MGP Database

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MGP001343

UniProt Annotations

Entry Information
Gene Nameglycogen synthase kinase 3 alpha
Protein EntryGSK3A_HUMAN
UniProt IDP49840
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
Catalytic ActivityATP + [tau protein] = ADP + [tau protein] phosphate.
Enzyme RegulationActivated 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. {ECO:0000269|PubMed:11749387, ECO:0000269|PubMed:19366350}.
FunctionConstitutively 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. Regulates glycogen metabolism in liver, but not in muscle. 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. May be involved in the regulation of replication in pancreatic beta-cells. 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. {ECO:0000269|PubMed:12761548, ECO:0000269|PubMed:17229088}.
InteractionO15169:AXIN1; NbExp=2; IntAct=EBI-1044067, EBI-710484; O75398:DEAF1; NbExp=2; IntAct=EBI-1044067, EBI-718185; P08238:HSP90AB1; NbExp=2; IntAct=EBI-1044067, EBI-352572; O75581:LRP6; NbExp=2; IntAct=EBI-1044067, EBI-910915; Q8IUH5:ZDHHC17; NbExp=3; IntAct=EBI-1044067, EBI-524753;
MiscellaneousHigher expression and activity of GSK3A are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350). {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}.
PtmPhosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279. {ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:19369195}.
SimilarityBelongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SubunitMonomer. Interacts with ARRB2 (By similarity). Interacts with AXIN1 and CTNNB1/beta-catenin. {ECO:0000250, ECO:0000269|PubMed:17229088}.
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