GSK3B
Entrez ID: 2932
Full name: glycogen synthase kinase 3 beta
External links: HGNC UniprotKB Ensembl RefSeq COSMIC
Family: CMGC: GSK: GSK
Chromosomal location: 3q13.33
Substructure location: Gatekeeper: [N/A] A-loop: [N/A] G-loop: [N/A] αC-helix: 96...102
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GSK3B
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,...
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. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. 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. 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. 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). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. 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. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain 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 ARNTL/BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110).
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GO - Biological processes (BP):
beta-catenin destruction complex assembly, beta-catenin destruction complex disassembly, cellular response to amyloid-beta, cellular response to interleukin-3, circadian rhythm, dopamine receptor signaling pathway, epithelial to mesenchymal transition, ER overload response, establishment of cell pol...
beta-catenin destruction complex assembly, beta-catenin destruction complex disassembly, cellular response to amyloid-beta, cellular response to interleukin-3, circadian rhythm, dopamine receptor signaling pathway, epithelial to mesenchymal transition, ER overload response, establishment of cell polarity, excitatory postsynaptic potential, extrinsic apoptotic signaling pathway, extrinsic apoptotic signaling pathway in absence of ligand, glycogen metabolic process, hippocampus development, insulin receptor signaling pathway, intracellular signal transduction, maintenance of cell polarity, negative regulation of apoptotic process, negative regulation of calcineurin-NFAT signaling cascade, negative regulation of canonical Wnt signaling pathway, negative regulation of dopaminergic neuron differentiation, negative regulation of extrinsic apoptotic signaling pathway via death domain receptors, negative regulation of glycogen (starch) synthase activity, negative regulation of glycogen biosynthetic process, negative regulation of neuron death, negative regulation of phosphoprotein phosphatase activity, negative regulation of protein acetylation, negative regulation of protein binding, negative regulation of protein-containing complex assembly, negative regulation of protein localization to nucleus, negative regulation of type B pancreatic cell development, neuron projection development, neuron projection organization, peptidyl-serine phosphorylation, peptidyl-threonine phosphorylation, positive regulation of autophagy, positive regulation of cell-matrix adhesion, positive regulation of gene expression, positive regulation of GTPase activity, positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway, positive regulation of mitochondrion organization, positive regulation of neuron death, positive regulation of proteasomal ubiquitin-dependent protein catabolic process, positive regulation of protein binding, positive regulation of protein catabolic process, positive regulation of protein-containing complex assembly, positive regulation of protein export from nucleus, positive regulation of protein localization to centrosome, protein autophosphorylation, protein phosphorylation, regulation of axon extension, regulation of axonogenesis, regulation of cellular response to heat, regulation of circadian rhythm, regulation of dendrite morphogenesis, regulation of long-term synaptic potentiation, regulation of microtubule anchoring at centrosome, regulation of microtubule-based process, regulation of microtubule cytoskeleton organization, regulation of neuron projection development, regulation of synaptic vesicle exocytosis, signal transduction, superior temporal gyrus development, Wnt signaling pathway
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GO - Molecular function (MF):
ATP binding, beta-catenin binding, dynactin binding, kinase activity, NF-kappaB binding, p53 binding, protease binding, protein kinase A catalytic subunit binding, protein kinase activity, protein kinase binding, protein serine/threonine kinase activity, RNA polymerase II transcription factor bindin...
ATP binding, beta-catenin binding, dynactin binding, kinase activity, NF-kappaB binding, p53 binding, protease binding, protein kinase A catalytic subunit binding, protein kinase activity, protein kinase binding, protein serine/threonine kinase activity, RNA polymerase II transcription factor binding, tau protein binding, tau-protein kinase activity, ubiquitin protein ligase binding
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GO - Cellular component (CC):
centrosome, cytosol, mitochondrion, nucleoplasm, nucleus, plasma membrane, axon, beta-catenin destruction complex, cytoplasm, dendrite, glutamatergic synapse, postsynapse, Wnt signalosome...
centrosome, cytosol, mitochondrion, nucleoplasm, nucleus, plasma membrane, axon, beta-catenin destruction complex, cytoplasm, dendrite, glutamatergic synapse, postsynapse, Wnt signalosome
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glycogen synthase kinase 3 beta
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*NOTE: the Kaplan plots were collected from OncoLnc