DegronMD - P49841(GSK3B)

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:1846781, PubMed:9072970, PubMed:14690523, PubMed:20937854, PubMed:12554650, PubMed:11430833, PubMed:16484495). Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507). In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes (PubMed:12554650). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781). Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin (PubMed:9072970). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin (PubMed:9819408). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281). Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including 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, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). {ECO:0000250|UniProtKB:P18266, ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20067585, ECO:0000269|PubMed:20932480, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:30704899, ECO:0000269|PubMed:8397507, ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}. View more >>

GO - Biological processes (BP): beta-catenin destruction complex disassembly [GO:1904886]; cellular response to amyloid-beta [GO:1904646]; cellular response to interleukin-3 [GO:0036016]; cellular response to retinoic acid [GO:0071300]; circadian rhythm [GO:0007623]; dopamine receptor signaling pathway [GO:0007212]; epithelial to mesenchymal transition [GO:0001837]; ER overload response [GO:0006983]; establishment of cell polarity [GO:0030010]; excitatory postsynaptic potential [GO:0060079]; extrinsic apoptotic signaling pathway [GO:0097191]; extrinsic apoptotic signaling pathway in absence of ligand [GO:0097192]; glycogen metabolic process [GO:0005977]; hippocampus development [GO:0021766]; insulin receptor signaling pathway [GO:0008286]; intracellular signal transduction [GO:0035556]; maintenance of cell polarity [GO:0030011]; negative regulation of apoptotic process [GO:0043066]; negative regulation of calcineurin-NFAT signaling cascade [GO:0070885]; negative regulation of canonical Wnt signaling pathway [GO:0090090]; negative regulation of canonical Wnt signaling pathway involved in osteoblast differentiation [GO:1905240]; negative regulation of dopaminergic neuron differentiation [GO:1904339]; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors [GO:1902042]; negative regulation of gene expression [GO:0010629]; negative regulation of glycogen (starch) synthase activity [GO:2000466]; negative regulation of glycogen biosynthetic process [GO:0045719]; negative regulation of mesenchymal stem cell differentiation [GO:2000740]; negative regulation of neuron death [GO:1901215]; negative regulation of phosphoprotein phosphatase activity [GO:0032515]; negative regulation of protein acetylation [GO:1901984]; negative regulation of protein binding [GO:0032091]; negative regulation of protein-containing complex assembly [GO:0031333]; negative regulation of protein localization to nucleus [GO:1900181]; negative regulation of type B pancreatic cell development [GO:2000077]; neuron projection development [GO:0031175]; neuron projection organization [GO:0106027]; peptidyl-serine phosphorylation [GO:0018105]; peptidyl-threonine phosphorylation [GO:0018107]; positive regulation of autophagy [GO:0010508]; positive regulation of cell differentiation [GO:0045597]; positive regulation of cell-matrix adhesion [GO:0001954]; positive regulation of cilium assembly [GO:0045724]; positive regulation of gene expression [GO:0010628]; positive regulation of GTPase activity [GO:0043547]; positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway [GO:1901030]; positive regulation of mitochondrion organization [GO:0010822]; positive regulation of neuron death [GO:1901216]; positive regulation of proteasomal ubiquitin-dependent protein catabolic process [GO:0032436]; positive regulation of protein binding [GO:0032092]; positive regulation of protein catabolic process [GO:0045732]; positive regulation of protein-containing complex assembly [GO:0031334]; positive regulation of protein export from nucleus [GO:0046827]; positive regulation of protein localization to centrosome [GO:1904781]; positive regulation of protein localization to cilium [GO:1903566]; proteasome-mediated ubiquitin-dependent protein catabolic process [GO:0043161]; protein autophosphorylation [GO:0046777]; protein phosphorylation [GO:0006468]; regulation of axon extension [GO:0030516]; regulation of axonogenesis [GO:0050770]; regulation of cellular response to heat [GO:1900034]; regulation of circadian rhythm [GO:0042752]; regulation of dendrite morphogenesis [GO:0048814]; regulation of long-term synaptic potentiation [GO:1900271]; regulation of microtubule anchoring at centrosome [GO:0150101]; regulation of microtubule-based process [GO:0032886]; regulation of microtubule cytoskeleton organization [GO:0070507]; regulation of neuron projection development [GO:0010975]; regulation of protein export from nucleus [GO:0046825]; regulation of synaptic vesicle exocytosis [GO:2000300]; signal transduction [GO:0007165]; superior temporal gyrus development [GO:0071109]; viral protein processing [GO:0019082] View more >>

GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.Q19R	TCGA-V5-A7RE	ESCA	TCGA	PRTTS	DEG_SPOP_SBC_1	5:9	Mutation rewiring degron network	0.0556
p.A11S	DO48374	BLCA	ICGC	PRTTS	DEG_SPOP_SBC_1	5:9	Mutation rewiring degron network	0.2778

DegronMD: protein-targeted degradation, mutation and drug response to degrons

GSK3B

UniProt ID: P49841

Entrez ID: 2932

Protein name: Glycogen synthase kinase-3 beta (GSK-3 beta) (EC 2.7.11.26) (Serine/threonine-protein kinase GSK3B) (EC 2.7.11.1)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for GSK3B in