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FUNCTION Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1 (PubMed:15791206, PubMed:22057101, PubMed:23395175). Requires primed phosphorylation of the majority of its substrates (PubMed:15791206, PubMed:22057101, PubMed:23395175). 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 (By similarity). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (By similarity). 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 (By similarity). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (By similarity). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (By similarity). 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 (PubMed:21295697). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF (TNF/TNFA) (PubMed:10894547). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (PubMed:18288891). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (PubMed:16543145). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:17391670). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (By similarity). Phosphorylates ZC3HAV1 which enhances its antiviral activity (By similarity). Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation (By similarity). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (By similarity). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation (By similarity). Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2 (PubMed:20049328, PubMed:20123978, PubMed:28556462, PubMed:28903391). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (By similarity). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:20049328, PubMed:28903391). Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation (PubMed:23542741). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity (By similarity). 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 (PubMed:28556462). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:22539723). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors (By similarity). Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B (By similarity). 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). Phosphorylates mTORC2 complex component RICTOR at 'Ser-1235' in response to endoplasmic stress, inhibiting mTORC2 (By similarity). Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome (PubMed:26240334, PubMed:29142209). Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its proteasomal degradation (PubMed:24742671). Phosphorylates and inhibits the CTP synthase and protein-asparagine deamidase activities of CTPS1 (PubMed:39719712). Phosphorylates DSP at multiple sequential serine residues in the C-terminus tail, promoting its recruitment to developing desmosome cell-cell junctions (PubMed:25733715).CATALYTIC ACTIVITY L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H(+)CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)ACTIVITY REGULATION Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 and RPS6KA3; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site (By similarity). Inhibited by IL22 treatment which also triggers phosphorylation at Ser-9, promoting inactivation (PubMed:24742671). Inhibited by lithium (By similarity).SUBUNIT 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 CABYR, MMP2, MUC1, NIN and PRUNE1 (By similarity). Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction (PubMed:19141611). Interacts with and phosphorylates SNAI1 (By similarity). Interacts with DNM1L (via a C-terminal domain) (By similarity). Interacts with ARRB2 (PubMed:16051150). Interacts with DISC1 (PubMed:19303846). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with SGK3 (By similarity). Interacts with the CLOCK-BMAL1 heterodimer (By similarity). Interacts with ZBED3 (PubMed:19141611). Interacts with the BMAL1 (PubMed:20049328, PubMed:28903391). 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 (PubMed:28903391). Interacts with LMBR1L (PubMed:31073040). Interacts with DDX3X (By similarity). Interacts with BIRC2 (By similarity). Interacts with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity (By similarity). Found in a complex with SLC39A6, SLC39A10 and with GSK3B that controls NCAM1 phosphorylation (PubMed:28098160). Interacts with PKP3 (via ARM repeats); the interaction may be involved in PKP3 protein degradation (By similarity).SUBCELLULAR LOCATION The phosphorylated form shows localization to cytoplasm and cell membrane. The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosphorylated form to the cell membrane (By similarity).TISSUE SPECIFICITY Expressed in the liver (at protein level).PTM Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216. Phosphorylation of Ser-9 in the hippocampus peaks at CT0, whereas in the liver it peaks at CT12. Inactivated by phosphorylation at Ser-9 (By similarity). Phosphorylated in a circadian manner in the hippocampus (PubMed:28556462).PTM Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.PTM Palmitoylated. Palmitoylation by ZDHHC4 prevents AKT1-mediated phosphorylation.DISRUPTION PHENOTYPE Embryonic lethality at 16 dpc due to hepatocyte apoptosis.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.
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