DegronMD - P49840(GSK3A)

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), CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, PubMed:19366350). Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350). Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350). 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 (PubMed:10868943, PubMed:17478001). In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088). Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548). May be involved in the regulation of replication in pancreatic beta-cells (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity). 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 which activates KAT5/TIP60 acetyltransferase activity and promotes 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 (By similarity). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). {ECO:0000250|UniProtKB:P18265, ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q2NL51, ECO:0000269|PubMed:10868943, ECO:0000269|PubMed:12761548, ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:30704899, ECO:0000303|PubMed:11749387, ECO:0000303|PubMed:17478001, ECO:0000303|PubMed:19366350}. View more >>

GO - Biological processes (BP): cardiac left ventricle morphogenesis [GO:0003214]; cellular response to insulin stimulus [GO:0032869]; cellular response to interleukin-3 [GO:0036016]; dopamine receptor signaling pathway [GO:0007212]; 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]; insulin receptor signaling pathway [GO:0008286]; negative regulation of canonical Wnt signaling pathway [GO:0090090]; negative regulation of cell growth involved in cardiac muscle cell development [GO:0061052]; negative regulation of glucose import [GO:0046325]; negative regulation of glycogen (starch) synthase activity [GO:2000466]; negative regulation of glycogen biosynthetic process [GO:0045719]; negative regulation of glycogen synthase activity, transferring glucose-1-phosphate [GO:1904227]; negative regulation of insulin receptor signaling pathway [GO:0046627]; negative regulation of TOR signaling [GO:0032007]; negative regulation of type B pancreatic cell development [GO:2000077]; negative regulation of UDP-glucose catabolic process [GO:0010905]; nervous system development [GO:0007399]; peptidyl-threonine phosphorylation [GO:0018107]; positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway [GO:0071879]; positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway [GO:0106071]; positive regulation of amyloid-beta formation [GO:1902004]; positive regulation of autophagy [GO:0010508]; positive regulation of gene expression [GO:0010628]; positive regulation of glycogen (starch) synthase activity [GO:2000467]; positive regulation of heart contraction [GO:0045823]; positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway [GO:1901030]; positive regulation of proteasomal ubiquitin-dependent protein catabolic process [GO:0032436]; positive regulation of protein catabolic process [GO:0045732]; positive regulation of protein targeting to mitochondrion [GO:1903955]; positive regulation of protein ubiquitination [GO:0031398]; proteasome-mediated ubiquitin-dependent protein catabolic process [GO:0043161]; protein phosphorylation [GO:0006468]; regulation of autophagy of mitochondrion [GO:1903146]; regulation of neuron projection development [GO:0010975]; regulation of systemic arterial blood pressure [GO:0003073]; signal transduction [GO:0007165]; viral protein processing [GO:0019082]; Wnt signaling pathway [GO:0016055] 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.W470S	TCGA-85-6561	LUSC	TCGA	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation rewiring degron network	0.2778
p.W470S	DO26518	LUSC	ICGC	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation rewiring degron network	0.2778
p.P477S	DO222765	COCA	ICGC	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation rewiring degron network	0.0833
p.P465L	DO233207	GACA	ICGC	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation altering degron motif	0.7582
p.S467R	DO229045	LICA	ICGC	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation altering degron motif	0.6316
p.T452N	DO229009	LICA	ICGC	AGTTT	DEG_SPOP_SBC_1	449:453	Mutation altering degron motif	0.7055
p.L454I	SIDM01113	Other Sarcomas	GDSC	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation rewiring degron network	0.1389
p.L454I	SIDM01113	Other Sarcomas	GDSC	AGTTT	DEG_SPOP_SBC_1	449:453	Mutation rewiring degron network	0.3056
p.L454I	ACH-000939	Sarcoma	CCLE	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation rewiring degron network	0.1389
p.L454I	ACH-000939	Sarcoma	CCLE	AGTTT	DEG_SPOP_SBC_1	449:453	Mutation rewiring degron network	0.3056
p.L454I	SK-UT-1	soft tissue	COSMIC	LTETPTSS	DEG_SCF_FBW7_1	461:468	Mutation rewiring degron network	0.1389
p.L454I	SK-UT-1	soft tissue	COSMIC	AGTTT	DEG_SPOP_SBC_1	449:453	Mutation rewiring degron network	0.3056
p.V22I	SK-UT-1	soft tissue	COSMIC	ARTSS	DEG_SPOP_SBC_1	17:21	Mutation rewiring degron network	0.3056

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

GSK3A

UniProt ID: P49840

Entrez ID: 2931

Protein name: Glycogen synthase kinase-3 alpha (GSK-3 alpha) (EC 2.7.11.26) (Serine/threonine-protein kinase GSK3A) (EC 2.7.11.1)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for GSK3A in