is stimulated by 8-bromo-3',5'-cyclic AMP or prostaglandin E2.
Acetylated at Lys-247. May be deacetylated by HDAC6, HDAC10 or SIRT1.
E3 SUMO-protein ligase helping SUMO1 conjugation to its coregulators NAB1 and NAB2, whose sumoylation down-regulates EGR2 transcriptional activity.
Interacts with HCFC1 (By similarity). Interacts with WWP2 (By similarity). Interacts with UBC9 (By similarity). Interacts with CITED1 (By similarity). Interacts (via phosphorylated form) with SFN (By similarity).
Sequence-specific DNA-binding transcription factor (By similarity). 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).
Ubiquitinated by WWP2 leading to proteasomal degradation.
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).
Mitochondrial inner membrane calcium uniporter that mediates calcium uptake into mitochondria. Constitutes a pore-forming and calcium-conducting subunit. Mitochondrial calcium homeostasis plays key roles in cellular physiology and regulates cell bioenergetics, cytoplasmic calcium signals and activation of cell death pathways.
Identified in the spliceosome C complex. Component of the XAB2 complex, a multimeric protein complex composed of XAB2, PRPF19, AQR, ZNF830, ISY1, and PPIE.
Intron-binding spliceosomal protein required to link pre-mRNA splicing and snoRNP (small nucleolar ribonucleoprotein) biogenesis. Plays a key role in position-dependent assembly of intron-encoded box C/D small snoRNP, splicing being required for snoRNP assembly. May act by helping the folding of the snoRNA sequence. Binds to intron of pre-mRNAs in a sequence-independent manner, contacting the region between snoRNA and the branchpoint of introns (40 nucleotides upstream of the branchpoint) during the late stages of splicing.
Homooligomer and heterooligomer with HEXIM2; probably dimeric. 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). Interacts with the N-CoR complex through NCOR1. Interacts with ESR1 and NR3C1. May interact with NF-kappa-B through RELA. Interacts with CCNT2; mediates formation of a tripartite complex with KPNA2. 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.
The coiled-coil domain mediates oligomerization.
Transcriptional regulator which functions as a general RNA polymerase II transcription inhibitor. 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. May also regulate NF-kappa-B, ESR1, NR3C1 and CIITA-dependent transcriptional activity. 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.
Up-regulated by HMBA (hexamethylene bisacetamide).
Expressed in mature oligodendrocytes in the brain.
Expressed in the course of oligodendrocytes maturation.
May serve as a cell-surface marker for oligodendrocyte differentiation.
Expressed specifically in placenta. Highly expressed in invasive trophoblast cells lining the central placental vessel.
Highest levels are observed from day 11 to day 20, with peak levels on day 13.
May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules.
Expressed in epithelial structures of the embryonic metanephric kidneys including the ureteric bud and its derivatives, and coma-shaped and S-shaped bodies differentiating from the metanephric mesenchyme. In the adult brain, expressed in the adrenal medulla, Purkinje cells of the cerebellum, hypothalamus, midbrain and pons. Also expressed in the adult testis.
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 (By similarity).
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).
Expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.
In osteosarcoma cells, a chromosomal translocation with FGFR2 results in an in-frame fusion of the two genes. This generates FGFR2-ROS, a chimeric protein with transforming activity.
Involved in the lipid remodeling steps of GPI-anchor maturation. Required for stable expression of GPI-anchored proteins at the cell surface.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family. NOG subfamily.
Involved in the biogenesis of the 60S ribosomal subunit.
May act as an transcriptional repressor for PCK1 gene expression, in turns may participate in the hepatic gluconeogenesis regulation through the activated AMPK signaling pathway.
Phosphorylation at Ser-471 results in loss of DNA-binding activity.
Expressed in spleen but not in astrocytes or microglia.
Receptor for C-C type chemokine. Binds and responds to a variety of chemokines, including CCL11, CCL26, CCL7, CCL13, RANTES(CCL5) and CCL15. Subsequently transduces a signal by increasing the intracellular calcium ions level. In addition acts as a possible functional receptor for NARS1.
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 (PubMed:22952235). Activated by noradrenaline and reactive oxygen species (By similarity).
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. However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs (PubMed:12479871, PubMed:16814247). 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).
Most probably functions as a monomer (By similarity). Binds one purine nucleotide per monomer (PubMed:12479871, PubMed:22952235). However, has also been suggested to function as a homodimer or a homotetramer (By similarity). Tightly associates with cardiolipin in the mitochondrion inner membrane; may stabilize and regulate its activity (By similarity).
Detected in eosinophils (PubMed:12467520). Detected in lung, placenta, spleen and thymus (at protein level) (PubMed:3020049).
Functions at least in part by activating the formyl peptide receptors and downstream signaling cascades. Promotes chemotaxis of granulocytes and monocytes via activation of the formyl peptide receptors. Promotes rearrangement of the actin cytoskeleton, cell polarization and cell migration. Promotes resolution of inflammation and wound healing. Acts via neutrophil N-formyl peptide receptors to enhance the release of CXCL2.
Homodimer; non-covalently linked (By similarity). Homodimer; linked by transglutamylation. Homodimers linked by transglutamylation are observed in placenta, but not in other tissues. Interacts with S100A11. Heterotetramer, formed by two molecules each of S100A11 and ANXA1 (By similarity). Interacts with DYSF (By similarity). Interacts with EGFR (By similarity).
Phosphorylated by protein kinase C, EGFR and TRPM7. Phosphorylated in response to EGF treatment.
Plays important roles in the innate immune response as effector of glucocorticoid-mediated responses and regulator of the inflammatory process. Has anti-inflammatory activity. Plays a role in glucocorticoid-mediated down-regulation of the early phase of the inflammatory response. 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. Promotes the differentiation of T-cells into Th1 cells and negatively regulates differentiation into Th2 cells (By similarity). Has no effect on unstimulated T-cells. Negatively regulates hormone exocytosis via activation of the formyl peptide receptors and reorganization of the actin cytoskeleton (By similarity). 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:3020049). 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). Inhibition of phospholipase activity is mediated via its phospholipid binding activity that limits the access of phospholipase to its substrates.
Has a role in nuclear-cytoplasmic transport of proteins and mRNAs.
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. Supplies nona and decaprenyl diphosphate, the precursors for the side chain of the isoprenoid quinones ubiquinone-9 (Q9) and ubiquinone-10 (Q10) respectively. The enzyme adds isopentenyl diphosphate molecules sequentially to farnesyl diphosphate with trans stereochemistry (By similarity). May play a role during cerebellar development (By similarity). May regulate mitochondrial respiratory chain function (By similarity).
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).
Highly expressed in brain, thymus and testis with lower levels in lung and spleen and barely detectable in heart or liver (at protein level).
Belongs to the DNA glycosylase MPG family.
Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from the damaged DNA polymer formed by alkylation lesions.
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.
Homodimer when bound to DNA, completely encircles its DNA target (By similarity). Interacts with CIDEC; this interaction is direct and retains NFAT5 in the cytoplasm (PubMed:23233732). Does not bind with Fos and Jun transcription factors. Interacts with DDX5 and DDX17; this interaction leads to DDX5/DDX17 recruitment to LNC2 and S100A4 promoters and NFAT5-mediated DDX5/DDX17-enhanced transactivation (By similarity).
Phosphorylated. Phosphorylated at Thr-152 by CDK5 in response to osmotic stress; this phosphorylation mediates its rapid nuclear localization.
Poly-ADP-ribosylated by PARP1 in response to DNA damage, promoting recruitment to sites of R-loop-associated DNA damage.
Transcription factor involved, among others, in the transcriptional regulation of osmoprotective and inflammatory genes (PubMed:23233732). Binds the DNA consensus sequence 5'-[ACT][AG]TGGAAA[CAT]A[TA][ATC][CA][ATG][GT][GAC][CG][CT]-3'. Mediates the transcriptional response to hypertonicity. Positively regulates the transcription of LCN2 and S100A4 genes; optimal transactivation of these genes requires the presence of DDX5/DDX17. 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 (By similarity).
Up-regulated under hypertonic conditions.
Component of the cleavage and polyadenylation specificity factor (CPSF) complex.
Binds to GRB2 (By similarity). Isoform 2A binds to SYNJ2BP/OMP25.
Inositol 5-phosphatase which may be involved in distinct membrane trafficking and signal transduction pathways. May mediate the inhibitory effect of Rac1 on endocytosis (By similarity).
The PDZ domain of isoform 2A binds SYNJ2BP/OMP25. Mutagenesis of Ser-1246 or Val-1248 to Ala abolishes SYNJ2BP/OMP25 binding.
Widely expressed. Isoforms 2B1 and 2B2 are concentrated at nerve terminals in brain and at spermatid manchette in testis.
Induced by androgens and suppressed by estrogens. The expression is under the influence of pituitary growth hormone and thyroid hormone.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules bearing a hydroxyl or an amine groupe. Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites. Displays broad substrate specificity for small phenolic compounds (PubMed:8447833, PubMed:7889867, PubMed:1513323). Plays an important roles in the sulfonation of endogenous molecules such as steroid hormones and 3,3'-diiodothyronin (By similarity). Mediates the sulfate conjugation of a variety of xenobiotics, including the drugs acetaminophen and minoxidil (PubMed:1513323). Mediates also the metabolic activation of carcinogenic N-hydroxyarylamines leading to highly reactive intermediates capable of forming DNA adducts, potentially resulting in mutagenesis (By similarity). 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.
Detected in the hypothalamus (at protein level).
Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with IRS1 in nuclear extracts. Interacts with RUFY3. Interacts with RASD2. Interacts with APPL1. Interacts with HRAS and KRAS. Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2. Interacts with FAM83B; activates the PI3K/AKT signaling cascade.
Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and 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. 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 (PubMed:20236230). 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 (By similarity). 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.
Inhibits translocation of GLUT4 from intracellular vesicles to the plasma membrane (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. Competes with STXBP1 for STX1 binding.
Isoform 1 is detected in heart, brain, lung, liver, skeletal muscle, kidney and testis. Isoform 2 is detected in brain and in testis. Isoform 3 is detected in testis.
Part of a complex that contains STXBP5, STX4A and SNAP23 (By similarity). Interacts with STX1A and STX4A via its v-SNARE homology domain. Part of a complex that contains STX1, STXBP5, SNAP25 and SYT1.
Phosphorylation by PKA reduces interaction with STX1A and enhances synaptic neurotransmitter release.
Adds the first 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 Man(9)GlcNAc(2)-PP-Dol (By similarity).
Gln-155 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin--tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.
Probable tubulin polyglutamylase that generates side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of target proteins. Similar to TTLL1, may acquire enzymatic activity only in complex with other proteins as it is most likely lacking domains important for autonomous activity. Mediates tubulin polyglutamylation which induces establishment of microtubule heterogeneity in sperm flagella, thereby playing a role in normal motile flagella axoneme structure and sperm flagella beating pattern.
Component of the GPI transamidase complex. Essential for transfer of GPI to proteins, particularly for formation of carbonyl intermediates (By similarity).
Forms a complex with PIGK/GPI8, PIGT, PIGU and GAA1.
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 (By similarity). Hydrolyzes adenosine 5'monophosphomorpholidate (AMP-morpholidate) and guanosine 5'monophosphomorpholidate (GMP-morpholidate) (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). Modulates p53/TP53 levels and p53/TP53-mediated apoptosis. Modulates proteasomal degradation of target proteins by the SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (By similarity). Also exhibits SUMO-specific isopeptidase activity, deconjugating SUMO1 from RANGAP1 and RGS17 (By similarity).
Homodimer (By similarity). Interacts with CDK7 (By similarity). Interacts with RUVBL1 and RUVBL2 and is associated with the LEF1/TCF1-CTNNB1 complex and with a KAT5 histone acetyltransferase complex (By similarity). Identified in a complex with MITF and CTNNB1 (By similarity). Interacts with CDC34 and RBX1, and is part of a SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex (By similarity). 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.
Brain (neurons and oligodendrocytes), skeletal muscle, regenerating liver, tumor cell lines. Expressed in enterocytes of the small intestine villi and colonic surface, zymogen cells of the stomach, proximal tubule cells of the kidney, bronchiolar epithelium, but not in esophagus and heart (at protein level).
By hepatectomy, mitogens, and ischemia-reperfusion.
Expressed in fetal brain. Up-regulated during oligodendroglial differentiation. Expressed in the developing intestine, esophagus, liver, kidney and lung (at protein level).
Farnesylated. Farnesylation is required for membrane targeting (By similarity).
Homotrimer. Interacts with ATF5 and tubulin (By similarity).
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 (By similarity).
Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa.
Expressed in heart, brain, liver, and muscle but not in kidney or testis.
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 neuron-enriched regions of the developing brain, but down-regulated to low levels in the adult brain.
Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis, it proteolytically cleaves poly(ADP-ribose) polymerase PARP1 at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Triggers cell adhesion in sympathetic neurons through RET cleavage (By similarity). Cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes (By similarity). Cleaves and inhibits serine/threonine-protein kinase AKT1 in response to oxidative stress. 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. Also involved in pyroptosis by mediating cleavage and activation of gasdermin-E (GSDME) (By similarity). Cleaves XRCC4 and phospholipid scramblase proteins XKR4, XKR8 and XKR9, leading to promote phosphatidylserine exposure on apoptotic cell surface (By similarity).
S-nitrosylated on its catalytic site cysteine in unstimulated 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.
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.
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 an alternative exon of the WNK1 gene in other mammalian species, including human and mouse. Isoforms bearing this exon (isoform 2 and isoform 3 in this entry) are specifically expressed in the nervous system in these species. system.
Interacts with SYT2. Interacts with KLHL3, WNK3 and WNK4 (PubMed:17975670). Isoform 5: Interacts with isoform 1 (PubMed:16204408).
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).
This isoform which includes the HSN2 exon has been identified in human and mouse. The sequence shown here is the result of gene prediction.
Ubiquitinated in vitro by the BCR(KLHL3) complex and in vivo by a BCR(KLHL2) complex, leading to proteasomal degradation.
Methylated at Arg-217 by CARM1 in macrophages in response to LPS challenge.
Monomer and homodimer (in vitro). Interacts with ANP32A (By similarity). 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. Interacts with AGO1 and AGO2. Interacts with IGF2BP1. Interacts with IGF2BP2 and IGF2BP3 (By similarity). Interacts with HNRNPL (PubMed:18161049). Interacts with DHX36; this interaction occurs in a RNA-dependent manner. Interacts with ILF3; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with PLEKHN1 (By similarity). Interacts with SHFL; the interaction increases in presence of RNA (By similarity). Interacts with YBX1; interaction recruits ELAVL1 on C5-methylcytosine (m5C)-containing mRNAs, thereby promoting mRNA stability (By similarity).
Phosphorylated by MAPKAPK2. Phosphorylated by PRKCD.
RNA-binding protein that binds to the 3'-UTR region of mRNAs and increases their stability (By similarity). 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 (By similarity). Binds to poly-U elements and AU-rich elements (AREs) in the 3'-UTR of target mRNAs. 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 (By similarity). 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 (By similarity).
The first RRM (RNA recognition motif) domain is essential for binding to AU-rich elements.
Contains 2 copies 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 leading to down-regulation of cell activation.
Heterodimer with KLRE1. Interacts with PTPN6.
Lectin-like receptor for natural killer (NK) cells. Heterodimer formation with KLRE1 mediates inhibition of NK cell cytolytic activity.
Belongs to the eukaryotic ATPase epsilon 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(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.
Hydrolase highly specific for thiamine triphosphate (ThTP).
Acts as a acyl-protein thioesterase hydrolyzing fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins, GAP43, ZDHHC6 or HRAS (By similarity). Deacylates GAP43 (By similarity). Mediates depalmitoylation of ZDHHC6 (By similarity). Has lysophospholipase activity (By similarity). Hydrolyzes prostaglandin glycerol esters (PG-Gs) in the following order prostaglandin D2-glycerol ester (PGD2-G) > prostaglandin E2 glycerol ester (PGE2-G) > prostaglandin F2-alpha-glycerol ester (PGF2-alpha-G) (By similarity). Hydrolyzes 1-arachidonoylglycerol but not 2-arachidonoylglycerol or arachidonoylethanolamide (By similarity).
Belongs to the AB hydrolase superfamily. AB hydrolase 2 family.
Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes. Part of the cAMP response element-binding protein (CREB) shut-off signaling pathway. Stimulates outgrowth of olfactory axons and migration of gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH) neuronal cells.
Expressed in the radiatum and pyramidale strata of the hippocampus (at protein level). Strongly expressed in the brain. Expressed in the sensory and motor cortex, hippocampus, olfactory bulb, thalamus and amygdala. In the olfactory bulb expressed in the granular cell layer, mitral cell layer and the glomerular layer. In the hippocampus highly expressed in the regions associated with neuronal cell types as CA1, CA2, CA3 and granule cells of the dentate gyrus. All isoforms have been detected in the molecular layers of the hippocampus (PubMed:19608740).
Interacts with KPNA1; the interaction occurs in a calcium-independent manner after synaptic NMDA receptor stimulation and is required for nuclear import of NSMF but is competed by CABP1. Interacts (via the central NLS-containing motif region) with CABP1 (via EF-hands 1 and 2); the interaction occurs in a calcium-dependent manner after synaptic NMDA receptor stimulation and prevents the nuclear import of NSMF. Cannot be competed by calmodulin.
NSMF mRNAs expressed in the hippocampus exhibit a prominent dendritic localization which is mediated by a dendritic targeting element (DTE) residing in the 3'-untranslated region (3'UTR). Transport from dendrites to the nucleus is induced by NMDA receptor activation and results in a rapid stripping of synaptic contacts and a reduction of dendritic complexity.
Proteolytically processed after NMDA receptor activation. Cleaved in a calcium-dependent and calpain-sensitive manner. Calpain cleavage is essential for the translocation process from dendrites to the nucleus.
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 (By similarity).
Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A. Could play a role during central nervous system development.
Phosphorylation increases its ability to inhibit calcineurin and decreases protein half-life.
Acts as a acyl-protein thioesterase hydrolyzing fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins or HRAS (PubMed:9624183). Has depalmitoylating activity toward KCNMA1 (By similarity). Could also depalmitoylate ADRB2 (By similarity). Acts as a lysophospholipase hydrolyzing various lysophospholipids including lysophosphatidylcholine (lyso-PC), lysophosphatidylethanolamine (lyso-PE), lysophosphatidylinositol (lyso-PI) and lysophosphatidylserine (lyso-PS) (PubMed:8631810, PubMed:9644627). Has much higher thioesterase activity than lysophospholipase activity (By similarity). 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 (By similarity).
Ubiquitous. Detected at low levels in all tissues tested.
Forms a complex with UTP4, NOL11, WDR43 and WDR75.
Enzyme that can either act as an ADP-sugar pyrophosphatase in absence of diphosphate or catalyze the synthesis of ATP in presence of diphosphate. 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. Can also hydrolyze other nucleotide sugars with low activity. 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. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming. Does not play a role in U8 snoRNA decapping activity. Binds U8 snoRNA.
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.
Belongs to the D-glucuronyl C5-epimerase family.
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.
Binds and is activated by Bj-BPP-10c, a bioactive anti-hypertensive proline-rich decapeptide, part of the C-type natriuretic peptide precursor.
Homotetramer. Interacts with NMRAL1. Interacts with CLOCK; in a circadian manner (By similarity). 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 (By similarity).
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 (Probable). 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 (Probable). Indirectly, may be involved in the control of blood pressure (PubMed:19491403).
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.
Forms a heteromeric complex with ALS2CL. Interacts with ALS2CL (By similarity).
May act as a GTPase regulator (By similarity). Controls survival and growth of spinal motoneurons.
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 (By similarity).
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 (By similarity). 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 (By similarity). In the central nervous system, it is involved in the regulation of neurite formation and arborization. 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).
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.
Expressed in brain; highly enriched in neurons.
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 (By similarity). Interacts with cytoplasmic dynein light chain DYNLT1. 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. May interact with UNC13A; the interaction mediates targeting to the plasma membrane.
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.
Earliest expression is detected at 12.5 dpc in the developing brain in regions corresponding to the future rostral and caudal serotonergic neuron clusters.
Functions as a transcriptional regulator. May function as a transcriptional repressor. Functions in the differentiation and the maintenance of the central serotonergic neurons. May play a role in cell growth.
Specifically expressed in central serotonergic neurons. Also expressed in adrenal gland and to a lower extent in small intestine and eye.
Detected in Schwann cells (at protein level).
Expression increases in myelinating Schwann cells during the initial period of active myelination.
Homotrimer (via collagen-like domains) (PubMed:17485493) (Probable). Interacts with NRCAM (PubMed:16039564, PubMed:22009740). Interacts with NFASC/neurofascin (PubMed:16039564, PubMed:17485493, PubMed:22009740). Interaction with glial NRCAM enhances interaction with axonal NFASC. Interacts with MYOC (By similarity).
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 (PubMed:16039564). 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 (By similarity).
Proteolytic proccessing by a furin-like protease causes shedding of the ectodomain (PubMed:17485493). Further cleavage by BMP1 releases the olfactomedin-like domain.
The olfactomedin-like domain mediates NFASC/neurofascin and NRCAM binding.
Binds to the C-terminal propeptide of type I procollagen and enhances procollagen C-proteinase activity.
Expressed at highest levels in collagen-rich tissues, especially tendon. Also expressed in cornea and sterna.
Phosphorylation at Ser-33 inhibits the kinase and activates the bisphosphatase.
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 (By similarity).
Belongs to the Mediator complex subunit 9 family.
Induced by estrogens and suppressed by androgens.
Male specific. Maximum at 9 weeks and maintained in 9-month-old rats. Can be detected at low level in females up to 9-weeK-old rats but then decreases to undetectable level.
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of drugs, xenobiotic compounds, hormones, and neurotransmitters. May be involved in the activation of carcinogenic hydroxylamines (By similarity).
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 (By similarity). Interacts with DBF4 (By similarity). Interacts with MCM10. 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. Interacts with POLQ (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 (By similarity). Binds histone H3 and H4 trimethylation marks H3K9me3, H3K20me3 and H4K27me3. Stabilizes LRWD1, by protecting it from ubiquitin-mediated proteasomal degradation. Also stabilizes ORC3 (By similarity).
Activity with myo-inositol monophosphate and D-galactose 1-phosphate is inhibited by Li(+), Ca(2+) and Mn(2+), but also by Mg(2+) at concentrations above 3 mM.
Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain. Has broad substrate specificity and can use myo-inositol 1,3-diphosphate, myo-inositol 1,4-diphosphate, scyllo-inositol-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates (By similarity). Is equally active with myo-inositol monophosphate and D-galactose 1-phosphate.
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 transcriptional transactivator of ELL, ELL2 and TCEA1 elongation activities (By similarity). Potent inducer of apoptosis in prostatic and non-prostatic cell lines.
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, ELL2 and TCEA1 (By similarity).
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. Pre-alpha-inhibitor (P-alpha-I) is composed of ITIH3/HC3 and bikunin.
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.
Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.
Belongs to the cyclophilin-type PPIase family. PPIase E subfamily.
Catalyzes the cis-trans isomerization of proline imidic peptide bonds in proteins.
Although it belongs to the glycosyl hydrolase 18 family, Leu-138 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 (By similarity).
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.
Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells). 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.
Heterodimer with CCNQ, the interaction is required for kinase activity. Interacts with ETS2. Interacts with PRK2.
Homooligomer. Interacts with TNFAIP3. Interacts with STARD13. Interacts with MYO6. Interacts with TOM1; the interaction is indirect and is mediated by MYO6, which acts as a bridge between TOM1 and TAX1BP1. Interacts with MAVS; this interaction induces MAVS polyubiquitination. Interacts with TNIP1. Interacts with TRAF6; this interaction mediates deubiquitination of TRAF6 and inhibition of NF-kappa-B activation. Interacts with RIPK1; this interaction negatively regulates RIPK1 ubiquitination. Interacts with NBR1. Interacts with TBK1. Interacts with RB1CC1. Interacts with SQSTM1. Interacts with AZI2.
Phosphorylated in the C-terminal region by CHUK/IKKA leading to NF-kappa-B signaling down-regulation.
The C-terminal UBZ-type zinc fingers function as ubiquitin-binding domains.
Ubiquitin-binding adapter that participates in inflammatory, antiviral and innate immune processes as well as selective autophagy regulation. Plays a key role in the negative regulation of NF-kappa-B and IRF3 signalings by acting as an adapter for the ubiquitin-editing enzyme A20/TNFAIP3 to bind and inactivate its substrates. Disrupts the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKBKE to attenuate 'Lys63'-linked polyubiquitination of TBK1 and thereby IFN-beta production. Recruits also A20/TNFAIP3 to ubiquitinated signaling proteins TRAF6 and RIPK1, leading to their deubiquitination and disruption of IL-1 and TNF-induced NF-kappa-B signaling pathways. Inhibits virus-induced apoptosis by inducing the 'Lys-48'-linked polyubiquitination and degradation of MAVS via recruitment of the E3 ligase ITCH, thereby attenuating MAVS-mediated apoptosis signaling. As a macroautophagy/autophagy receptor, facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis. Upon NBR1 recruitment to the SQSTM1-ubiquitin condensates, acts as the major recruiter of RB1CC1 to these ubiquitin condensates to promote their autophagic degradation.
Expressed specifically in the caput region of the epididymis.
May play an important role in male reproduction including sperm maturation and gonadotrope function. This is a non catalytic metalloprotease-like protein (By similarity).
Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. MCAK/KIF2 subfamily.
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. Plays a role in chromosome congression.
Brain. High level expression seen in the cingulate gyrus within the retrospinal cortex, ventral and medial divisions of the anterior thalamus and the medial geniculate nucleus. Expressed at moderate levels in the parietal and temporal cortex. Expressed in the cerebellum.
Dual specificity phosphatase that dephosphorylates MAP kinase MAPK1/ERK2 on both 'Thr-183' and 'Tyr-185', regulating its activity during the meiotic cell cycle.
Exhibits night/day variations with a 100-fold increased expression at night in the pineal gland (at protein level). Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway.
Phosphorylation at Ser-359 and Ser-364 by MAPK1/ERK2 and MAPK3/ERK1 reduces its rate of degradation.
Homodimer. Can also form heterodimers with TPST2.
E3 ubiquitin-protein ligase involved in DNA damage response by promoting DNA resection and homologous recombination. Recruited to sites of double-strand breaks following DNA damage and specifically promotes double-strand break repair via homologous recombination. 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. 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. Together with NLK, involved in the ubiquitination and degradation of TCF/LEF. Also exhibits auto-ubiquitination activity in combination with UBE2K. May act as a negative regulator in the Wnt/beta-catenin-mediated signaling pathway.
Interacts with NLK. Interacts with XRCC5/Ku80. Interacts with RBBP8/CtIP.
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.
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 (PubMed:15383280). Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation (PubMed:12191471). 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:15383280). Inhibits calcium-mediated cell death by functioning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis (PubMed:23382383). Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation (PubMed:16639714). Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner (PubMed:10590251). 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 (PubMed:17292893).
CARD is critical for both extrinsic and intrinsic apoptotic pathways (PubMed:15383280). CARD domain mediates a protective effect against myocardial ischemia/reperfusion, oxidative stress and TNF-induced necrosis (By similarity). The C-terminal domain (amino acids 99 to 221) is involved in calcium binding and plays a protective role in calcium-mediated cell death (By similarity).
Highly expressed in skeletal muscle, heart and medulla.
Increased by chronic hypoxia (PubMed:22082675). Activated by FOXO3 (PubMed:23382383). Negatively regulated by TP53 (PubMed:17998337).
Oligomerizes (via CARD doamin) (By similarity). 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. Interacts directly (via CARD domain) with FAS and FADD (via DED domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation. 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. Interacts (via CARD domain) with BBC3 (via BH3 domain); preventing the association of BBC3 with BCL2 and resulting in activation of CASP8. Interacts (via CARD domain) with BAD(via BH3 domain); preventing the association of BAD with BCL2. Interacts directly (via CARD domain) with TNFRSF1A; inhibits TNF-signaling pathway (By similarity).
Phosphorylation at Thr-149 is required for its antiapoptotic effect by blocking 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 (PubMed:12191471). Dephosphorylated at Thr-149 by calcineurin; doesn't inhibit the association between FADD and CASP8 and the consequent apoptosis (PubMed:19001025).
Polyubiquitinated by MDM2; promoting proteasomal-dependent degradation in response to apoptotic stimuli.
Acts as an inhibitory receptor for myeloid cells and mast cells. 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. Negatively regulates Fc epsilon receptor-dependent mast cell activation and allergic responses via binding to ceramide and sphingomyelin which act as ligands. 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. Negatively regulates the Toll-like receptor (TLR) signaling mediated by MYD88 and TRIF through activation of PTPN6/SHP-1 and PTPN11/SHP-2. Inhibits osteoclast formation. Induces macrophage cell death upon engagement.
Interacts with PTPN6/SHP-1 in a tyrosine phosphorylation dependent manner. Interacts with IL4R.
Hydrolase with high activity towards palmitoylcarnitine. Is also active with p-nitrophenylacetate and alpha-naphthylacetate (By similarity). May also hydrolyze retinyl esters (PubMed:12230550).
Hydrolyzes nucleoside diphosphates with a preference for GDP, IDP and UDP compared to ADP and CDP (By similarity). In the lumen of the endoplasmic reticulum, hydrolyzes UDP that acts as an end-product feedback inhibitor of the UDP-Glc:glycoprotein glucosyltransferases. UMP can be transported back by an UDP-sugar antiporter to the cytosol where it is consumed to regenerate UDP-glucose. Therefore, it positively regulates protein reglucosylation by clearing UDP from the ER lumen and by promoting the regeneration of UDP-glucose. Protein reglucosylation is essential to proper glycoprotein folding and quality control in the ER (By similarity).
Monomer; active form. Homodimer; disulfide-linked. Homodimers are enzymatically inactive.
Belongs to the amidase family. GatA subfamily.
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 and chromosome segregation, and nuclear envelope sealing and spindle disassembly during anaphase (By similarity). In conjunction with the ESCRT machinery also appears to function in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis. 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. VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan (By similarity). Critical for normal erythroblast cytokinesis and correct erythropoiesis (By similarity).
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 (By similarity).
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) (By similarity).
Directly or indirectly cross-linked to cornifelin (CNFN).
Keratinocytes of epidermis and other stratified squamous epithelia.
Part of the insoluble cornified cell envelope (CE) of stratified squamous epithelia.
Substrate of transglutaminase. Specific glutamines or lysines are cross-linked to keratins, desmoplakin and to inter involucrin molecules.
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.
Very low expression levels is detected in brain, while high levels are found in adrenals, stomach, lung and spleen.
ADP-ribosylated by tankyrase TNKS and TNKS2. Poly-ADP-ribosylated protein is recognized by RNF146, followed by ubiquitination and subsequent activation of the Wnt signaling pathway.
Inhibitor of the Wnt signaling pathway. Down-regulates beta-catenin. Probably facilitate the phosphorylation of beta-catenin and APC by GSK3B.
Interacts with SMAD7 and RNF111. Interacts with ANKRD6 (By similarity). Interacts with glycogen synthase kinase-3 beta (GSK3B) and beta-catenin (PubMed:9566905). The interaction between axin and beta-catenin occurs via the armadillo repeats contained in beta-catenin (PubMed:9566905). Interacts with SIAH1 (By similarity). Interacts with SIAH2 (By similarity).
Probably phosphorylated by GSK3B and dephosphorylated by PP2A.
Ubiquitinated by RNF146 when poly-ADP-ribosylated, leading to its degradation and subsequent activation of the Wnt signaling pathway. Deubiquitinated by USP34, deubiquitinated downstream of beta-catenin stabilization step: deubiquitination is important Wnt signaling to positively regulate beta-catenin (CTNBB1)-mediated transcription.
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:27516594). Interaction of a single pore-forming alpha subunit with a calmodulin chain is sufficient to promote channel closure. Channel activity is not regulated by cyclic nucleotides. 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 (By similarity).
Channel activity is regulated via tyrosine phosphorylation/dephosphorylation by SRC and PTPN6.
Detected in cerebellum, at parallel fiber synapses on Purkinje cell spines (PubMed:25556795). Detected in hippocampus neurons (at protein level) (PubMed:24495567). Detected in brain, but not in the other tissues tested; expression is highest in granular cells of the dentate gyrus, in hippocampus CA3 pyramidal cells, and in cerebellar granule cells (PubMed:7925287). Detected in pituitary (PubMed:10718922).
Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel (PubMed:7925287, PubMed:9400421, PubMed:24495567, PubMed:27516594). Channel properties are modulated by subunit assembly. Mediates IK(NI) current in myoblasts. Involved in the regulation of cell proliferation and differentiation, in particular adipogenic and osteogenic differentiation in bone marrow-derived mesenchymal stem cells (MSCs) (By similarity).
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. 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 (PubMed:9400421, PubMed:27516594). Heteromultimer with KCNH5/EAG2 (By similarity). Interacts with ALG10B (PubMed:9722534). Interacts with RABEP1 (PubMed:22841712). Interacts (via C-terminus) with CTTN (PubMed:23144454). Interacts (via cytoplasmic region) with Ca(2+)-bound calmodulin (PubMed:27516594).
A peptide arising from positions 166 to 174 was originally termed neurotensin-related peptide (NRP) and was thought to regulate fat digestion, lipid absorption, and blood flow.
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (By similarity). 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 (By similarity). Does not prevent iron uptake by the bacterial siderophore aerobactin (By similarity).
Interacts with FCGRT; this interaction regulates ALB homeostasis (By similarity). Interacts with TASOR (By similarity). In plasma, occurs in a covalently-linked complex with chromophore-bound alpha-1-microglobulin; this interaction does not prevent fatty acid binding to ALB.
Involved in ribosomal large subunit assembly. May regulate the localization of the 5S RNP/5S ribonucleoprotein particle to the nucleolus.
Acetylated. Could occur at proximity of the cofactor-binding sites and reduce the catalytic activity. Could be deacetylated by SIRT3.
Homotetramer (PubMed:3968063, PubMed:3813556). Interacts with the heterodimeric electron transfer flavoprotein ETF (By similarity).
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:3968063). 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:3968063). Electron transfer flavoprotein (ETF) is the electron acceptor that transfers electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase) (By similarity). 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:3968063).
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).
Component of the large ribosomal subunit. Interacts with IFIT1 (via TPR repeats 1-4).
Developmentally regulated in the intestine.
Homodimerization could regulate efficiency for zinc transport.
No change in response to zinc deprivation.
Probable proton-coupled zinc ion antiporter mediating zinc import from cytoplasm potentially into the endocytic compartment (By similarity). Controls zinc deposition in milk (By similarity).
Widely expressed. Highly expressed in brain and testis. Also expressed in small intestine, medulla, lung, kidney, stomach and colon. Expressed at lower level in other tissues.
Increases during lens maturation (at protein level).
Lens-specific. Located at the interface between lens fiber cells (at protein level).
The galectin domain is atypical and does not bind beta-galactoside sugars.
Belongs to the peptidase S26 family. IMP2 subfamily.
Belongs to the glycogen debranching enzyme family.
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.
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). Interacts with METTL16. 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. Associates with box C/D small nucleolar ribonucleoprotein (snoRNP) complexes.
RNA-binding protein that specifically binds distinct small nuclear RNA (snRNAs) and regulates their processing and function. 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. 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. The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC). 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. LARP7 also acts as a regulator of mRNA splicing fidelity by promoting U6 snRNA processing. 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. U6 snRNA 2'-O-methylation is required for mRNA splicing fidelity. Binds U6 snRNAs with a 5'-CAGGG-3' sequence motif (By similarity). 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.
Detected in neurons in brain cortex and hippocampus. Detected in pyramidal cell bodies and processes, in granule cells and interneurons in the CA1 and CA3 region of the hippocampus. Detected on astrocyte processes in brain cortex. Detected on endothelial cells in hippocampus capillaries (at protein level) (PubMed:16914199). Restricted to brain and skeletal muscle (PubMed:8798769).
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 (PubMed:8798769, PubMed:9486131). 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. Required for normal oligodendrocyte differentiation and for normal myelination. Mediates Ca(2+) efflux from mitochondria and contributes to mitochondrial Ca(2+) ion homeostasis.
Up-regulated during in vitro differentiation of oligodendrocytes (at protein level).
Component of pre-catalytic, catalytic and post-catalytic spliceosomes. Associates with the spliceosome prior to recognition of the 3'-splice site for step II, probably during catalysis of step I.
Required for pre-mRNA splicing as component of the spliceosome. Participates in the second catalytic step of pre-mRNA splicing, when the free hydroxyl group of exon I attacks the 3'-splice site to generate spliced mRNA and the excised lariat intron. Required for holding exon 1 properly in the spliceosome and for correct AG identification when more than one possible AG exists in 3'-splicing site region. May be involved in the activation of proximal AG. Probably also involved in alternative splicing regulation.
The CCHC-type zinc finger is required to retain the protein within the nucleus and prevent its shuttle back to the cytoplasm via the CRM1 pathway.
Sulfotransferase with broad substrate specificity that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of catecholamines, such as dopamine, prostaglandins, leukotriene E4, drugs and xenobiotic compounds. Has sulfotransferase activity towards p-nitrophenol, 2-naphthylamine and minoxidil (in vitro). Sulfonation increases the water solubility of most compounds, and therefore their renal excretion, but it can also result in bioactivation to form active metabolites (By similarity).
Component of the sarcomeric M-band which plays a role in myocyte response to biomechanical stress. May regulate expression of other M-band proteins via an SRF-dependent pathway. Important for normal contractile function in heart.
Expressed in heart and skeletal muscle (at protein level). Also detected in kidney (at protein level). Not detected in other tissues tested (at protein level).
In cardiomyocytes, down-regulated in response to biomechanical stress.
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. Within the GARP complex, required to tether the complex to the TGN. Not involved in endocytic recycling.
Component of the Golgi-associated retrograde protein (GARP) complex, also called VFT (VPS fifty-three) complex, composed of VPS51, VPS52, VPS53 and VPS54 (By similarity). EIPR1 interacts with GARP complex and mediates its recruitment to the trans-Golgi network (By similarity). Interacts with VPS51 in an EIPR1-independent manner (By similarity).
Expressed in brain, spleen, kidney, testis and lung, with highest levels in brain.
Homotrimer; each subunit contains a pore through which urea permeates (By similarity). Identified in a complex with STOM (By similarity).
Mediates the transport of urea driven by a concentration gradient across the cell membrane (PubMed:8982255). Mediates the transport of urea across the cell membranes of erythrocytes and the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism (By similarity). Facilitates water transport in erythrocytes (By similarity).
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 (By similarity).
A paper showing a role in apoptosis in neurons has been retracted due to panel duplication in several figures.
Interacts with HSP90AB1; HSP90AB1 is essential for FAM162A mitochondrial localization and pro-apoptotic activity. Interacts with VDAC2; the interaction is probably involved in inducing mitochondrial permeability transition.
Proposed to be involved in regulation of apoptosis; the exact mechanism may differ between cell types/tissues. 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. 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.
Expressed in the flagellum of epididymal sperm but not in testicular sperm (at protein level).
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).
Binds MET and MST1R. Interacts with RIT2/RIN. Interacts (via cytoplasmic domain) with FSCN1 and RAC1. May form homodimers (via Sema domain) (By similarity). Interacts (via cytoplasmic domain) with ARHGDIA.
Expressed in glioma cells (at protein level). Expressed in glioma cells and oligodendrocyte precursor cells.
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.
Plays a role in cytoplasmic trafficking of RNA. Binds to the cis-acting response element, A2RE. May be involved in pre-mRNA splicing.
Allosterically activated by benzodiazepines (By similarity). Activated by pentobarbitol (PubMed:2561970). Inhibited by the antagonist bicuculline (PubMed:2561970). Inhibited by zinc ions (By similarity).
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:2561970).Interacts with GABARAP (By similarity). Interacts with KIF21B (PubMed:25172774). Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3 (PubMed:28279354). 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:2561970). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (By similarity). 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, alpha2/beta2/gamma2 receptor and the alpha1/beta3/gamma2 receptor exhibit synaptogenic 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 acetyltransferase family.
Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. A similar role in the mediation of ubiquitination has also been suggested with INSR. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2 (By similarity).
Interacts with ligand-activated tyrosine kinase receptors, including FGFR1, INSR, IGF1R, MET and PDGFRB in a phosphotyrosine-dependent manner through the SH2 domain. Poorly binds to the EGFR. Directly interacts with MAP3K14/NIK and is recruited to the EGFR-ERBB2 complex. Interacts with GIGYF1/PERQ1 and GIGYF2/TNRC15. When unphosphorylated, interacts with AKT1 and when phosphorylated with YWHAE/14-3-3 epsilon. Interacts with NEDD4. Interacts with LRP6, thus interfering with the binding of AXIN1 to LRP6. Binds relatively non-specifically to several phosphoinositides, including PI(5)P, PI(4,5)P2, PI(3,4)P2 and PI(3,4,5)P3, with modest affinities through the PH domain. Binds to activated NRAS (By similarity).
Phosphorylated on serine residues upon EGF, FGF and PDGF stimulation.
Phosphorylation by mTORC1 stabilizes and activates GRB10 constituting a feedback pathway by which mTORC1 inhibits INSR-dependent signaling.
Catalyzes the NAD-dependent oxidation of highly active 17beta-hydroxysteroids, such as estradiol (E2), testosterone (T), and dihydrotestosterone (DHT), to their less active forms and thus regulates the biological potency of these steroids. Oxidizes estradiol to estrone, testosterone to androstenedione, and dihydrotestosterone to 5alpha-androstan-3,17-dione (PubMed:8612487). Also has 20-alpha-HSD activity (By similarity).
Highly expressed in the placenta, and in the small intestine, and liver.
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).
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates.
Expressed predominantly in neuronal tissue. Expressed in brain.
Interacts (through the Ig-like domains) with NLGN2.
May be involved in cell-cell interactions.
Activation is generally mediated by guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by GTPases activating protein (GAP). Inactivated by ACAP1 and ACAP2 (By similarity). Activated by NGF via NTRK1 (PubMed:26446845).
GTP-binding protein involved in protein trafficking that regulates endocytic recycling and cytoskeleton remodeling (PubMed:26446845). Required for normal completion of mitotic cytokinesis. Involved in the regulation of dendritic spine development, contributing to the regulation of dendritic branching and filopodia extension (PubMed:16672654). Plays an important role in membrane trafficking, during junctional remodeling and epithelial polarization. Regulates surface levels of adherens junction proteins such as CDH1. Required for NTRK1 sorting to the recycling pathway from early endosomes (PubMed:26446845).
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. 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.
Interacts (when activated) with GGA1, GGA2 and GGA3; the interaction is required for proper subcellular location of GGA1, GGA2 and GGA3 (By similarity). Interacts with PIP5K1C. Interacts with USP6 (via Rab-GAP TBC domain). Interacts with RAB11FIP3 and RAB11FIP4. Interacts with HERC1. Interacts with ARHGAP21. Interacts with ASAP3; the interaction is stabilized by calcium ions. Interacts with NCS1/FREQ at the plasma membrane. Interacts with TBC1D24. Interacts with ECPAS. Interacts with MICALL1. Interacts with SPAG9 homodimers, forming heterotetramers. Interacts with CYTH3 (By similarity). Interacts with ASAP2 (PubMed:10022920). 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).
Belongs to the eukaryotic ribosomal protein eL18 family.
Catalyzes a carbon-carbon cleavage reaction; cleaves a 2-hydroxy-3-methylacyl-CoA into formyl-CoA and a 2-methyl-branched fatty aldehyde.
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. Involved in the degradation of 3-methyl-branched fatty acids like phytanic acid (PubMed:10468558). Involved also in the shortening of 2-hydroxy long-chain fatty acids (By similarity). Plays a significant role in the biosynthesis of heptadecanal in the liver (By similarity).
Olfactory receptor activated by several primary trace amines, including isoamylamine. Activated by isoamylamine and cyclohexylamine, but not to the corresponding alcohols, isoamylalcohol and cyclohexanol. This receptor is probably mediated by the G(s)-class of G-proteins which activate adenylate cyclase (By similarity).
Binds DNA as a heterodimer with TCFL4/MLX.
Phosphorylation at Ser-568 by AMPK inactivates the DNA-binding activity.
Transcriptional repressor. Binds to the canonical and non-canonical E box sequences 5'-CACGTG-3' (By similarity).
Interacts (via ankyrin repeat region) with LYN (via SH3-domain) in an activation-independent status of LYN. Forms a multiprotein complex with LYN and HCLS1 (By similarity). Interacts with TSN2, VAV1, DBNL and LASP1 (By similarity).
Plays an important role in regulating intracellular signaling events associated with erythroid terminal differentiation.
Involved in the second step of GPI biosynthesis. De-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol.
Homodimer; homodimerization takes place upon caspase cleavage. Interacts with the processed C-terminus of XRCC4 (protein XRCC4, C-terminus); interaction promotes the phospholipid scramblase activity.
Homodimerizes upon caspase cleavage. Phospholipid scramblase activity is activated following interaction with the processed C-terminus of XRCC4 (protein XRCC4, C-terminus).
Phospholipid scramblase activity is activated upon caspase cleavage to generate the XK-related protein 4, processed form. Does not act prior the onset of apoptosis.
Phospholipid scramblase that promotes phosphatidylserine exposure on apoptotic cell surface. Phosphatidylserine is a specific marker only present at the surface of apoptotic cells and acts as a specific signal for engulfment.
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.
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). Can catalyze the reverse reaction but at a much lower rate in vitro. HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate. 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). Originally it was identified as an RNA-binding protein as it binds to AU-rich elements (AREs) in vitro. AREs direct rapid RNA degradation and mRNA deadenylation (By similarity). Might have itaconyl-CoA hydratase activity, converting itaconyl-CoA into citramalyl-CoA in the C5-dicarboxylate catabolism pathway. 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:13783048).
Expressed predominantly in kidney and much less in brain, heart, muscle, fat, liver, spleen, adrenal gland, ovary, thymus and lung. Not expressed in testis and intestine.
The small GTPases Rab are key regulators in vesicle trafficking (PubMed:23395371). Essential for maintaining the integrity of endosome-trans-Golgi network structure (PubMed:23395371). 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:23395371). Recruits LRRK2 to the Golgi apparatus and stimulates LRRK2 kinase activity (By similarity). Regulates also neuronal process morphology in the intact central nervous system (CNS) (PubMed:23395371).
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.
Belongs to the replication factor A protein 1 family.
Component of the heterotrimeric canonical replication protein A complex (RPA).
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. Interacts with ADRM1. Interacts with ZFAND1 (By similarity).
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. Also acts as a decay-accelerating factor, preventing the formation of C4b2a and C3bBb, the amplification convertases of the complement cascade. Seems to act as a costimulatory factor for T-cells. May play a crucial role in early embryonic development by maintaining fetomaternal tolerance.
Belongs to the receptors of complement activation (RCA) family.
Activity is inhibited by binding to OTUB1, which prevents 'Lys-63'-linked polyubiquitination (By similarity). 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 (By similarity). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (By similarity). Interacts with RNF8 and RNF168 (By similarity). Interacts with RNF11 (By similarity). 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 (By similarity). Interacts with ARIH2 (via RING-type 2) (By similarity). Interacts with OTUB1; leading to inhibit E2-conjugating activity (By similarity). Interacts with GPS2; leading to inhibit E2-conjugating activity (By similarity). Interacts with RIGI and RNF135; involved in RIGI ubiquitination and activation (By similarity).
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 (By similarity). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.
Transcriptional factor that defines subclasses of motoneurons that segregate into columns in the spinal cord and select distinct axon pathways.
Required for the transport of GPI-anchored proteins to the plasma membrane (By similarity). 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 (PubMed:14517336).
Associates with mitochondrial leucine tRNAs. Interacts with ELAC2.
Mitochondrial protein implicated in negative regulation of leucine tRNA levels, as well as negative regulation of mitochondria-encoded proteins and COX activity. Affects also the 3'-processing of mitochondrial tRNAs.
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 (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 CPSF1, CPSF4, CSTF2 and CSTF3. Interacts with AHCYL1 (when phosphorylated); the interaction is direct and associates AHCYL1 with the CPSF complex and RNA. Interacts with PAPOLA; the interaction seems to be increased by the interaction with AHCYL1. Interacts with NUDT21/CPSF5; this interaction occurs in a RNA sequence-specific manner. 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. 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.
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 (By similarity).
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 (By similarity).
Expressed within the somatodendritic compartment of neurons, is also present on dendritic growth cones, but is not found in astrocytes.
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.
Actin-binding protein that enhances membrane ruffling and RAC activation. Enhances the actin-bundling activity of LCP1. Binds calcium. Plays a role in RAC signaling and in phagocytosis. May play an role in macrophage activation and function. Promotes the proliferation of vascular smooth muscle cells and of T-lymphocytes. Enhances lymphocyte migration. Plays a role in vascular inflammation (By similarity).
Cardiac allograft, spleen and testis. Expressed by inflammatory cells (macrophages and neutrophils).
Expressed early and persistently in chronically rejecting cardiac allografts but is absent in cardiac syngrafts and host hearts. In the embryonic cerebellum, expression peaks at day 7.
Homodimer (Potential). Monomer. Interacts with LCP1 (By similarity).
Arg-15 is dimethylated, probably to asymmetric dimethylarginine.
Blocks interferon-dependent interphase and stimulates DNA synthesis in cells.
Heterotetramer of two type I and two type II keratins. Interacts with eukaryotic translation initiator factor 3 (eIF3) subunit EIF3S10. Interacts with GPER1 (By similarity).
Exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity (PubMed:12553736, PubMed:10615013). Capable of producing kinin potentiating peptides (PubMed:10615013).
The disulfide bridge formed between Cys-35 in the propeptide and the active site residue Cys-94 may prevent activation of the zymogen through formation of a reversible covalent bond with the active site residue.
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. Interacts with SCA7. Interacts with NGLY1. Interacts with PAAF1.
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.
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 (By similarity).
Highly expressed in the brain. High levels of expression were seen in fiber tracts such as the corpus callosum, anterior commissure, fornix, internal capsule, cerebral peduncles, and stria terminalis. Additionally, moderate levels of expression were seen in the pyramidal tracts and cerebellar peduncles, as well as in the spinal tract of the trigeminal nerve and the spinal fasciculi.
Receptor for the neuroprotective and glioprotective factor prosaposin. Ligand binding induces endocytosis, followed by an ERK phosphorylation cascade (By similarity).
Ubiquitinated by PRKN in the presence of ubiquitin-conjugating enzymes in the endoplasmic reticulum.
Detected in astrocytes, brain, lung, liver, kidney, spleen and testis.
Interacts with SEC61B, SEC61A1 and the SEC61 complex. Interacts with CANX.
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.
Up-regulated in cultured astrocytes in response to hypoxia; levels remain elevated for at least 4 hours after return to normoxia. Up-regulated in ischemic brain.
Expressed in all tissues tested including adipose, brain, testis, intestine, liver, heart, spleen, skeletal muscle and kidney.
Found in a complex with VAMP8 and SNAP23. Detected in a complex with SNAP23 and STXBP4. Interacts with SNAP23 and SNAPIN. Interacts with VAMP2. Interacts with LLGL1. Interacts (via C-terminus) with CENPF. Interacts with DOC2B. Interacts with STXBP3; excludes interaction with DOC2B and SNAP25. Interacts with STXBP4; excludes interaction with VAMP2 (By similarity). Component of the SNARE complex composed of STX4, SNAP23 and VAMP7 that interacts with SYT7 during lysosomal exocytosis. Interacts with STXBP6. Interacts with STXBP5L (By similarity).
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 (PubMed:32963038). 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).
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. 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). 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. Promotes profound chromatin decondensation during the innate immune response to infection in neutrophils by mediating formation of H1R54ci (By similarity). 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. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1 (By similarity).
Calcium/calmodulin-regulated and magnesium-dependent enzyme that catalyzes the hydrolysis of ATP coupled with the transport of calcium out of the cell (By similarity). By regulating sperm cell calcium homeostasis, may play a role in sperm motility (By similarity).
Interacts with PDZD11. Interacts with SLC35G1 and STIM1. Interacts with calmodulin.
Ubiquitously expressed. Not detected in liver. The highest levels are found in uterus and stomach. Isoform XA is found in uterus, brain, stomach, small intestine, colon and pancreas. Isoform XB is found in uterus, skeletal muscle, lung, kidney, spleen, stomach, small intestine and pancreas. Isoform ZA is found in testis and isoform ZB is found in testis and heart.
Homodimer, or homooligomer. Interacts with TGFA and HBEGF. Interacts with EGF; may retain EGF in the endoplasmic reticulum and regulates its degradation through the endoplasmic reticulum-associated degradation (ERAD). Interacts (via cytoplasmic N-terminus) with FRMD8/iTAP; this interaction leads to mutual protein stabilization. Interacts with ADAM17/TACE.
Appears to have histone acetyltransferase (HAT) activity, specifically towards histones H2B and H4 in vitro (By similarity). 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 (By similarity). Interacts with the HK1/VDAC1 complex. Interacts with NBN, MRE11, XPO1, KAT5 and CUL3 (By similarity).
Phosphorylation of Thr-51 by MAPK14 and MAPK11, and at Thr-53 by MAPK1/ERK2, MAPK3/ERK1, MAPK11, MAPK12 and MAPK14 in response to external stimulus like insulin causes increased transcriptional activity. Phosphorylated by PLK3 following hyperosmotic stress. Also phosphorylated and activated by JNK and CaMK4. ATM-mediated phosphorylation at Ser-472 and Ser-480 stimulates its function in DNA damage response. Phosphorylation at Ser-44, Thr-55 and Ser-103 activates its transcriptional activity. Phosphorylation at Thr-51 or Thr-53 enhances acetylation of histones H2B and H4.
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. 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 (By similarity).
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.
Binds DNA as a monomer. Can form homomers (By similarity). Directly interacts with CEBPD/NF-IL6-beta; this interaction does not affect DNA-binding properties of each partner. Interacts with NONO/p54(nrb) (By similarity). Interacts with RUNX1/AML1. Interacts with GFI1; the interaction represses SPI1 transcriptional activity, hence blocks SPI1-induced macrophage differentiation of myeloid progenitor cells. Interacts with CEBPE. Interacts with IRF4/Pip and IRF8. Interacts with JUN. Interacts with RB1. Interacts with TBP (By similarity).
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 (By similarity). Transcriptionally activates genes important for myeloid and lymphoid lineages, such as CSF1R or FCER1A (PubMed:15304324). 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 (PubMed:15304324). May be particularly important for the pro- to pre-B cell transition. Binds (via the ETS domain) onto the purine-rich DNA core sequence 5'-GAGGAA-3', also known as the PU-box (By similarity). 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 sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A20 subfamily.
Highly expressed in epithelial cells of duodenum, jejunum, ileum, stomach, cecum, colon and kidney proximal tubule. Also expressed in the choroid plexus, microglia and meniges of the brain and in the ovary.
Mediates the Na(+)- and Cl(-)-dependent uptake of imino acids such as L-proline, N-methyl-L-proline and pipecolate as well as N-methylated amino acids (PubMed:15632147). Also transports glycine, regulates proline and glycine homeostasis in the brain playing a role in the modulation of NMDAR currents (By similarity).
Autocatalytically cleaved in response to mitochondrial depolarization both at the N-terminus and C-terminus to generate the short active form (S-OMA1). Autocatalytic processing at the C-terminus takes place at residues 426-435. The S-OMA1 form is unstable (By similarity). Degradaded by YMEL1 in response to membrane depolarization (By similarity). 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 (By similarity).
Metalloprotease that is part of the quality control system in the inner membrane of mitochondria. Activated in response to various mitochondrial stress, leading to the proteolytic cleavage of target proteins, such as OPA1, UQCC3 and DELE1. 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 (By similarity). 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. In depolarized mitochondria, may also act as a backup protease for PINK1 by mediating PINK1 cleavage and promoting its subsequent degradation by the proteasome. May also cleave UQCC3 in response to mitochondrial depolarization. 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 (By similarity). 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. Binds cardiolipin, possibly regulating its protein turnover. 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.
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. 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 (By similarity). 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. Plays a role in the proximal tubule function by regulating its endosomal acidification. May play a role in postnatal kidney development (By similarity).
Expressed in retina specifically at retinal Mueller glial cells (PubMed:27107718). Expressed in adult testis, in the elongated spermatids (ES) and in residual bodies inside Sertoli cells (PubMed:19812234).
Homodimer; disulfide-linked. Homotrimer (By similarity). Can also form homomultimer (By similarity).
The NPC motif is essential for oligomerization and water permeability function.
Belongs to the class IV-like SAM-binding methyltransferase superfamily.
Belongs to the proteasome subunit S14 family.
Belongs to the SLC3A transporter family.
Component of several heterodimeric complexes involved in amino acid transport (PubMed:9480885, PubMed:9726963, PubMed:10391916). The precise substrate specificity depends on the other subunit in the heterodimer (By similarity). The complexes function as amino acid exchangers (PubMed:9480885). The heterodimer functions as sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as tyrosine, L-DOPA, methionine, valine and isoleucine (By similarity). The heterodimer with SLC7A5/LAT1 mediates the uptake of leucine, phenylalanine, tryptophan and histidine (PubMed:9726963, PubMed:10049700, PubMed:12614332). The heterodimer formed by SLC3A2 and SLC7A6 or SLC3A2 and SLC7A7 mediates the uptake of dibasic amino acids (By similarity). The heterodimer with SLC7A5/LAT1 mediates the transport of thyroid hormones diiodothyronine (T2), triiodothyronine (T3) and thyroxine (T4) across the cell membrane (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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 (PubMed:23426681). Together with ICAM1, regulates the transport activity of SLC7A8/LAT2 in polarized intestinal cells by generating and delivering intracellular signals (By similarity). Required for targeting of SLC7A5/LAT1 and SLC7A8/LAT2 to the plasma membrane and for channel activity (By similarity). Plays a role in nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) via transport of L-arginine (By similarity). May mediate blood-to-retina L-leucine transport across the inner blood-retinal barrier (Probable).
Disulfide-linked heterodimer with a non-glycosylated light chain (SLC7A5, SLC7A6, SLCA7A7, SLC7A8, SLC7A10 or SLCA7A11) (Probable) (PubMed:9726963, PubMed:10391916, PubMed:10049700). Interacts with TLCD3A/CT120 and ICAM1. 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. Interacts with LAPTM4B; recruits SLC3A2 and SLC7A5 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation (By similarity).
Expression induced in normal hepatic cells in the presence of actinomycin-D.
In brain expressed on capillary endothelia in cerebral cortex (at protein level) (PubMed:11095508). Highest expression in kidney, jejunum, ileum, colon, placenta, testis and spleen. Lower levels found in liver, lung and brain with weakest expression in heart. Expressed in retina, inner blood-retinal barrier of retina, retinal vascular endothelial cells. Also expressed in C6 glioma cells and in the retinal capillary endothelial cell line TR-iBRB2.
Phosphorylation on Ser-300 and on Ser-421 by ecto-protein kinases favors heterotypic cell-cell interactions.
Binds SLC9A3R1 and SLC9A3R2. Interacts with PDZD3 and interactions decrease in response to elevated calcium ion levels. Interacts with PDZK1 (via C-terminal PDZ domain) (By similarity). Interacts with CHP1, CHP2 and SHANK2 (PubMed:12576672, PubMed:16293618). Interacts with AHCYL1; the interaction is required for SLC9A3 activity (PubMed:20584908).
Most abundant in colon and small intestine, followed by kidney and stomach. In kidney, expressed in proximal tubules and outer medulla (at protein level) (PubMed:20584908).
Phosphorylated by PKA, which inhibits activity (PubMed:9933588). Phosphorylation at Ser-661 by SGK1 is associated with increased abundance at the cell membrane (By similarity).
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:14987998, PubMed:18408734, PubMed:15707587). Regulates the degradation of several proteins including PML and the transcriptional activator PEA3 (PubMed:15707587, PubMed:20943951). Involved in chromosome alignment and spindle assembly, it regulates the kinetochore CENPH-CENPI-CENPK complex by targeting polysumoylated CENPI to proteasomal degradation (By similarity). Regulates the cellular responses to hypoxia and heat shock through degradation of respectively EPAS1 and PARP1 (By similarity). 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:11319220, PubMed:9710597). Catalyzes ubiquitination of sumoylated PARP1 in response to PARP1 trapping to chromatin, leading to PARP1 removal from chromatin by VCP/p97 (By similarity).
Homodimer (via RING-type zinc finger domain) (PubMed:20681948). Interacts with GSC2 (By similarity). Interacts with AR/the androgen receptor and TBP (PubMed:9710597). Interacts with TCF20 (By similarity). Interacts with PATZ1. Interacts with TRPS1; negatively regulates TRPS1 transcriptional repressor activity. 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). Interacts with PRDM1/Blimp-1 (By similarity).
Sumoylated; conjugated by one or two SUMO1 moieties.
The RING-type zinc finger domain is required for the ubiquitination of polysumoylated substrates.
The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate.
Inhibited by N-methyl-D-glucamine (PubMed:10747860). Inhibited by choline (PubMed:10811809, PubMed:10859363, PubMed:11716780). Allosteric regulation of sodium ions binding by pH (PubMed:16629640, PubMed:11756489).
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:10747860, PubMed:10811809, PubMed:10859363, PubMed:11716780, PubMed:12054432, PubMed:11756489, PubMed:16629640, PubMed:27355203, PubMed:18832333, PubMed:18319257, PubMed:19589777, PubMed:18330498, PubMed:21158741). 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 (PubMed:10747860, PubMed:10811809, PubMed:10859363, PubMed:11716780, PubMed:12054432, PubMed:11756489, PubMed:16629640, PubMed:18319257, PubMed:19589777, PubMed:21158741). May function in the transport of amino acids at the blood-brain barrier (PubMed:12021389). 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 (PubMed:18832333). 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.
Up-regulation upon amino acid deprivation results from both increased transcription and protein stabilization (PubMed:11311116, PubMed:17488712, PubMed:18330498). Up-regulated by TGFB1 (PubMed:11716780). Up-regulation by insulin and osmotic shock (PubMed:18330498).
Widely expressed (PubMed:10747860, PubMed:10859363, PubMed:10811809). Expressed in skeletal muscle and adipose tissue (at protein level) (PubMed:15561425, PubMed:11311116). Expressed by glutamatergic and GABAergic neurons together with astrocytes and other non-neuronal cells in the cerebral cortex (at protein level) (PubMed:15561425, PubMed:16616430, PubMed:18832333). Widely expressed in the central nervous systeme where, it is enriched in the spinal cord and the brainstem nuclei, especially those of the auditory system (PubMed:15561425).
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 (By similarity). Binds repolymerizing microtubules (By similarity). Binds unpolymerized tubulins via its WD repeat region (By similarity). 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.
Phosphorylation regulates FOXC2 transcriptional activity by promoting its recruitment to chromatin.
Transcriptional activator. Might be involved in the formation of special mesenchymal tissues (By similarity).
Smooth muscle and mesenchymal cells but not in skeletal muscle or lymphocytes.
Becomes detectable at the second postnatal week in the cerebral cortex and hippocampus and at the third postnatal week in the cerebellum and olfactory bulb. The expression level is maximal during the third and fourth postnatal weeks and remains high during adulthood. Its expression is closely correlated with neuronal differentiation (at protein level).
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 (By similarity).
Highly expressed in brain; neuron-specific (at protein level). Isoform 2, isoform 3 and isoform 4 are predominantly expressed in neuronal tissues and correlate well with the differentiation of neurons, while isoform 1 is strongly expressed in embryonic brain.
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 (By similarity). 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.
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 (By similarity).
Involved in ribosomal large subunit biogenesis. Binds the approximately 50 base pairs internal control region (ICR) of 5S ribosomal RNA genes. It is required for their RNA polymerase III-dependent transcription and may also maintain the transcription of other genes (By similarity). Also binds the transcribed 5S RNA's (By similarity).
It is uncertain whether Met-1 is the initiator. Based on the lack of an in-frame AUG codon, mammalian TFIIIA may be translated from this non-AUG initiation site, which has a good Kozak context and which is well conserved among mammals.
Abundant in hindlimb and cardiac muscles throughout embryogenesis (at protein level).
Interacts with ABCB1, ABCB4 and ABCB11 (PubMed:15159385). Directly associates with HCLS1/HS1, through binding to its N-terminal region (By similarity). Interacts with CTTN (PubMed:15159385). Interacts with PKD2. Interacts with GNA13. Interacts with CASP9. Interacts with ITGB6. Interacts with PLN and ATP2A2; these interactions are inhibited by calcium. Interacts with GRB7. Interacts (via C-terminus) with XIAP/BIRC4 (via BIR 2 domain and BIR 3 domain) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with TPC2. Interacts with KCNC3. Interacts with XPO1 (By similarity). Interacts with RNF217 (By similarity).
Present in striated muscles (at protein level).
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. Slows down the rate of inactivation of KCNC3 channels. 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.
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:9099857) (By similarity). 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. 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 (By similarity).
ATPase activity is enhanced in the presence of homomeric poly(U) RNAs, but not by double-stranded DNA (dsDNA), double-stranded RNA (dsRNA) and tRNA.
Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without dsRNA poly(I:C) ligand stimulation. Interacts (via C-terminus) with TICAM1 (via TIR domain). 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). Interacts with DKC1; this interaction is dependent on the ability of DHX36 to bind to the G4-RNA structure present in TERC. Interacts with PARN; this interaction stimulates PARN to enhance uPA mRNA decay. Interacts with EXOSC3; this interaction occurs in a RNase-insensitive manner. Interacts with EXOSC10; this interaction occurs in a RNase-insensitive manner. Interacts with ILF3; this interaction occurs in a RNA-dependent manner. Interacts with ELAVL1; this interaction occurs in an RNA-dependent manner. Interacts with DDX5; this interaction occurs in a RNA-dependent manner. Interacts with DDX17; this interaction occurs in a RNA-dependent manner. Interacts with HDAC1; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with HDAC3; this interaction occurs in a RNA-dependent manner (By similarity). Interacts with HDAC4 (By similarity). Interacts with AGO1. Interacts with AGO2 (By similarity). Interacts with ERCC6 (By similarity).
Multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures (By similarity). Plays a role in many biological processes such as genomic integrity, gene expression regulations and as a sensor to initiate antiviral responses (PubMed:23651854). 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) (By similarity). Plays a role in genomic integrity. 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 (By similarity). Plays a role in transcriptional regulation. Resolves G4-DNA structures in promoters of genes, such as YY1, KIT/c-kit and ALPL and positively regulates their expression (By similarity). Plays a role in post-transcriptional regulation. 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 (By similarity). Binds to the precursor-microRNA-134 (pre-miR-134) terminal loop and regulates its transport into the synapto-dendritic compartment (PubMed:23651854). Involved in the pre-miR-134-dependent inhibition of target gene expression and the control of dendritic spine size (PubMed:23651854). Plays a role in the regulation of cytoplasmic mRNA translation and mRNA stability. 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. 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. Binds also to ARE sequences present in several mRNAs mediating exosome-mediated 3'-5' mRNA degradation. Involved in cytoplasmic urokinase-type plasminogen activator (uPA) mRNA decay (By similarity). 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. Required for the 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 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 probably 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 (By similarity).
Contains a cryptic mitochondrial transit peptide at positions 1-23. Mutagenesis of Lys-2 to Ala greatly reduces interaction with TOMM22, the outer mitochondrial membrane (OMM) localization and proapoptotic activity. Mutagenesis of Arg-6 to Ala greatly reduces outer mitochondrial membrane (OMM) localization and proapoptotic activity. Combined mutagenesis of Thy-7 and Leu-8 to Ala or Thy-10 and Ile-11 and Phe-12 to Ala or Ile-18 and Leu-19 to Ala strongly impaired mitochondrial localization and proapoptotic activity. Mutagenesis of Arg-13 to Ala does not inhibit OMM localization and proapoptotic activity. Mutagenesis of Cys-3 to Ala or Ser does not inhibit OMM localization and proapoptotic activity. Mutagenesis of Phe-4 to Ala or Thy-7 to Ala or Leu-8 to Ala or Tyr-10 to Ala or Ile-11 to Ala or Phe-12 to Ala weakly impaired mitochondrial localization and proapoptotic activity.
Expressed in the brain. Isoform 1 and isoform 2 are expressed in the forbrain. Isoform 1 is more strongly expressed than isoform 2 in the olfactory bulb. Isoform 1 and isoform 2 are weakly expressed in the cerebellum. Isoform 1 is expressed in the testis. Isoform 2 expression is undetectable at birth rising to adult level at day 14.
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 (via N- and C-terminal regions) (By similarity). Interacts with TOMM22 (PubMed:15923182).
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. Isoform 2 regulates neuronal survival through the mitochondrial fission and fusion balance.
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.
Up-regulated postnatally and in response to neuronal differentiation.
Acetylation at Lys-595 and Lys-598 increases nuclear localization whereas deacetylation by SIRT1 enhances cytoplasmic presence.
Glycation impairs transcription factor activity by preventing heterodimerization with small Maf proteins. Deglycation by FN3K restores activity.
Heterodimer; heterodimerizes with small Maf proteins (PubMed:16314513). Interacts (via the bZIP domain) with MAFG and MAFK; required for binding to antioxidant response elements (AREs) on DNA (PubMed:16314513). Interacts with KEAP1; the interaction is direct and promotes ubiquitination by the BCR(KEAP1) E3 ubiquitin ligase complex (By similarity). Forms a ternary complex with PGAM5 and KEAP1. Interacts with EEF1D at heat shock promoter elements (HSE) (By similarity). Interacts via its leucine-zipper domain with the coiled-coil domain of PMF1 (By similarity). Interacts with CHD6; involved in activation of the transcription (PubMed:16314513). 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 (By similarity).
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:16314513). In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. 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. 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 (By similarity). 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 (By similarity). Also plays an important role in the regulation of the innate immune response. 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. Suppresses macrophage inflammatory response by blocking pro-inflammatory cytokine transcription and the induction of IL6. 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 (By similarity).
Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin ligase complex leading to its degradation. 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. In response to autophagy, the BCR(KEAP1) complex is inactivated.
Expressed in pituitary gland, testis and liver. Isoform 2 is expressed pituitary gland and testis.
Interacts with INHA; the interaction is not confirmed by standard receptor binding assays. 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 (By similarity). Interacts with HECTD1 (By similarity).
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. Necessary to mediate a specific antagonistic effect of inhibin B on activin-stimulated transcription (By similarity).
Differentially expressed in fetal lung with highest levels at gestational days 14 to 16.
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 (By similarity).
Interacts with UBC9, RAN, RBM8A, eIF-1A and PAX6.
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.
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.
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.
Widely expressed. Highly expressed in colon and spleen.
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 chloride channel (TC 2.A.49) family. CLCNKB subfamily.
Expressed predominantly in the kidney. Expressed in all segments of the nephron examined, including the S2 segment and the glomerulus.
Expression is consitently weaker in the absence of BSND protein expression than it is in its presence. The half-life with BSND protein is much longer than that without it. Rapidly degraded without BSND protein, exhibiting a very short half-life of less than 1 hour.
NADH-cytochrome b5 reductases are involved in desaturation and elongation of fatty acids, cholesterol biosynthesis, drug metabolism, and, in erythrocyte, methemoglobin reduction. 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) (By similarity).
High affinity receptor for urotensin-2 and urotensin-2B. The activity of this receptor is mediated by a G-protein that activate a phosphatidylinositol-calcium second messenger system.
Preferentially expressed in neural and sensory tissues.
Detected at 12 dpc and found at markedly increased levels at 15 dpc and 18 dpc in both the head and the body. At birth the level decreases significantly.
Expressed in many regions of the developing nervous system, probably in neurons and their precursors, but also in nonneural tissue such as immature muscle and dermis. In adult, strong expression in the skeletal muscle and moderate expression in the brain, where cerebellum shows the highest expression. Also expressed in almost all areas of the CNS.
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.
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.
Part of a ternary complex containing FUBP2, PTBP1, PTBP2 and HNRPH1. Interacts with PARN. Interacts with PQBP1.
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 (By similarity). Binds to the dendritic targeting element and may play a role in mRNA trafficking.
The exocyst complex is composed of EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC6, EXOC7 and EXOC8 (PubMed:9405631). Interacts with EXOC3L1 (By similarity). Interacts with BIRC6/bruce (By similarity). Interacts with MYRIP (By similarity). Interacts with SLC6A9 (PubMed:16181645).
Widely expressed, with highest levels in kidney, followed by brain (at protein level).
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 central and peripheral neurons.
Interacts with RIC3 (By similarity). Forms pentahomomeric complex as well as pentaheteromeric complex with HTR3B; homomeric complex is functional but exhibits low conductance with modified voltage dependence and antagonist affinity.
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.
Adapter protein that provides a link between the endocytic membrane traffic and the actin assembly machinery. Acts as guanine nucleotide exchange factor (GEF) for CDC42, and thereby stimulates actin nucleation mediated by WASL and the ARP2/3 complex (By similarity). Plays a role in the assembly and maturation of clathrin-coated vesicles (PubMed:20448150). Recruits FCHSD2 to clathrin-coated pits (By similarity). 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 (By similarity). 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 (By similarity). Required for rapid replenishment of release-ready synaptic vesicles at presynaptic active zones (PubMed:23633571). Inhibits ARHGAP31 activity toward RAC1 (By similarity).
Detected in brain, spleen, lung, liver and heart (at protein level). Ubiquitous. Detected in brain, spleen, lung, liver, skeletal muscle and kidney.
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. Interacts (via SH3 domain 1) with WASL (By similarity). Interacts with dynamin, SNAP25 and SNAP23 (PubMed:10373452). 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). Interacts (via SH3 domains) with REPS1 and SGIP1. Interacts with ARHGAP31. Interacts with ADAM15 (By similarity). Interacts with PRRT2 (PubMed:26797119). Interacts (via SH3 domain 4) with FCHSD2 (via SH3 domain 2). Interacts (via SH3 domain 1) with DENND2B (By similarity). Interacts (via SH3 domains) with CBL (By similarity). Isoform 2: Interacts with CBL and DNM1. Isoform 2: Interacts with LMNA. Isoform 2: Interacts with importin subunit KPNA1; this is likely to mediate its import into the nucleus (By similarity).
Plays a role in synaptic vesicle endocytosis in brain neurons.
SH3-1 and SH3-4 bind to ARHGAP31 (By similarity). SH3-3, SH3-4 and SH3-5, but not SH3-1 and SH3-2 domains, bind to dynamin.
The KLERQ domain binds to SNAP-25 and SNAP-23.
Interacts with CDKN2A/p14ARF, p53/TP53 and MDM2. Interacts with CHEK2 and MAPK3. Interacts with XRN2.
Regulates DNA damage response and cell proliferation in a dose-dependent manner through a number of signaling pathways involved in cell proliferation, apoptosis and senescence.
Interacts with EIF4B, IMP8, PRMT5, TNRC6A and TNRC6B. Interacts with ZFP36.
Able to act as transcription factor, cannot regulate the expression of the same subset of genes than isoform 1. Does not have anitapoptotic effect on neuronal cells.
Detected in brain, spinal cord and dorsal root ganglion (PubMed:2739723, PubMed:8835784). Isoform 2 is detected in brain, spinal cord, dorsal root ganglion and spleen (PubMed:8835784).
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 (PubMed:10640682). 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 (PubMed:11053412). 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 (By similarity).
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.
Phosphorylated on tyrosine residues; which may be important for nuclear import.
Antiporter that exchanges vesicular protons for cytosolic 4-aminobutanoate or to a lesser extend glycine, thus allowing their secretion from nerve terminals (By similarity) (PubMed:9349821). The transport is equally dependent on the chemical and electrical components of the proton gradient (PubMed:9349821). May also transport beta-alanine (PubMed:23919636). Acidification of GABAergic synaptic vesicles is a prerequisite for 4-aminobutanoate uptake (By similarity).
Brain (PubMed:9822734, PubMed:9349821). Expressed at high levels within the neocortex, hippocampus, cerebellum, striatum, septal nuclei and the reticular nucleus of the thalamus (PubMed:9349821). Also expressed in islets where it is more abundant in the peripheral/mantle region (PubMed:12031963). Highly expressed in the nerve endings of GABA neurons in the brain and spinal cord but also in glycinergic nerve endings (PubMed:9822734). Expressed in glycine-, GABA- or GABA- and glycine-containing boutons (PubMed:10036231, PubMed:9822734).
Juge et al. shows that SLC32A1 is a symporter of both 4-aminobutanoate or glycine or beta-alanine with Cl(-) that operates according an electrical gradient without the need for a chemical gradient (PubMed:19843525, PubMed:23919636). However Farsi et al. and Egashira et al. confirm that SLC32A1 is an antiporter that exchanges vesicular protons for cytosolic 4-aminobutanoate or glycine and exclude any coupling with chloride (By similarity).
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).
Brain. Predominantly associated with nerve endings and synaptic vesicles.
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:25253725). Interacts with SYT1, SYT5 and SYT7, and with SYT9, forming a complex with SNAP25 (By similarity). Interacts with SYT1 in a phosphorylation-dependent manner (PubMed:11931641).
Palmitoylated. Could be palmitoylated by DHHC3, DHHC7, DHHC15 and DHHC17. Palmitoylation occurs probably in the cysteine-rich domain and regulates DNAJC5 membrane attachment.
Phosphorylated (PubMed:11931641). Phosphorylation results in a profound decrease in the affinity for syntaxin but has no effect on the affinity for HSC70 (PubMed:11604405, PubMed:11931641). Ser-10 phosphorylation induces an order-to-disorder transition triggering the interaction with Lys-58 (By similarity). This conformational switch modulates DNAJC5's cellular functions by reducing binding to syntaxin and synaptogamin without altering HSC70 interactions (By similarity).
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 (By similarity).
Binds to mTORC1 in a guanyl nucleotide-independent manner. Interacts directly with MTOR, MLST8 and RPTOR. Interacts with TSC2 (By similarity). Interacts (when prenylated) with PDE6D; this promotes release from membranes (By similarity).
Expressed at high levels in normal adult cortex as well as a number of peripheral tissues, including lung and intestine.
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.
Involved in neurite outgrowth by regulating cell-cell adhesion via the N-cadherin signaling pathway (PubMed:23615299, PubMed:22531377, PubMed:24071057, PubMed:27822498). May act by regulating expression of protein-coding genes, such as N-cadherins and integrin beta-1 (ITGB1) (PubMed:24071057, PubMed:27822498).
Belongs to the phage and mitochondrial RNA polymerase family.
Adopts an immunoglobulin-like beta-sandwich fold forming a hydrophobic cavity that captures N-terminally myristoylated target peptides. Phe residues within the hydrophobic beta sandwich are required for myristate binding (By similarity).
Begins to be highly expressed around postnatal day 5 in the outer retina when the photoreceptors begin to differentiate and rapidly increases in expression to reach the mature adult level by postnatal day 23.
Interacts with CABP4; in the absence of calcium. May interact with GTP-bound ARL1. Interacts with ARL2 and ARL3 (GTP-bound forms); this promotes the release of myristoylated cargo proteins (By similarity). 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 (By similarity). Interacts with ARL1 and ARL3 GTP-bound forms (By similarity). Interacts with ARL2. Interacts with ARL2.Interacts with LCK; this interaction plays a crucial role in activation of LCK (By similarity). Interacts with FYN (By similarity). Interacts with RAB11A; in a cell cycle-dependent manner (By similarity). Interacts with LYN (via SH2 and SH3 domains); leading to LYN activation (By similarity). Interacts with DNM1; leading to a decrease of DNM1 GTPase activity (By similarity). Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (By similarity). Interacts with CD44 (By similarity). Interacts with KLHL18 (via kelch repeats) (By similarity). 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. Phosphorylated more under light conditions than dark conditions. Dephosphorylated by calcineurin.
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, 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 (By similarity). Interacts with UBC9 (By similarity). Forms a complex with UBC9 and p53/TP53 (By similarity). Interacts with DUS2L (via DRBM domain) (By similarity).
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 (By similarity).
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.
Olfactory epithelium. Mainly found in the sustentacular cells and to a lesser extent in Bowman's gland cells. Also expressed in the olfactory sensory neuron nuclei. Neuronal localization within the olfactory bulb is mainly found in the deeper granular cells.
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. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds. Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (testosterones) and estrogens (estradiol and estriol). Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption. Shows a high affinity to aliphatic odorants such as citronellol as well as olfactory tissue specificity, and therefore may be involved in olfaction.
tRNA nucleus export receptor which facilitates tRNA translocation across the nuclear pore complex.
Component of splicing factor SF3B complex which is composed of at least eight subunits; SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, PHF5A and DDX42. 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 SF3B2. Found in a complex with PRMT9, SF3B2 and SF3B4. The SF3B complex composed of SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6 and PHF5A interacts with U2AF2. Component of the U11/U12 snRNPs that are part of the U12-type spliceosome.
Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex. 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. May also be involved in the assembly of the 'E' complex. SF3B4 has been found in complex 'B' and 'C' as well. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron.
Catalyzes the dephosphorylation and concomitant reactivation of the alpha subunit of the E1 component of the pyruvate dehydrogenase complex.
Heterodimer of a catalytic subunit and a FAD protein of unknown function.
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.
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.
This protein has both trypsin- and chymotrypsin-like activities, being able to release angiotensin II from angiotensin I or angiotensinogen.
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.
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. Interacts with CTNND2; prevents interaction with RHOA (By similarity).
Phosphorylated on tyrosine upon stimulation of cells by laminin.
Homomultimer; homooligomerized following recruitment by CARD domain-containing proteins that form a nucleating helical template that recruits BCL10 via CARD-CARD interaction. Self-associates by CARD-CARD interaction and interacts with other CARD-proteins such as CARD9, CARD10, CARD11 and CARD14. Forms a complex with CARD14 and MALT1; resulting in the formation of a CBM (CARD14-BCL10-MALT1) complex. Forms a complex with CARD11 and MALT1; resulting in the formation of a CBM (CARD11-BCL10-MALT1) complex (By similarity). 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. Binds caspase-9 with its C-terminal domain. Interacts with TRAF2 and BIRC2/c-IAP2 (By similarity). 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. Phosphorylated by IKBKB/IKKB.
Plays a key role in both adaptive and innate immune signaling by bridging CARD domain-containing proteins to immune activation. 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. 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. 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. Activated by CARD9 downstream of C-type lectin receptors; CARD9-mediated signals are essential for antifungal immunity. Activated by CARD11 downstream of T-cell receptor (TCR) and B-cell receptor (BCR). Promotes apoptosis, pro-caspase-9 maturation and activation of NF-kappa-B via NIK and IKK.
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. 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. 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. CARD11 is required for linear ubiquitination by HOIP by promoting the targeting of BCL10 to RNF31/HOIP.
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 (By similarity). Forms a heterodimer with AHRR, as well as with other bHLH proteins. Interacts with NOCA7 (By similarity). 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 (By similarity). 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. 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 (By similarity). 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 (By similarity).
2-oxoglutarate(2OG)-dependent dioxygenase that catalyzes the conversion of 2-oxoglutarate to succinate and CO(2) in an iron-dependent manner. 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. Does not show detectable activity towards fatty acid CoA thioesters.
Belongs to the PhyH family. PHYHD1 subfamily.
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.
Inhibited by mono-unsaturated fatty acids, palmitoleic acid and oleic acid and nonionic detergents, triton X-100 and polyethylene glycol hexadecyl ether (Brij 58).
Mediates the import of long-chain fatty acids (LCFA) by facilitating their transport across cell membranes (By similarity). Also catalyzes the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates (By similarity). Mainly functions as a bile acyl-CoA synthetase catalyzing the activation of bile acids via formation of bile acid CoA thioesters which is necessary for their subsequent conjugation with glycine or taurine (PubMed:12454267, PubMed:12951368). In particular, catalyzes the activation of the primary bile acid, chenodeoxycholic acid (PubMed:12454267, PubMed:12951368). Primary bile acid cholic acid and secondary bile acids (deoxycholic acid and lithocholic acid) are principal substrates too (By similarity). 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 (By similarity). 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).
Predominantly expressed in liver (at protein level).
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 (By similarity). May play a role in spermatogenesis or folliculogenesis (By similarity).
Homodimer. Interacts with E2F1 and with histone H4 acetylated at 'Lys-13' (By similarity).
One bromodomain is sufficient for a partial interaction with histone H4 acetylated at 'Lys-13'.
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). 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. 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.
Homooligomer; homooligomerizes following phosphorylation at Thr-9. Interacts with IRAK1, TRAF2 and TRAF6. Interacts with TIFAB; binding to TIFAB inhibits TRAF6 activation, possibly by inducing a conformational change in TIFA. Interacts with ZCCHC11; binding to ZCCHC11 suppresses the TRAF6-dependent activation of NF-kappa-B.
Phosphorylated at Thr-9 following detection of ADP-D-glycero-beta-D-manno-heptose (ADP-Heptose) by ALPK1. 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.
The FHA domain recognizes and binds phosphorylated Thr-9, promoting homooligomerization and subsequent activation of NF-kappa-B.
ATP-dependent RNA helicase. Involved in pre-mRNA splicing as component of the spliceosome. 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). 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; the function is different from the established EJC assembly. Involved in craniofacial development.
Expressed in the CA1 field and dentate gyrus of the hippocampus (at protein level).
Identified in the spliceosome C complex. Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A. Interacts with CASC3, MAGOH, NXF1, RBM8A and ALYREF/THOC4. May interact with NOM1. Interacts with POLDIP3. Interacts with CWC22 and PRPF19 in an RNA-independent manner. Direct interaction with CWC22 is mediated by the helicase C-terminal domain. 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). Interacts with NCBP3 (By similarity). Interacts with NRDE2 (By similarity). Interacts with DHX34; the interaction is RNA-independent (By similarity).
The ATPase activity is increased some 4-fold in the presence of RNA.
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.
Component of the endosomal sorting complex required for transport II (ESCRT-II).
Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity.
Specifically expressed in brain. Not expressed in peripheral tissues such as heart, lung, liver, spleen, kidney and skeletal muscle. In brain, it is restricted to subsets of neurons such as Purkinje cells of the cerebellum, granule cells of the dentate gyrus, and neurons in the superficial layers of the cerebral cortex.
Weakly or not expressed from 12 dpc to 20 dpc. Expressed at much higher level from postnatal day 2, reaching a maximum level in adult brain.
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. May play a role in the processing of autolysosomes.
Expressed in testis, epididymis, lung and brain.
Methionine-sulfoxide reductase that specifically reduces methionine (R)-sulfoxide back to methionine. While in many cases, methionine oxidation is the result of random oxidation following oxidative stress, methionine oxidation is also a post-translational modification that takes place on specific residue. Upon oxidative stress, may play a role in the preservation of mitochondrial integrity by decreasing the intracellular reactive oxygen species build-up through its scavenging role, hence contributing to cell survival and protein maintenance.
Binding of cGMP results in enzyme activation.
Crucial regulator of intestinal secretion and bone growth (By similarity). Phosphorylates and activates CFTR on the plasma membrane (PubMed:9465038). Plays a key role in intestinal secretion by regulating cGMP-dependent translocation of CFTR in jejunum (Probable). 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 (PubMed:18031684). 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 expressed in intestinal mucosa and is 20 times less abundant in brain and kidney (PubMed:7937783). Expressed in jejunum, in the apical domain of the villus epithelium (PubMed:15872007).
Myristoylation mediates membrane localization.
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. Interacts with ZNF8.
Phosphorylated on serine by BMP (bone morphogenetic proteins) type 1 receptor kinase.
Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD5 is a receptor-regulated SMAD (R-SMAD) (By similarity).
Ubiquitin-mediated proteolysis by SMAD-specific E3 ubiquitin ligase SMURF1.
Expression restricted to late round spermatids and elongating spermatids but not detected in late elongate spermatids and Sertoli cells (at protein level).
Palmitoylated on Cys-331, Cys-332, Cys-343 and Cys-348; which plays an important role in plasma membrane localization.
Sphingomyelin synthase that primarily contributes to sphingomyelin synthesis and homeostasis at the plasma membrane. Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction appears to depend on the levels of CER and DAG in the plasma membrane (By similarity). Does not use free phosphorylcholine or CDP-choline as donors (By similarity). Can also transfer phosphoethanolamine head group of phosphatidylethanolamine (PE) on to ceramide (CER) to form ceramide phosphoethanolamine (CPE) (By similarity). 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 (By similarity). To a lesser extent, plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1 (PubMed:21980337). Required for normal bone matrix mineralization (By similarity).
At 18 dpc and P1 expressed predominantly in thymus and liver, and at lower levels in brain, muscle and kidney.
Detected specifically in spleen, thymus, lungs, and bone marrow.
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) (By similarity).
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 (By similarity). Interacts with CKAP5 and TACC3 forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges; the complex implicates clathrin triskelions (By similarity).
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 (By similarity).
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. 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). 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. Additional evidence is however required to confirm these data.
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. 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). 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. Additional evidences are 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 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. The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin. The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs).
Does not appear to contribute to radiation susceptibility in the LEC strain.
Homodimer; disulfide-linked (By similarity). Interacts with FBN1 (via N-terminal domain) and FBN2. Interacts with ENG (By similarity).
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.
Belongs to the HpcH/HpaI aldolase family. Citrate lyase beta subunit-like subfamily.
Mitochondrial citramalyl-CoA lyase indirectly involved in the vitamin B12 metabolism. Converts citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway. The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, a vitamin B12-poisoning metabolite. Also acts as a malate synthase in vitro, converting glyoxylate and acetyl-CoA to malate. Also displays malyl-CoA thioesterase activity. Also acts as a beta-methylmalate synthase in vitro, by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate. Also has very weak citramalate synthase activity in vitro.
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.
Component of the signal peptidase complex.
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 (By similarity). Binding of ceramide promotes the Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway (By similarity).
Highly expressed in heart, kidney, brain and ascitic tumor with very low levels in liver. Expressed in the head region of epididymal sperm.
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).
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 (By similarity).
Inhibited by CGP57380 and staurosporine.
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/ER2K. Interaction with phosphorylated MAPK3/ERK1 and MAPK1/ER2K protects it from dephosphorylation and inactivation. Interacts with ESR2 and EIF4E in the nucleus (By similarity).
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. Enhances the formation of EIF4F complex in pachytene spermatocytes, thus promoting mRNA translation during spermatogenesis. Displays a high basal 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 (By similarity).
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 (By similarity).
Forms a homodimer or heterodimer with other members of the family. Interacts with MAL2 (By similarity).
Homodimers. Homooligomer. Interacts with UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to form heterodimers.
Induced in 3-methylcholanthrene-treated rats.
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:8554318). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:8554318). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (By similarity). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (By similarity). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (By similarity). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (By similarity). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (By similarity).
Autoubiquitinates upon viral infection. In turn, autoubiquitinated TRIM26 recruits NEMO and bridges TBK1-NEMO interaction.
E3 ubiquitin-protein ligase which regulates the IFN-beta production and antiviral response downstream of various DNA-encoded pattern-recognition receptors (PRRs). Promotes nuclear IRF3 ubiquitination and proteasomal degradation. Bridges together TBK1 and NEMO during the innate response to viral infection leading to the activation of TBK1.
Interacts with TBK1; this interaction bridges together TBK1 and NEMO in order to activate TBK1. Interacts with INCA1.
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.
Acts as a ligand for C-C chemokine receptor CCR2 (By similarity). Signals through binding and activation of CCR2 and induces a strong chemotactic response and mobilization of intracellular calcium ions (By similarity). Exhibits a chemotactic activity for monocytes and basophils but not neutrophils or eosinophils (By similarity). Plays an important role in mediating peripheral nerve injury-induced neuropathic pain (By similarity). Increases NMDA-mediated synaptic transmission in both dopamine D1 and D2 receptor-containing neurons, which may be caused by MAPK/ERK-dependent phosphorylation of GRIN2B/NMDAR2B (By similarity).
In pancreatic islets, secretion is stimulated by IL1B (PubMed:23955712). In islets from Zucker diabetic fatty (ZDF) rats, but not lean animals, secretion is also increased by endocannabinoid anandamide/AEA (PubMed:23955712).
Monomer or homodimer; in equilibrium. Is tethered on endothelial cells by glycosaminoglycan (GAG) side chains of proteoglycans. Interacts with TNFAIP6 (via Link domain).
Processing at the N-terminus can regulate receptor and target cell selectivity (By similarity). Deletion of the N-terminal residue converts it from an activator of basophil to an eosinophil chemoattractant (By similarity).
Isoform GRK4A is expressed in testis. Isoform GRK4B is heterogeneously distributed in the kidney, with 20-fold enrichment in the outer medulla. Has a widespread but low level of expression in tissues other than testis.
Specifically phosphorylates the activated forms of G protein-coupled receptors. Plays an important role in the regulation of renal sodium handling and blood pressure.
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 HSP60/HSPD1. Forms heterooligomers with ATAD3B; this interaction may affect ATAD3A activity (By similarity). 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 (PubMed:20351179). Interacts with CLPB (By similarity).
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.
The transmembrane domain and a C-terminal adjacent region contain all information necessary for mitochondrial targeting.
Up-regulated during oligodendrocyte progenitor cell differentiation.
G-protein coupled receptor activated by glutamate that regulates axon outgrowth through the MAPK-cAMP-PKA signaling pathway during neuronal development (By similarity). 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.
Homodimer (By similarity). Interacts with PICK1.
Widely distributed throughout the brain.
G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Binds SLC9A3R1. Forms a complex with PECAM1 and BDKRB2. Interacts with PECAM1 (By similarity). Interacts with GAS2L2 (By similarity).
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Required for platelet activation. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro) (By similarity). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs) (By similarity). Together with GNA11, required for heart development (By similarity).
Histaminylated at Gln-209 residues by TGM2.
Palmitoylated by ZDHHC3 and ZDHHC7. Palmitoylation occurs in the Golgi and participates in the localization of GNAQ to the plasma membrane.
May play a role in axonemal outer row dynein assembly.
In neural tissues in embryos, and in adult brain, spinal cord and cerebellum.
May play a role in the initial growth and guidance of axons. May be involved in cell adhesion. 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 (By similarity).
Transiently expressed on a subset of axons in the developing rat nervous system.
Expressed at high levels in kidney, liver, lung, brain, and testis and at low levels in heart, spleen and skeletal muscle.
Homodimer (By similarity). Heterodimer with PEX11G (By similarity). Probably interacts with COPB2 and COPA (PubMed:9548716). Interacts with PEX19 (By similarity). Interacts with FIS1 (By similarity).
Induced by clofibrate and di(2-ethylhexyl)phtalate (DEHP).
May be involved in peroxisomal proliferation and may regulate peroxisomes division. May mediate binding of coatomer proteins to the peroxisomal membrane (PubMed:9548716). Promotes membrane protrusion and elongation on the peroxisomal surface.
Heterodimer with RABGEF1. The dimer binds RAB5A that has been activated by GTP-binding. Interacts with SDCCAG8; this interaction is important for ciliogenesis regulation. Interacts with RAB4A; this interaction may mediate VEGFR2 cell surface expression.
Plays a role in membrane trafficking and in homotypic early endosome fusion. Participates in arteriogenesis by regulating vascular endothelial growth factor receptor 2/VEGFR2 cell surface expression and endosomal trafficking. By interacting with SDCCAG8, localizes to centrosomes and plays a critical role in ciliogenesis.
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. Behaves as a kinesin cargo, providing a functional binding site for kinesin-1 at the nuclear envelope. Hence may contribute to the establishment of secretory epithelial morphology, by promoting kinesin-dependent apical migration of the centrosome and Golgi apparatus and basal localization of the nucleus (By similarity).
Core component of LINC complexes which are composed of inner nuclear membrane SUN domain-containing proteins coupled to outer nuclear membrane KASH domain-containing nesprins. SUN and KASH domain-containing proteins seem to bind each other promiscuously; however, differentially expression of LINC complex constituents can give rise to specific assemblies. Probably part of a SUN1-containing LINC complex. Interacts with kinesins KIF5B and KLC1 (By similarity).
The KASH domain, which contains a transmembrane domain, mediates the nuclear envelope targeting and is involved in the binding to SUN1 and SUN2 through recognition of their SUN domains.
By transforming growth factor beta-1 and other growth factors.
Fairly ubiquitous, slightly higher in bone.
Homodimer or heterodimer. Can form a heterodimer with TSC22D4 (By similarity).
Transcriptional repressor. Acts on the C-type natriuretic peptide (CNP) promoter.
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.
Homodimer. Interacts with MDM4 (phosphorylated); negatively regulates MDM4 activity toward TP53. Interacts with RAF1, SSH1 and CRTC2/TORC2. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with GAB2, SAMSN1 and SIRT2 (By similarity). Interacts with PKA-phosphorylated AANAT. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (By similarity). Interacts with SLITRK1 (By similarity). Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation (By similarity). Interacts with MARK2 and MARK3 (By similarity). Interacts with MEFV (By similarity). Interacts with ENDOG, TSC2 and PIK3C3; interaction with ENDOG weakens its interaction with TSC2 and PIK3C3 (By similarity). Interacts with TH (phosphorylated form); one YWHAG dimer bounds to one TH tetramer, this interaction may influence the phosphorylation and dephosphorylation of TH (By similarity).
Localized in neurons, and axonally transported to the nerve terminals. May be also present, at lower levels, in various other tissues.
Activated following N-terminal proteolytic cleavage by thrombin and/or proteases.
Mainly expressed in the central nervous system cholinergic neurons. Expressed (at protein level) in motor regions of the spinal cord and rhombencephalon, in mesopontine cholinergic neurons, the medial habenula, cholinergic areas of the forebrain, and the gut myenteric plexus.
By ethoxyquin, oltipraz, butylated hydroxyanisole, and phenobarbitol.
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Has substantial activity toward aflatoxin B1-8,9-epoxide.
Liver from adult female rats contains about 10-fold greater levels of YC2 than is found in liver from adult male rats.
May play an important regulatory role in corticotrophs.
Pituitary, hypothalamus and pancreas (PubMed:8132649). Found in alpha, beta and delta cells in the pancreatic islets (PubMed:17951542).
Belongs to the universal ribosomal protein uS19 family.
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 (By similarity).
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. Interacts with ZDHHC17 (By similarity).
Phosphorylated by PKA; phosphorylation abolishes binding to SH3 domains of ABL and SRC.
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.
Expressed in stem and progenitor cells in the subventricular zone of the hippocampus (at protein level) (PubMed:16554442). Detected throughout the hippocampus (PubMed:12205668). Detected in astrocytes, ependymal cells and in the anterior subventricular zone. Detected in proliferating cells (PubMed:12205668).
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.
Up-regulated in the CA1 region of the hippocampus after ischemia.
Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts with ATF2, MAP3K2 and MAPK8. Interacts with GTP-bound HRAS and KRAS. Interacts with IFNAR2, NBN and SGK1. Interacts with CCDC28B (By similarity).
Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-421'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex (By similarity).
Converts protoheme IX and farnesyl diphosphate to heme O.
Component of the nexin-dynein regulatory complex (N-DRC) a key regulator of ciliary/flagellar motility which maintains the alignment and integrity of the distal axoneme and regulates microtubule sliding in motile axonemes.
Component of the nexin-dynein regulatory complex (N-DRC). Interacts with TCTE1/DRC5 (By similarity). Interacts with DRC7 (By similarity).
Expressed in the peripheral nervous system.
Forms both disulfide-linked homodimers and higher homooligomers as well as heterooligomers with other members of the tetraspanin family. Interacts (via the second extracellular domain) with integrin ITGAV:ITGB3 (By similarity). Interacts with integrin ITGA6:ITGB1; interaction takes place in oocytes and is involved in sperm-egg fusion (By similarity). Part of integrin-tetraspanin complexes composed of CD81, beta-1 and beta-2 integrins in the membrane of monocyte/macrophages (By similarity). Interacts with CD63; identified in a complex with CD63 and ITGB3. Associates with CR2/CD21 and with PTGFRN/CD9P1. Part of a complex composed of CD9, CD81, PTGFRN and IGSF8 (By similarity). Interacts directly with IGSF8. Interacts with PDPN; this interaction is homophilic and attenuates platelet aggregation and pulmonary metastasis induced by PDPN. Interacts (on T cell side) with CD81 at immunological synapses between antigen-presenting cells and T cells (By similarity).
Integral membrane protein associated with integrins, which regulates different processes, such as sperm-egg fusion, platelet activation and aggregation, and cell adhesion (By similarity). Present at the cell surface of oocytes and plays a key role in sperm-egg fusion, possibly by organizing multiprotein complexes and the morphology of the membrane required for the fusion (By similarity). In myoblasts, associates with CD81 and PTGFRN and inhibits myotube fusion during muscle regeneration (By similarity). In macrophages, associates with CD81 and beta-1 and beta-2 integrins, and prevents macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles (By similarity). Also prevents the fusion between mononuclear cell progenitors into osteoclasts in charge of bone resorption (By similarity). Acts as a receptor for PSG17 (By similarity). Involved in platelet activation and aggregation (By similarity). Regulates paranodal junction formation (By similarity). Involved in cell adhesion, cell motility and tumor metastasis (By similarity).
Palmitoylated at a low, basal level in unstimulated platelets. The level of palmitoylation increases when platelets are activated by thrombin (in vitro). The protein exists in three forms with molecular masses between 22 and 27 kDa, and is known to carry covalently linked fatty acids. Palmitoylation by ZDHHC2 regulates CD9 expression, association with other tetraspanin family proteins and function in cell adhesion.
Expressed in Leydig cells of the testis, and weakly in the theca interna cells of antral follicles and the corpus luteum of the ovary.
Highly expressed in adult testis and low expression in the ovary. Highly up-regulated in testes of day 19 embryos, but not in later neonatal stages, nor any ovarian tissue from this period.
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 (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. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds. Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol, estriol,catechol estrogens). Also regulates the levels of retinoic acid, a major metabolite of vitamin A involved in apoptosis, cellular growth and differentiation, and embryonic development. Contributes to bile acid (BA) detoxification by catalyzing the glucuronidation of BA substrates, which are natural detergents for dietary lipids absorption. Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, caderastan and zolarsatan, drugs which can inhibit the effect of angiotensin II. Also metabolizes mycophenolate, an immunosuppressive agent.
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 (By similarity). Interacts with CUL3; interaction is direct and forms a 5:5 heterodecamer (By similarity). Interacts (via PXXXPR motifs) with SH3KBP1 (via SH3 domains) (PubMed:11152963). Directly interacts with cathepsin B/CTSB (By similarity).
Expressed in the liver, but not detected in the adrenal gland (at protein level) (PubMed:28267642). Restricted expression in adrenal gland, kidney, liver, brain and lungs (PubMed:1312497). Strong expression in heart and muscles (PubMed:1312497).
Homodimer (By similarity). Heterodimer with a RAR molecule (By similarity). Binds DNA preferentially as a RAR/RXR heterodimer (By similarity). Interacts with RARA (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) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid (By similarity).
Involved in the biosynthesis of gangliosides GM2, GD2, GT2 and GA2 from GM3, GD3, GT3 and GA3, respectively.
Strongly expressed in brain, testis, spleen, and to a lesser extent in liver.
By sleep deprivation in the brain stem and in the hypothalamus.
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. 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. In addition, acts in complex with the Ca(2+)-binding protein S100A4 as a chemoattractant able to induce lymphocyte movement. Mechanistically, this complex acts as a ligand of the chemotactic receptors CCR5 and CXCR3 which are present on the cells of the immune system. 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. Induction of cytotoxicity on monocyte surface requires interaction with TREM1 receptor.
Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM2 sub-subfamily.
Interacts with ARRB1 and ARRB2. Interacts with RACK1; the interaction regulates CHRM2 internalization (By similarity).
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. 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 (By similarity).
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.
Could act as a modulator of transcription.
NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) (By similarity). 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:11524419) (By similarity). 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 (By similarity). Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site (By similarity). Plays 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:11524419). Inactivates 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles (PubMed:11524419).
Called DUO because the encoded protein is closely related to but shorter than TRIO.
Highly expressed in the brain and nervous system. Isoform 6 is highly enriched in the postsynaptic density fraction of the cerebral cortex.
Interacts with the C-terminal of peptidylglycine alpha-amidating monooxygenase (PAM) and with the huntingtin-associated protein 1 (HAP1). Interacts with FASLG (By similarity).
Isoforms 1 and 7 are prevelant 2 dpp, isoform 6 is not detectable until 2 weeks after birth.
Produced by alternative initiation at Met-624 of isoform 6.
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. Isoforms 1 and 7 are necessary for neuronal development and axonal outgrowth. Isoform 6 is required for dendritic spine formation.
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.
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 (By similarity).
Predominantly expressed in testis and prostate. Found predominantly in non-germinal Sertoli cells.
TFIIA is a heterodimer of the large unprocessed subunit 1 and a small subunit gamma. It was originally believed to be a heterotrimer of an alpha (p35), a beta (p19) and a gamma subunit (p12). Interacts with NCOA6 general coactivator. TFIIA forms a complex with TBP. Interacts with HSF1 (via transactivation domain). Interacts with HSF1 (via transactivation domain). Interacts with HSF1 (via transactivation domain).
Phosphorylated by MELK, leading to inhibit its pro-apoptotic function.
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. Interacts with TAF13 both in vitro and intracellularly; also interacts directly with TBP.
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. 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). 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. TAF11, together with TAF13 and TBP, play key roles during promoter binding by the TFIID and TFIIA transcription factor complexes.
Belongs to the eukaryotic ribosomal protein eS25 family.
Expressed at a high level in the heart and at a much lower level in the brain.
G proteins are composed of 3 units, alpha, beta and gamma. Interacts with RASD2 (By similarity).
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 (By similarity).
Forms a homo/heterooligomeric complex with EXT2. Interacts with NDST1.
Belongs to the eukaryotic/archaeal RNase P protein component 1 family.
Component of nuclear RNase P and RNase MRP ribonucleoproteins. RNase P consists of a catalytic RNA moiety and 10 different protein chains; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40. 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. 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.
Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends.
Interacts with the IFT B complex components IFT27, IFT46, IFT74, IFT52, IFT57, IFT80, IFT81 and IFT88 (By similarity). Interacts with KIF17 (By similarity).
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. Activation of NLRP3 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. 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 (By similarity). 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 (By similarity). 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).
Intramolecular interactions between NACHT and leucine-rich repeat (LRR) domains may be important for autoinhibition in the absence of activating signal.
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. NLRP3 localizes at the end of each PYCARD filament. 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. 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. 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. Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation. Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents. Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli. 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 (By similarity). 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). Interacts with PYDC5 (By similarity). 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). Interacts with CARD8; leading to inhibit formation of the NLRP3 inflammasome (By similarity). 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).
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. 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. Activation in presence of cytosolic dsRNA is mediated by DHX33.
Auto-methylated on Arg-551. Methylation enhances transcription coactivator activity. Methylation is required for its role in the regulation of pre-mRNA alternative splicing (By similarity).
Homodimer (PubMed:17882262). Interacts with NR1H4 (By similarity). Interacts with SNRPC (PubMed:15944154). Interacts with the C-terminus of NCOA2/GRIP1, NCO3/ACTR and NCOA1/SRC1. Part of a complex consisting of CARM1, EP300/P300 and NCOA2/GRIP1. Interacts with FLII, TP53, myogenic factor MEF2, EP300/P300, TRIM24, CREBBP and CTNNB1. Interacts with RELA. Identified in a complex containing CARM1, TRIM24 and NCOA2/GRIP1. Interacts with NCOA3/SRC3. Interacts with SKP2. Interacts (via PH domain-like fold) with C9orf72 (By similarity). Interacts with PARP1; promoting PARP1 recruimtent to replication forks (By similarity).
Isoform 1 is expressed at low levels in brain, liver and testis.
Isoform 2 is highly expressed in brain, liver, skeletal muscle and testis.
Isoform 3 is highly expressed in spleen, liver and kidney.
Isoform 3 specifically affects pre-mRNA splicing (PubMed:15944154). This activity is independent from methyltransferase activity (PubMed:15944154).
Isoform 4 is expressed in spleen, liver and kidney.
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:16508003). 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 (By similarity). 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 (By similarity). 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 (PubMed:16508003). 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 (By similarity).
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.
Phosphorylation at Ser-217 interferes with S-adenosyl-L-methionine binding and strongly reduces methyltransferase activity. Phosphorylation at Ser-217 is strongly increased during mitosis, and decreases rapidly to a very low, basal level after entry into the G1 phase of the cell cycle. Phosphorylation at Ser-217 may promote location in the cytosol (By similarity).
Associates with IL12B to form the pro-inflammatory cytokine IL-23 that plays different roles in innate and adaptive immunity. 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. 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. In turn, participates in the early and effective intracellular bacterial clearance. 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.
Heterodimer with IL12B; disulfide-linked. The heterodimer is known as interleukin IL-23. Interacts with IL23R; this interaction enables recruitment of IL12RB1.
Tachykinins are active peptides which excite neurons, evoke behavioral responses, are potent vasodilators and secretagogues, and contract (directly or indirectly) many smooth muscles. Is a critical central regulator of gonadal function (By similarity).
Component of the CIA complex. Interacts with CIAO2A and forms a complex with CIAO2B and MMS19; the interactions with CIAO2A and CIAO2B are mutually exclusive. Interacts with CHD1L, ERCC2, IREB2 and POLD1. Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5. Interacts with WT1. Interacts with CIAO3. Interacts (via LYR motif) with HSC20.
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 (By similarity). 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 (By similarity). Seems to specifically modulate the transactivation activity of WT1. As part of the mitotic spindle-associated MMXD complex it may play a role in chromosome segregation (By similarity).
Activated by chloride and fluoride, but not bromide. Inhibited by MLN-4760, cFP_Leu, and EDTA, but not by the ACE inhibitors linosipril, captopril, enalaprilat.
Down-regulated in hypertensive animals. Up-regulated after myocardial infarction.
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. 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. Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin. Also cleaves other biological peptides, such as apelins, casomorphins and dynorphin A. Plays an important role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 in intestine, regulating trafficking, expression on the cell surface, and its catalytic activity.
Expressed in heart, kidney and forebrain. In testis, expression is restricted to Leydig cells. In heart, expressed in endothelial cells from small and large arteries, arterial smooth muscle cells, and myocytes (at protein level). Ubiquitously expressed, with highest levels in ileum, bladder and lung.
Homodimer. Interacts with the catalytically active form of TMPRSS2 (By similarity). Interacts with SLC6A19; this interaction is essential for expression and function of SLC6A19 in intestine (By similarity). Interacts with ITGA5:ITGB1 (By similarity). Probably interacts (via endocytic sorting signal motif) with AP2M1; the interaction is inhibited by phosphorylation of Tyr-781 (By similarity). Interacts (via PDZ-binding motif) with SLC9A3R1 (via PDZ domains); the interaction may enhance ACE2 membrane residence (By similarity).
In contrast to its human and palm-civet orthologs, does not interact with SARS-CoV spike glycoprotein.
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. Also cleaved by serine proteases: TMPRSS2, TMPRSS11D and HPN/TMPRSS1 (By similarity).
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.
Catalyzes the oxidative ring opening of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinate.
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.
Present at high level in duodenum and small intestine (at protein level).
Expressed in liver, kidney, heart, lung and retina. Widely distributed in all brain regions.
Mediates the transport of organic anions such as taurocholate, the prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), leukotriene C4 and thromboxane B2 (PubMed:10973807). Most likely contributes to the absorption and disposition of a wide range of drugs in the intestine and the liver (PubMed:34628357). In contrast with human ortholog, not able to transport steroid sulfate conjugates estrone 3-sulfate (E1S), dehydroepiandrosterone sulfate (DHEA-S) and pregnenolone sulfate (PregS) (PubMed:34628357).
Converts big endothelin-1 to endothelin-1.
Catalyzes calcium-induced ATP-independent rapid bidirectional and non-specific distribution of phospholipids (lipid scrambling or lipid flip-flop) between the inner and outer leaflet of the plasma membrane resulting in collapse of the phospholipid asymmetry which leads to phosphatidylserine externalization on the cell surface (By similarity). Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with TRPC5 (By similarity). Also exhibits magnesium-dependent nuclease activity against double-stranded DNA and RNA but not single-stranded DNA and can enhance DNA decatenation mediated by TOP2A (By similarity). Negatively regulates FcR-mediated phagocytosis in differentiated macrophages (By similarity). May contribute to cytokine-regulated cell proliferation and differentiation (By similarity).
Forms homooligomers in the presence of calcium (By similarity). Interacts with ABL (By similarity). Interacts with RELT, RELL1 and RELL2 (By similarity). Interacts with OXSR1 in the presence of RELT (By similarity). Interacts with OCLN, TOP2A and TOP2B (By similarity). Interacts with TRPC1, TRPC4 and TRPC5 (By similarity).
Magnesium. Can also use zinc with lower efficiency.
Palmitoylation is required for its phospholipid scramblase activity (By similarity). 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 (By similarity).
Phosphorylated on tyrosine residues (PubMed:11259432). Phosphorylated by OXSR1 in the presence of RELT (By similarity). Phosphorylation at Thr-178 by PKC/PKCD increases its phospholipid scramblase activity during both cell stimulation and apoptosis (By similarity).
The N-terminal proline-rich domain (PRD) is required for phospholipid scramblase activity.
The transmembrane domain is essential for membrane insertion, phospholipid scramblase activity and proper calcium-binding.
Catalyzes the oxidation of sulfhydryl groups in peptide and protein thiols to disulfides with the reduction of oxygen to hydrogen peroxide.
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 the C-terminus of PSEN2 and probably PSEN1 (By similarity). Interacts with KCND2 and KCND3 (By similarity).
Expressed in brain. Colocalizes with KCND2 in excitatory neurons including cortical and hippocampal CA1 pyramidal cells.
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.
The KIS (K-channel inactivation suppressor) domain is required for converting A-type Kv4 current to a slowly inactivating delayed rectifier potassium current.
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. May have a role in nuclear energy homeostasis. Has also ATPase activity. May be involved in regulation of Cajal body (CB) formation.
Monomer and homodimer. Interacts with COIL (via C-terminus).
Activity is increased following LPS stimulation and down-regulated by the anti-inflammatory glucocorticoid dexamethasone.
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:10869354, PubMed:11067848). 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. In addition, displays low glutathione transferase and glutathione-dependent peroxidase activities, toward 1-chloro-2,4-dinitrobenzene and 5-hydroperoxyicosatetraenoic acid (5-HPETE), respectively (By similarity).
Up-regulated after treatment with LPS or in a rat model of adjuvant-induced arthritis (PubMed:10869354, PubMed:11067848). Down-regulated by the anti-inflammatory glucocorticoid dexamethasone (PubMed:10869354).
Belongs to the class IV-like SAM-binding methyltransferase superfamily. RNA methyltransferase NEP1 family.
Expressed in the brain at 16 dpc, 18 dpc, P2, P8 and P90.
Expression is increased by cocaine, selectively in the nucleus accumbens. mRNA is present at increased levels in the nucleus accumbens 3 weeks after withdrawal from cocaine self-administration.
Functions as a transcriptional repressor. Isoform 1 is a stronger transcriptional repressor than isoform 2. 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.
Highly expressed in the hippocampus, brain cortex, cerebellum and brainstem. Expressed in the nucleus accumbens, olfactory tubercle, the striatum, frontal and parietal cortex and ventral pallidum. Weakly expressed in the heart, liver, kidney, spleen, testis, and skeletal muscle. Isoform 2 is expressed in the brain and liver, less abundantly expressed in the brain than isoform 1.
Homooligomer; mediated by the BTB domain (By similarity). Both isoforms interact with HDAC3 and HDAC4. Interacts (via BTB domain) with CUL3, PSMD7 and RCOR1.
Phosphorylated by protein kinase C (PKC).
Cleaved by a 20S proteasomal protease in response to agents that damage DNA. Cleavage takes place in the absence of ubiquitination and ATP. The resulting N-terminal fragment accumulates in the nucleus (By similarity).
DNA- and RNA-binding protein involved in various processes, such as translational repression, RNA stabilization, mRNA splicing, DNA repair and transcription regulation. Predominantly acts as a RNA-binding protein: binds preferentially to the 5'-[CU]CUGCG-3' RNA motif and specifically recognizes mRNA transcripts modified by C5-methylcytosine (m5C). Promotes mRNA stabilization: acts by binding to m5C-containing mRNAs and recruiting the mRNA stability maintainer ELAVL1, thereby preventing mRNA decay. Component of the CRD-mediated complex that promotes MYC mRNA stability (By similarity). Contributes to the regulation of translation by modulating the interaction between the mRNA and eukaryotic initiation factors (By similarity). Plays a key role in RNA composition of extracellular exosomes by defining the sorting of small non-coding RNAs, such as tRNAs, Y RNAs, Vault RNAs and miRNAs. Probably sorts RNAs in exosomes by recognizing and binding C5-methylcytosine (m5C)-containing RNAs. Acts as a key effector of epidermal progenitors by preventing epidermal progenitor senescence: acts by regulating the translation of a senescence-associated subset of cytokine mRNAs, possibly by binding to m5C-containing mRNAs. Also involved in pre-mRNA alternative splicing regulation: binds to splice sites in pre-mRNA and regulates splice site selection. Also able to bind DNA: regulates transcription of the multidrug resistance gene MDR1 is enhanced in presence of the APEX1 acetylated form at 'Lys-6' and 'Lys-7'. Binds to promoters that contain a Y-box (5'-CTGATTGGCCAA-3'), such as MDR1 and HLA class II genes. Promotes separation of DNA strands that contain mismatches or are modified by cisplatin. Has endonucleolytic activity and can introduce nicks or breaks into double-stranded DNA, suggesting a role in DNA repair. The secreted form acts as an extracellular mitogen and stimulates cell migration and proliferation (By similarity).
Homodimer in the presence of ATP. Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Component of the U11/U12 snRNPs that are part of the U12-type spliceosome (By similarity). Identified in a histone pre-mRNA complex, at least composed of ERI1, LSM11, SLBP, SNRPB, SYNCRIP and YBX1 (By similarity). Interacts with IGF2BP1 and RBBP6. Component of cytoplasmic messenger ribonucleoprotein particles (mRNPs). Interacts with AKT1, MBNL1, SFRS9, SFRS12, ALYREF/THOC4, MSH2, XRCC5, WRN and NCL. Interacts (via C-terminus) with APEX1 (via N-terminus); the interaction is increased with APEX1 acetylated at 'Lys-6' and 'Lys-7'. Interacts with AGO1 and AGO2. Interacts with ANKRD2. Interacts with DERA (By similarity). Interacts with FMR1; this interaction occurs in association with polyribosome. Interacts with ZBTB7B (By similarity). Interacts with HDGF. Interacts with ELAVL1; leading to ELAVL1 recruitment on C5-methylcytosine (m5C)-containing mRNAs and subsequent mRNA stability (By similarity).
In the CSD domain, Trp-63 specifically recognizes C5-methylcytosine (m5C) modification through its indole ring.
In the absence of phosphorylation the protein is retained in the cytoplasm.
Ubiquitinated by RBBP6; leading to a decrease of YBX1 transcactivational ability.
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.
Belongs to the MICU1 family. MICU2 subfamily.
Heterodimer; disulfide-linked; heterodimerizes with MICU1. Interacts with MCU. The heterodimer formed with MICU1 associates with MCU at low calcium concentration and dissociates from MCU at high calcium level. Component of the uniplex complex, composed of MCU, MCUB, MICU1, MICU2 and EMRE/SMDT1.
Key regulator of mitochondrial calcium uniporter (MCU) required to limit calcium uptake by MCU when cytoplasmic calcium is low. MICU1 and MICU2 form a disulfide-linked heterodimer that stimulate and inhibit MCU activity, depending on the concentration of calcium. 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.
The EF-hand domains have high affinity for calcium and act as sensors of mitochondrial matrix calcium levels. It is unclear which EF-hand binds calcium as none of the 4 EF-hand domains seem to contain a canonical calcium-binding site.
Could coordinate an aspect of bone turnover.
Multiply phosphorylated at serine residues.
Belongs to the potassium channel family. Calcium-activated (TC 1.A.1.3) subfamily. KCa4.1/KCNT1 sub-subfamily.
Detected in brain and brainstem, in vestibular and oculomotor nuclei, the medial nucleus of the trapezoid in the auditory system, in olfactory bulb, red nucleus, and deep cerebellar nuclei. Detected in thalamus, substantia nigra, and amygdala (at protein level). Highly expressed in the brain and kidney.
Interacts (via C-terminus) with FMR1; this interaction alters gating properties of KCNT1 (By similarity). Interacts with CRBN via its cytoplasmic C-terminus (PubMed:16045448).
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).
Phosphorylated by protein kinase C. Phosphorylation of the C-terminal domain increases channel activity.
Interacts with IGHMBP2 (By similarity). Interacts with ESF1/ABTAP.
May be a novel TATA-binding protein (TBP) which can function as a basal transcription activator. Can act as a regulator of basal transcription for class II genes (By similarity).
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 (By similarity).
Highly expressed in cerebral cortex, cerebellum, throughout the hippocampus, in medial habenula, anterior dorsal nucleus in the thalamus, tenia tecta, several nuclei of the general motor system and in optic nerve layer. Detected in a subset of elongated cells in taste buds.
Homotetramer. 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.
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). May mediate responses to sour stimuli.
Belongs to the lipase maturation factor family.
Involved in the maturation of specific proteins in the endoplasmic reticulum. May be required for maturation and transport of active lipoprotein lipase (LPL) through the secretory pathway (By similarity).
Induces bone formation in conjunction with TGF-beta-1 or TGF-beta-2.
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.
Detected in brain, lung, liver, skeletal muscle, kidney, testis and cultured hippocampal neurons.
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.
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.
Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin. Forms a complex with EPM2A/laforin and HSP70 (By similarity).
The RING domain is essential for ubiquitin E3 ligase activity.
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 (By similarity). 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.
Highest levels in liver with lower levels in jejunum, kidney and testis.
Expressed in epididymal sperm (at protein level).
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).
Belongs to the Mediator complex subunit 26 family.
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 (By similarity).
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.
Involved in the maturation of specific proteins in the endoplasmic reticulum.
Highly expressed at 30 dpc to 60 dpc in the testis. Reduced expression at 90 dpc.
Key downstream component of the canonical Wnt signaling pathway (By similarity). In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes (By similarity). Involved in the regulation of cell adhesion, as component of an E-cadherin:catenin adhesion complex (By similarity). Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2. Disrupts PML function and PML-NB formation by inhibiting RANBP2-mediated sumoylation of PML (By similarity). Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle. Involved in chondrocyte differentiation via interaction with SOX9: SOX9-binding competes with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity).
O-glycosylation at Ser-23 decreases nuclear localization and transcriptional activity, and increases localization to the plasma membrane and interaction with E-cadherin CDH1.
Phosphorylation by GSK3B requires prior phosphorylation of Ser-45 by another kinase. Phosphorylation proceeds then from Thr-41 to Ser-33. Phosphorylated by NEK2. EGF stimulates tyrosine phosphorylation. Phosphorylated on Ser-33 and Ser-37 by HIPK2. This phosphorylation triggers proteasomal degradation. Phosphorylation at Ser-552 by AMPK promotes stabilizion of the protein, enhancing TCF/LEF-mediated transcription. Phosphorylation on Ser-191 and Ser-246 by CDK5. Phosphorylation by CDK2 regulates insulin internalization. Phosphorylation by PTK6 at Tyr-64, Tyr-142, Tyr-331 and/or Tyr-333 with the predominant site at Tyr-64 is not essential for inhibition of transcriptional activity. Phosphorylation by SRC at Tyr-333 promotes interaction with isoform M2 of PKM (PKM2); promoting transcription activation.
S-nitrosylation at Cys-619 within adherens junctions promotes VEGF-induced, NO-dependent endothelial cell permeability by disrupting interaction with E-cadherin, thus mediating disassembly adherens junctions.
Two separate complex-associated pools are found in the cytoplasm. The majority is present as component of an E-cadherin/ catenin adhesion complex composed of at least E-cadherin/CDH1 and beta-catenin/CTNNB1, and possibly alpha-catenin/CTNNA1; the complex is located to adherens junctions. The stable association of CTNNA1 is controversial as CTNNA1 was shown not to bind to F-actin when assembled in the complex. Alternatively, the CTNNA1-containing complex may be linked to F-actin by other proteins such as LIMA1. Another cytoplasmic pool is part of a large complex containing AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1. Interacts directly with AXIN1; the interaction is regulated by CK2 via BTRC and its subsequent degradation by the proteasome. Interacts directly with AXIN1; the interaction is regulated by CDK2 phosphorylation. Wnt-dependent activation of DVL antagonizes the action of GSK3B. When GSK3B activity is inhibited the complex dissociates, CTNNB1 is dephosphorylated and is no longer targeted for destruction. The stabilized protein translocates to the nucleus, where it binds TCF/LEF-1 family members, BCL9, BCL9L and possibly also RUVBL1 and CHD8. Binds CTNNBIP and EP300. CTNNB1 forms a ternary complex with LEF1 and EP300 that is disrupted by CTNNBIP1 binding. Interacts with TAX1BP3 (via the PDZ domain); this interaction inhibits the transcriptional activity of CTNNB1. Interacts with AJAP1, BAIAP1, CARM1, CTNNA3, CXADR and PCDH11Y. Binds SLC9A3R1. Interacts with GLIS2. Interacts with XIRP1. Interacts with PTPRU (via the cytoplasmic juxtamembrane domain) and with SLC30A9. Interacts with EMD. Interacts with SCRIB. Interacts with TNIK and TCF7L2. Interacts with SESTD1 and TRPC4. Interacts directly with AXIN1; the interaction is regulated by CDK2 phosphorylation of AXIN1. Interacts with CAV1. Interacts with TRPV4. The TRPV4 and CTNNB1 complex can interact with CDH1. Interacts with VCL. Interacts with PTPRJ. Interacts with PKT7. Interacts with NANOS1. Interacts with CDK2, NDRG2, NEK2 and CDK5. Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B. Interacts with PTK6. Interacts with SOX7; this interaction may lead to proteasomal degradation of active CTNNB1 and thus inhibition of Wnt/beta-catenin-stimulated transcription. Identified in a complex with HINT1 and MITF. Interacts with FHIT. The CTNNB1 and TCF4 complex interacts with PML. Interacts with FERMT2. Identified in a complex with TCF4 and FERMT2. Interacts with RAPGEF2. Interacts with FAT1 (via the cytoplasmic domain). Interacts with RORA. May interact with P-cadherin/CDH3. Interacts with RNF220 (By similarity). Interacts with CTNND2 (By similarity). Interacts (via the C-terminal region) with CBY1 (By similarity). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9'). Interacts with DLG5 (By similarity). Interacts with FAM53B; promoting translocation to the nucleus. Interacts with TMEM170B (By similarity). Interacts with AHI1 (By similarity). Interacts with GID8 (By similarity). Component of an cadherin:catenin adhesion complex composed of at least of CDH26, beta-catenin/CTNNB1, alpha-catenin/CTNNA1 and p120 catenin/CTNND1 (By similarity). Forms a complex comprising APPL1, RUVBL2, APPL2, HDAC1 and HDAC2 (By similarity). Interacts with IRF2BPL; mediates the ubiquitination and degradation of CTNNB1 (By similarity). Interacts with AMFR (By similarity). Interacts with LMBR1L (By similarity). Interacts with SOX30; prevents interaction of CTNNB1 with TCF7L2/TCF4 and leads to inhibition of Wnt signaling (By similarity). Interacts with SOX9; inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1, thereby inhibiting the Wnt signaling (By similarity). Interacts with SPN/CD43 cytoplasmic tail (By similarity). Interacts (when phosphorylated at Tyr-333) with isoform M2 of PKM (PKM2); promoting transcription activation (By similarity). Interacts with PKP2 (via HEAD domain) (By similarity). Interacts with CDH1 (By similarity). Interacts (when unphosphorylated) with FLYWCH1, perhaps preventing interaction of CTNNB1 with TCF4, and thereby regulating transcription activation; phosphorylation of CTNNB1 may inhibit the interaction (By similarity). Interacts (via the central armadillo domains) with probable transcriptional regulator ADNP (via N-terminal region); interaction is direct and stabilizes CTNNB1 by modulating its phosphorylation by glycogen synthase kinase-3 beta GSK3B (By similarity).
Ubiquitinated by the SCF(BTRC) E3 ligase complex when phosphorylated by GSK3B, leading to its degradation. Ubiquitinated by a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X, leading to its subsequent proteasomal degradation (By similarity). Ubiquitinated and degraded following interaction with SOX9 (By similarity).
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. 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. Important for skeletal muscle and heart development. 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. Is a caveolae-associated protein important for the preservation of caveolae structural and functional integrity as well as for heart protection against ischemia injury (By similarity).
Homodimer. Homodimerization requires the C-terminus cytoplasmic region (By similarity). 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. Interacts with KCNK2; the interaction enhances KCNK2 surface expression and is inhibited by cAMP (By similarity). Interacts with CAV3 (By similarity).
Strongly expressed in heart and skeletal muscle. Weakly expressed in brain, spleen, liver, kidney and lung.
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.
N-glycosylated; N-linked glycans are of high mannose/hybrid type, as well as bi-, tri- and tetra-antennary complex types.
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. Interacts with ZP1 and ZP2.
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (PubMed:1321233). Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5 (By similarity).
Expressed in the anterior lobe of the pituitary gland (PubMed:2531656). Expressed in the caudate nucleus (PubMed:2137198). Not expressed in the wider brain (PubMed:2531656).
Expressed in the anterior lobe of the pituitary gland (PubMed:2531656). Expressed ventral tegmental area of the midbrain and the pars compacta of the substantia nigra (PubMed:2531656). Expressed seven times more than isoform short in the caudate nucleus (PubMed:2137198).
Forms homo- and heterooligomers with DRD4 (By similarity). The interaction with DRD4 may modulate agonist-induced downstream signaling (By similarity). Interacts with CADPS and CADPS2 (By similarity). Interacts with GPRASP1, PPP1R9B and CLIC6 (PubMed:10391935, PubMed:14499480, PubMed:16049099). Interacts with ARRB2 (PubMed:19332542). Interacts with HTR2A (By similarity). Interacts with DRD1 (By similarity). Interacts with KCNA2 (By similarity).
Palmitoylated. Palmitoylation which is required for proper localization to the plasma membrane and stability of the receptor could be carried on by ZDHHC4, ZDHHC3 and ZDHHC8.
Belongs to the 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 of the high level of iminoacids in collagen (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:18719240). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:18719240). Catalyzes the glucuronidation of the endogenous estrogen hormone estradiol (PubMed:18719240).
In the central nervous system, CXCL10 is predominantly localized to activated neurons (PubMed:30448292). Expressed in both microglia and astrocytes (PubMed:30257241).
Monomer, dimer, and tetramer. Interacts with CXCR3 (via N-terminus).
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 (By similarity). 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. In turn, recruitment of activated Th1 lymphocytes occurs at sites of inflammation (By similarity). 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) (PubMed:30257241, PubMed:30448292).
Expressed in epidermis and hair follicles.
Interacts with POU2AF1 and POU2AF2 in a DNA-dependent manner; this interaction increases POU2F3 transactivation activity.
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:7682011). 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 (By similarity).
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 (By similarity).
Tetramer of two alpha and two beta chains; disulfide-linked (By similarity). The hemoglobin/haptoglobin complex is composed of a haptoglobin dimer bound to two hemoglobin alpha-beta dimers (By similarity). Interacts with CD163 (By similarity). Interacts with ERGIC3 (By similarity).
The beta chain mediates most of the interactions with both subunits of hemoglobin, while the alpha chain forms the homodimeric interface.
Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.
Ubiquitinated by the DCX(DCAF12) complex specifically recognizes the diglutamate (Glu-Glu) at the C-terminus, leading to its degradation.
Interacts with APEX1, HUWE1/ARF-BP1, STUB1/CHIP and USP47 (By similarity). Monomer. Interacts with FAM168A (By similarity).
Methylation by PRMT6 stimulates the polymerase activity by enhancing DNA binding and processivity.
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 (By similarity).
Interacts with cytoplasmic tails of a variety of G-protein coupled receptors such as delta opioid receptor/OPRD1, beta-2 adrenergic receptor/ADRB2 and D4 dopamine receptor/DRD4. Interacts with BECN2; the interaction is direct (By similarity) and with D2 dopamine receptor/DRD2. Interacts with PER1.
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 (By similarity).
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.
Interacts with BACE1. Interacts with APP. Interacts with STMN2 (By similarity).
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 (By similarity).
By anisomycin (activator of MAP kinase pathway) and by dopamine and cocaine in dopamine D1 receptor-expressing striatal neurons and by EGF/epidermal growth factor or NGF/nerve growth factor in PC12 pheochromocytoma cells. Isoform 1 also is specifically induced by cycloheximide, potassium chloride (KCl) and forskolin or brain neurotrophic factor (BDNF). Isoform 2 is induced by glutamate.
Interacts with POLR2A via its hyperphosphorylated C-terminal domain (CTD). Interacts with CDK11A, CDK11B, CDK12 and CDK13. May form a ternary complex with CDK11B and casein kinase II (CKII). Interacts with pre-mRNA-splicing factors, including at least SRSF1, SRSF2 AND SRSF7/SLU7.
Involved in pre-mRNA splicing (PubMed:11683997). Functions in association with cyclin-dependent kinases (CDKs). May play a role in the regulation of RNA polymerase II (pol II). Inhibited by the CDK-specific inhibitor CDKN1A/p21 (By similarity).
Ubiquitous with higher level in liver; expressed in striatal neurons.
May be involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors.
ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated. Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Severing activity is not dependent on tubulin acetylation or detyrosination. Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex. Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex. Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling. Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing (By similarity). Probably plays a role in axon growth and the formation of axonal branches (PubMed:18234839).
ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated. Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Severing activity is not dependent on tubulin acetylation or detyrosination. Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex. Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex. Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling. Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing. Probably plays a role in axon growth and the formation of axonal branches.
Allosteric enzyme with a cooperative mechanism; at least two neighbor subunits influence each other strongly in spastin hexamers. Microtubule binding promotes cooperative interactions among spastin subunits.
Belongs to the AAA ATPase family. Spastin subfamily.
Homohexamer. Mostly monomeric, but assembles into hexameric structure for short periods of time. Oligomerization seems to be a prerequisite for catalytic activity. Binding to ATP in a cleft between two adjacent subunits stabilizes the homohexameric form. Binds to microtubules at least in part via the alpha-tubulin and beta-tubulin tails. The hexamer adopts a ring conformation through which microtubules pass prior to being severed. Does not interact strongly with tubulin heterodimers. Interacts (via MIT domain) with CHMP1B; the interaction is direct. Interacts with SSNA1. Interacts with ATL1. Interacts with RTN1. Interacts with ZFYVE27. Interacts with REEP1. Interacts (via MIT domain) with IST1.
Functions as a positive regulator of TNF-induced NF-kappaB signaling. Regulates angiogenesis and cellular metabolism through interaction with PKM.
Oligomer. Dimer. Interacts with PKM; regulates angiogenesis and metabolism.
Belongs to the proteasome subunit S5B/HSM3 family.
Binding to its receptor activates G proteins and stimulates adenylate cyclase in pituitary cells (By similarity). 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 (PubMed:18198219). Involved in the control of glucose homeostasis, induces insulin secretion by pancreatic beta cells (By similarity).
Interacts with ADCYAP1R1 (via N-terminal extracellular domain).
Belongs to the GMC oxidoreductase family.
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 (By similarity). 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. In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules (By similarity).
Predominantly expressed in the brain, including in glial cells of the cerebellum and forebrain. Expressed at lower levels in the kidney, and other peripheral tissues.
Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways (By similarity). Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif (By similarity). Binding generally results in the modulation of the activity of the binding partner (By similarity). Promotes cytosolic retention and inactivation of TFEB transcription factor by binding to phosphorylated TFEB (By similarity). Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (PubMed:16959763). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (PubMed:16959763).
Homodimer. Heterodimerizes with YWHAE (By similarity). Homo- and heterodimerization is inhibited by phosphorylation on Ser-58 (By similarity). Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with CDK16 and with WEE1 (C-terminal). Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with Thr-phosphorylated ITGB2. Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232. Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation. Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization (By similarity). Interacts with GAB2 and SAMSN1. Binds to TLK2 (By similarity). Interacts with BSPRY. Interacts with BCL2L11. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (By similarity). Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways (By similarity). Interacts with SLITRK1 (By similarity). Interacts with AK5, LDB1, MADD, MARK3, PDE1A and SMARCB1 (By similarity). Interacts with YWHAZ (By similarity). Interacts with MEFV (By similarity). Interacts with ADAM22 (via C-terminus) (By similarity).
The delta, brain-specific form differs from the zeta form in being phosphorylated. Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria. Phosphorylation on Thr-232; inhibits binding of RAF1. Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion. Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53.
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.
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.
Vas deferens, hippocampus, cerebral cortex, aorta, brain stem, heart and spleen.
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.
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.
Homodimer in endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and cis-Golgi network. Interacts with IL1RL1. Interacts with RNF26; this interaction is important to modulate innate immune signaling through the cGAS-STING pathway.
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. Plays also a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26.