ID GSK3A_HUMAN Reviewed; 483 AA. AC P49840; O14959; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2000, sequence version 2. DT 22-APR-2020, entry version 199. DE RecName: Full=Glycogen synthase kinase-3 alpha; DE Short=GSK-3 alpha; DE EC=2.7.11.26; DE AltName: Full=Serine/threonine-protein kinase GSK3A; DE EC=2.7.11.1 {ECO:0000269|PubMed:22539723}; GN Name=GSK3A; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Foreskin; RA He X., Saint-Jeannet J.P., Woodgett J.R., Varmus H.E., Dawid I.B.; RT "Glycogen synthase kinase 3 and dorsoventral patterning in Xenopus RT embryos."; RL Submitted (MAR-1995) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain; RA Hoshino T., Kondo K., Ishiguro K., Takashima A., Imahori K.; RT "Isolation of cDNA clones for human glycogen synthase kinase 3alpha."; RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye, and Pancreas; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION, AND ASSOCIATION WITH DIABETES MELLITUS. RX PubMed=10868943; DOI=10.2337/diabetes.49.2.263; RA Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L., RA Henry R.R.; RT "Potential role of glycogen synthase kinase-3 in skeletal muscle insulin RT resistance of type 2 diabetes."; RL Diabetes 49:263-271(2000). RN [6] RP ASSOCIATION WITH ALZHEIMER DISEASE, AND FUNCTION. RX PubMed=12761548; DOI=10.1038/nature01640; RA Phiel C.J., Wilson C.A., Lee V.M., Klein P.S.; RT "GSK-3alpha regulates production of Alzheimer's disease amyloid-beta RT peptides."; RL Nature 423:435-439(2003). RN [7] RP FUNCTION IN WNT SIGNALING, AND INTERACTION WITH AXIN1 AND RP CTNNB1/BETA-CATENIN. RX PubMed=17229088; DOI=10.1111/j.1460-9568.2006.05243.x; RA Asuni A.A., Hooper C., Reynolds C.H., Lovestone S., Anderton B.H., RA Killick R.; RT "GSK3alpha exhibits beta-catenin and tau directed kinase activities that RT are modulated by Wnt."; RL Eur. J. Neurosci. 24:3387-3392(2006). RN [8] RP REVIEW ON FUNCTION, AND ACTIVITY REGULATION. RX PubMed=11749387; DOI=10.1021/cr000110o; RA Ali A., Hoeflich K.P., Woodgett J.R.; RT "Glycogen synthase kinase-3: properties, functions, and regulation."; RL Chem. Rev. 101:2527-2540(2001). RN [9] RP REVIEW ON FUNCTION. RX PubMed=17478001; DOI=10.1016/j.diabres.2007.01.033; RA Lee J., Kim M.S.; RT "The role of GSK3 in glucose homeostasis and the development of insulin RT resistance."; RL Diabetes Res. Clin. Pract. 77:S49-S57(2007). RN [10] RP INTERACTION WITH DDX3X AND TNFRSF10B. RX PubMed=18846110; DOI=10.1038/cdd.2008.124; RA Sun M., Song L., Li Y., Zhou T., Jope R.S.; RT "Identification of an antiapoptotic protein complex at death receptors."; RL Cell Death Differ. 15:1887-1900(2008). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [13] RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [14] RP REVIEW ON FUNCTION, AND ACTIVITY REGULATION. RX PubMed=19366350; DOI=10.1111/j.1476-5381.2008.00085.x; RA Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A.; RT "Glycogen synthase kinase 3: more than a namesake."; RL Br. J. Pharmacol. 156:885-898(2009). RN [15] RP INTERACTION WITH CTNND2. RX PubMed=19706605; DOI=10.1074/jbc.m109.002659; RA Oh M., Kim H., Yang I., Park J.H., Cong W.T., Baek M.C., Bareiss S., Ki H., RA Lu Q., No J., Kwon I., Choi J.K., Kim K.; RT "GSK-3 phosphorylates delta-catenin and negatively regulates its stability RT via ubiquitination/proteosome-mediated proteolysis."; RL J. Biol. Chem. 284:28579-28589(2009). RN [16] RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE RP ANALYSIS] AT SER-2; SER-77 AND SER-97, CLEAVAGE OF INITIATOR METHIONINE RP [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE RP SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP CATALYTIC ACTIVITY. RX PubMed=22539723; DOI=10.1126/science.1217032; RA Lin S.Y., Li T.Y., Liu Q., Zhang C., Li X., Chen Y., Zhang S.M., Lian G., RA Liu Q., Ruan K., Wang Z., Zhang C.S., Chien K.Y., Wu J., Li Q., Han J., RA Lin S.C.; RT "GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to RT autophagy."; RL Science 336:477-481(2012). RN [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [22] RP FUNCTION. RX PubMed=30704899; DOI=10.1016/j.molcel.2018.12.017; RA Cheng X., Ma X., Zhu Q., Song D., Ding X., Li L., Jiang X., Wang X., RA Tian R., Su H., Shen Z., Chen S., Liu T., Gong W., Liu W., Sun Q.; RT "Pacer is a mediator of mTORC1 and GSK3-TIP60 signaling in regulation of RT autophagosome maturation and lipid metabolism."; RL Mol. Cell 73:1-15(2019). RN [23] RP INTERACTION WITH LMBR1L. RX PubMed=31073040; DOI=10.1126/science.aau0812; RA Choi J.H., Zhong X., McAlpine W., Liao T.C., Zhang D., Fang B., Russell J., RA Ludwig S., Nair-Gill E., Zhang Z., Wang K.W., Misawa T., Zhan X., Choi M., RA Wang T., Li X., Tang M., Sun Q., Yu L., Murray A.R., Moresco E.M.Y., RA Beutler B.; RT "LMBR1L regulates lymphopoiesis through Wnt/beta-catenin signaling."; RL Science 364:0-0(2019). RN [24] RP VARIANT [LARGE SCALE ANALYSIS] PHE-461. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Constitutively active protein kinase that acts as a negative CC regulator in the hormonal control of glucose homeostasis, Wnt signaling CC and regulation of transcription factors and microtubules, by CC phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CC CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, CC PubMed:19366350). Requires primed phosphorylation of the majority of CC its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350). CC Contributes to insulin regulation of glycogen synthesis by CC phosphorylating and inhibiting GYS1 activity and hence glycogen CC synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350). CC Regulates glycogen metabolism in liver, but not in muscle (By CC similarity). May also mediate the development of insulin resistance by CC regulating activation of transcription factors (PubMed:10868943, CC PubMed:17478001). In Wnt signaling, regulates the level and CC transcriptional activity of nuclear CTNNB1/beta-catenin CC (PubMed:17229088). Facilitates amyloid precursor protein (APP) CC processing and the generation of APP-derived amyloid plaques found in CC Alzheimer disease (PubMed:12761548). May be involved in the regulation CC of replication in pancreatic beta-cells (By similarity). Is necessary CC for the establishment of neuronal polarity and axon outgrowth (By CC similarity). Through phosphorylation of the anti-apoptotic protein CC MCL1, may control cell apoptosis in response to growth factors CC deprivation (By similarity). Acts as a regulator of autophagy by CC mediating phosphorylation of KAT5/TIP60 under starvation conditions, CC leading to activate KAT5/TIP60 acetyltransferase activity and promote CC acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer CC (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling CC pathway via death domain receptors. Promotes the formation of an anti- CC apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, CC including TNFRSF10B. The anti-apoptotic function is most effective with CC weak apoptotic signals and can be overcome by stronger stimulation (By CC similarity). {ECO:0000250|UniProtKB:P18265, CC ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q2NL51, CC ECO:0000269|PubMed:10868943, ECO:0000269|PubMed:12761548, CC ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:30704899, CC ECO:0000303|PubMed:11749387, ECO:0000303|PubMed:17478001, CC ECO:0000303|PubMed:19366350}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[tau protein]-L-serine + ATP = [tau protein]-O-phospho-L- CC serine + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, CC Rhea:RHEA-COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; CC EC=2.7.11.26; CC -!- CATALYTIC ACTIVITY: CC Reaction=[tau protein]-L-threonine + ATP = [tau protein]-O-phospho-L- CC threonine + ADP + H(+); Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703, CC Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.26; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:22539723}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-279. In CC response to insulin, inhibited by phosphorylation at Ser-21 by CC PKB/AKT1; phosphorylation at this site causes a conformational change, CC preventing access of substrates to the active site. Inhibited by CC lithium. {ECO:0000269|PubMed:11749387, ECO:0000269|PubMed:19366350}. CC -!- SUBUNIT: Monomer. Interacts with ARRB2 (By similarity). Interacts with CC AXIN1 and CTNNB1/beta-catenin (PubMed:17229088). Interacts with CTNND2 CC (PubMed:19706605). Interacts with LMBR1L (PubMed:31073040). Interacts CC with DDX3X (PubMed:18846110). Interacts with TNFRSF10B CC (PubMed:18846110). {ECO:0000250|UniProtKB:Q2NL51, CC ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:18846110, CC ECO:0000269|PubMed:19706605, ECO:0000305|PubMed:31073040}. CC -!- INTERACTION: CC P49840; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-1044067, EBI-2431589; CC P49840; O15169: AXIN1; NbExp=3; IntAct=EBI-1044067, EBI-710484; CC P49840; O75398: DEAF1; NbExp=2; IntAct=EBI-1044067, EBI-718185; CC P49840; Q92837: FRAT1; NbExp=3; IntAct=EBI-1044067, EBI-3934879; CC P49840; P08238: HSP90AB1; NbExp=2; IntAct=EBI-1044067, EBI-352572; CC P49840; O75581: LRP6; NbExp=2; IntAct=EBI-1044067, EBI-910915; CC P49840; Q14596: NBR1; NbExp=4; IntAct=EBI-1044067, EBI-742698; CC P49840; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-1044067, EBI-524753; CC -!- PTM: Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, CC the activated PKB/AKT1 protein kinase phosphorylates and desactivates CC GSK3A, resulting in the dephosphorylation and activation of GYS1. CC Activated by phosphorylation at Tyr-279. CC -!- MISCELLANEOUS: Higher expression and activity of GSK3A are found in the CC skeletal muscle (vastus lateralis) of patients with type 2 diabetes CC (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors CC have been identified and characterized in preclinical models for CC treatments of type 2 diabetes (PubMed:19366350). CC {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. GSK-3 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L40027; AAA62432.1; -; mRNA. DR EMBL; D63424; BAA23608.1; -; mRNA. DR EMBL; AC006486; AAD11986.1; -; Genomic_DNA. DR EMBL; BC027984; AAH27984.1; -; mRNA. DR EMBL; BC051865; AAH51865.1; -; mRNA. DR CCDS; CCDS12599.1; -. DR RefSeq; NP_063937.2; NM_019884.2. DR PDB; 2DFM; Model; -; A=98-449. DR PDBsum; 2DFM; -. DR SMR; P49840; -. DR BioGrid; 109186; 172. DR ComplexPortal; CPX-107; Beta-catenin destruction core complex, variant 5. DR ComplexPortal; CPX-441; Beta-catenin destruction core complex, variant 7. DR ComplexPortal; CPX-442; Beta-catenin destruction core complex, variant 6. DR ComplexPortal; CPX-443; Beta-catenin destruction core complex, variant 8. DR ELM; P49840; -. DR IntAct; P49840; 54. DR MINT; P49840; -. DR STRING; 9606.ENSP00000222330; -. DR BindingDB; P49840; -. DR ChEMBL; CHEMBL2850; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; P49840; -. DR GuidetoPHARMACOLOGY; 2029; -. DR iPTMnet; P49840; -. DR PhosphoSitePlus; P49840; -. DR SwissPalm; P49840; -. DR BioMuta; GSK3A; -. DR DMDM; 12644292; -. DR EPD; P49840; -. DR jPOST; P49840; -. DR MassIVE; P49840; -. DR MaxQB; P49840; -. DR PaxDb; P49840; -. DR PeptideAtlas; P49840; -. DR PRIDE; P49840; -. DR ProteomicsDB; 56150; -. DR Antibodypedia; 3833; 1102 antibodies. DR DNASU; 2931; -. DR Ensembl; ENST00000222330; ENSP00000222330; ENSG00000105723. DR Ensembl; ENST00000453535; ENSP00000412663; ENSG00000105723. DR GeneID; 2931; -. DR KEGG; hsa:2931; -. DR UCSC; uc002otb.2; human. DR CTD; 2931; -. DR DisGeNET; 2931; -. DR GeneCards; GSK3A; -. DR HGNC; HGNC:4616; GSK3A. DR HPA; ENSG00000105723; Low tissue specificity. DR MIM; 606784; gene. DR neXtProt; NX_P49840; -. DR OpenTargets; ENSG00000105723; -. DR PharmGKB; PA29008; -. DR eggNOG; KOG0658; Eukaryota. DR eggNOG; COG0515; LUCA. DR GeneTree; ENSGT00520000055635; -. DR InParanoid; P49840; -. DR KO; K08822; -. DR OMA; DMNPHYK; -. DR OrthoDB; 990896at2759; -. DR PhylomeDB; P49840; -. DR TreeFam; TF101104; -. DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol. DR Reactome; R-HSA-381038; XBP1(S) activates chaperone genes. DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer. DR Reactome; R-HSA-9635465; Suppression of apoptosis. DR SignaLink; P49840; -. DR SIGNOR; P49840; -. DR ChiTaRS; GSK3A; human. DR GeneWiki; GSK3A; -. DR GenomeRNAi; 2931; -. DR Pharos; P49840; Tclin. DR PRO; PR:P49840; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P49840; protein. DR Bgee; ENSG00000105723; Expressed in right frontal lobe and 231 other tissues. DR ExpressionAtlas; P49840; baseline and differential. DR Genevisible; P49840; HS. DR GO; GO:0097440; C:apical dendrite; NAS:ARUK-UCL. DR GO; GO:0030424; C:axon; IBA:GO_Central. DR GO; GO:0030877; C:beta-catenin destruction complex; TAS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005874; C:microtubule; IEA:Ensembl. DR GO; GO:0005739; C:mitochondrion; IEA:GOC. DR GO; GO:0043025; C:neuronal cell body; NAS:ARUK-UCL. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:1990635; C:proximal dendrite; NAS:ARUK-UCL. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:BHF-UCL. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL. DR GO; GO:0005102; F:signaling receptor binding; IPI:ARUK-UCL. DR GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL. DR GO; GO:0050321; F:tau-protein kinase activity; TAS:UniProtKB. DR GO; GO:0007568; P:aging; IEA:Ensembl. DR GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISS:BHF-UCL. DR GO; GO:0016477; P:cell migration; IEA:Ensembl. DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL. DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB. DR GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl. DR GO; GO:0007212; P:dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISS:ARUK-UCL. DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB. DR GO; GO:0005977; P:glycogen metabolic process; IEA:UniProtKB-KW. DR GO; GO:0044027; P:hypermethylation of CpG island; IEA:Ensembl. DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0036498; P:IRE1-mediated unfolded protein response; TAS:Reactome. DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IBA:GO_Central. DR GO; GO:0061052; P:negative regulation of cell growth involved in cardiac muscle cell development; ISS:BHF-UCL. DR GO; GO:2000171; P:negative regulation of dendrite development; IEA:Ensembl. DR GO; GO:0046325; P:negative regulation of glucose import; IMP:BHF-UCL. DR GO; GO:2000466; P:negative regulation of glycogen (starch) synthase activity; TAS:UniProtKB. DR GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; TAS:UniProtKB. DR GO; GO:1904227; P:negative regulation of glycogen synthase activity, transferring glucose-1-phosphate; IMP:BHF-UCL. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:BHF-UCL. DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:BHF-UCL. DR GO; GO:2000077; P:negative regulation of type B pancreatic cell development; TAS:UniProtKB. DR GO; GO:0010905; P:negative regulation of UDP-glucose catabolic process; IC:UniProtKB. DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IEA:Ensembl. DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:ARUK-UCL. DR GO; GO:0071879; P:positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0106071; P:positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; IMP:ARUK-UCL. DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:ARUK-UCL. DR GO; GO:2000467; P:positive regulation of glycogen (starch) synthase activity; ISS:BHF-UCL. DR GO; GO:0045823; P:positive regulation of heart contraction; ISS:BHF-UCL. DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IEA:Ensembl. DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IEA:Ensembl. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:ARUK-UCL. DR GO; GO:0045732; P:positive regulation of protein catabolic process; NAS:BHF-UCL. DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IMP:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:BHF-UCL. DR GO; GO:1903146; P:regulation of autophagy of mitochondrion; IMP:ParkinsonsUK-UCL. DR GO; GO:0006349; P:regulation of gene expression by genetic imprinting; IEA:Ensembl. DR GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central. DR GO; GO:0003073; P:regulation of systemic arterial blood pressure; ISS:BHF-UCL. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd14137; STKc_GSK3; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR InterPro; IPR039192; STKc_GSK3. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alzheimer disease; ATP-binding; KW Carbohydrate metabolism; Diabetes mellitus; Glycogen metabolism; Kinase; KW Neurogenesis; Nucleotide-binding; Phosphoprotein; Polymorphism; KW Reference proteome; Serine/threonine-protein kinase; KW Signal transduction inhibitor; Transferase; Wnt signaling pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000244|PubMed:19369195, FT ECO:0000244|PubMed:19413330" FT CHAIN 2..483 FT /note="Glycogen synthase kinase-3 alpha" FT /id="PRO_0000085978" FT DOMAIN 119..403 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT NP_BIND 125..133 FT /note="ATP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT COMPBIAS 3..83 FT /note="Gly-rich" FT ACT_SITE 244 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 148 FT /note="ATP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 2 FT /note="N-acetylserine" FT /evidence="ECO:0000244|PubMed:19369195, FT ECO:0000244|PubMed:19413330" FT MOD_RES 2 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:18691976, FT ECO:0000244|PubMed:19369195" FT MOD_RES 21 FT /note="Phosphoserine; by PKB/AKT1" FT /evidence="ECO:0000250|UniProtKB:Q2NL51" FT MOD_RES 72 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:18691976" FT MOD_RES 77 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:19369195" FT MOD_RES 97 FT /note="Phosphoserine" FT /evidence="ECO:0000244|PubMed:19369195" FT MOD_RES 279 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P18265" FT VARIANT 109 FT /note="Q -> E (in dbSNP:rs35978177)" FT /id="VAR_051625" FT VARIANT 461 FT /note="L -> F (in dbSNP:rs35454502)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040539" FT CONFLICT 449 FT /note="A -> S (in Ref. 1; AAA62432)" FT /evidence="ECO:0000305" SQ SEQUENCE 483 AA; 50981 MW; F18C012C03B7D786 CRC64; MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV GASSSGGGPG GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV TTVVATLGQG PERSQEVAYT DIKVIGNGSF GVVYQARLAE TRELVAIKKV LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY SSGEKKDELY LNLVLEYVPE TVYRVARHFT KAKLTIPILY VKVYMYQLFR SLAYIHSQGV CHRDIKPQNL LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN YTEFKFPQIK AHPWTKVFKS RTPPEAIALC SSLLEYTPSS RLSPLEACAH SFFDELRCLG TQLPNNRPLP PLFNFSAGEL SIQPSLNAIL IPPHLRSPAG TTTLTPSSQA LTETPTSSDW QSTDATPTLT NSS //