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 28-JAN-2026, entry version 227. 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, ECO:0000269|PubMed:25897075}; 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 INTERACTION WITH MYCOBACTERIUM TUBERCULOSIS PTPA, AND DEPHOSPHORYLATION RP (MICROBIAL INFECTION). RX PubMed=25187516; DOI=10.1074/jbc.m114.582502; RA Poirier V., Bach H., Av-Gay Y.; RT "Mycobacterium tuberculosis promotes anti-apoptotic activity of the RT macrophage by PtpA protein-dependent dephosphorylation of host GSK3alpha."; RL J. Biol. Chem. 289:29376-29385(2014). RN [23] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH RICTOR. RX PubMed=25897075; DOI=10.1074/jbc.m114.633057; RA Koo J., Wu X., Mao Z., Khuri F.R., Sun S.Y.; RT "Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7- RT mediated Ubiquitination and Proteasomal Degradation."; RL J. Biol. Chem. 290:14120-14129(2015). RN [24] 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 [25] 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 [26] 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 which activates KAT5/TIP60 acetyltransferase activity and promotes 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). Phosphorylates mTORC2 complex component RICTOR at 'Thr- CC 1695' which facilitates FBXW7-mediated ubiquitination and subsequent CC degradation of RICTOR (PubMed:25897075). {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:25897075, CC ECO:0000269|PubMed:30704899, ECO:0000303|PubMed:11749387, CC ECO:0000303|PubMed:17478001, ECO:0000303|PubMed:19366350}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] CC + ADP + H(+); Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA- CC COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau CC protein] + 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=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); 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=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:25897075}; 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). Interacts with RICTOR; the interaction results in CC phosphorylation of RICTOR at 'Thr-1695' by GSK3A which facilitates CC FBXW7-mediated ubiquitination and subsequent degradation of RICTOR CC (PubMed:25897075). {ECO:0000250|UniProtKB:Q2NL51, CC ECO:0000269|PubMed:17229088, ECO:0000269|PubMed:18846110, CC ECO:0000269|PubMed:19706605, ECO:0000269|PubMed:25897075, CC ECO:0000305|PubMed:31073040}. CC -!- SUBUNIT: (Microbial infection) Interacts with M.tuberculosis PtpA. CC {ECO:0000269|PubMed:25187516}. CC -!- INTERACTION: CC P49840; PRO_0000000093 [P05067]: APP; NbExp=3; IntAct=EBI-1044067, EBI-2431589; CC P49840; O15169: AXIN1; NbExp=6; IntAct=EBI-1044067, EBI-710484; CC P49840; Q9Y2T1: AXIN2; NbExp=4; IntAct=EBI-1044067, EBI-4400025; CC P49840; P15056: BRAF; NbExp=6; IntAct=EBI-1044067, EBI-365980; CC P49840; O75398: DEAF1; NbExp=3; IntAct=EBI-1044067, EBI-718185; CC P49840; Q6P3S6: FBXO42; NbExp=3; IntAct=EBI-1044067, EBI-2506081; CC P49840; Q92837: FRAT1; NbExp=5; IntAct=EBI-1044067, EBI-3934879; CC P49840; Q9P0R6: GSKIP; NbExp=6; IntAct=EBI-1044067, EBI-1052580; CC P49840; P08238: HSP90AB1; NbExp=3; IntAct=EBI-1044067, EBI-352572; CC P49840; P42858: HTT; NbExp=6; IntAct=EBI-1044067, EBI-466029; CC P49840; O75581: LRP6; NbExp=3; IntAct=EBI-1044067, EBI-910915; CC P49840; P10636-8: MAPT; NbExp=2; IntAct=EBI-1044067, EBI-366233; CC P49840; Q14596: NBR1; NbExp=7; IntAct=EBI-1044067, EBI-742698; CC P49840; P62258: YWHAE; NbExp=3; IntAct=EBI-1044067, EBI-356498; CC P49840; P61981: YWHAG; NbExp=5; IntAct=EBI-1044067, EBI-359832; 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 deactivates CC GSK3A, resulting in the dephosphorylation and activation of GYS1. CC Activated by phosphorylation at Tyr-279. CC -!- PTM: (Microbial infection) Dephosphorylated at Tyr-279 by CC M.tuberculosis PtpA, which leads to prevention of apoptosis during CC early stages of microbial infection. {ECO:0000269|PubMed:25187516}. 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; 7SXF; X-ray; 1.94 A; A=101-444. DR PDB; 7SXG; X-ray; 2.40 A; A=103-445. DR PDBsum; 7SXF; -. DR PDBsum; 7SXG; -. DR AlphaFoldDB; P49840; -. DR SMR; P49840; -. DR BioGRID; 109186; 479. DR ComplexPortal; CPX-107; Beta-catenin destruction core complex, APC-AXIN1-GSK3A variant. DR ComplexPortal; CPX-441; Beta-catenin destruction core complex, APC-AXIN2-GSK3A variant. DR ComplexPortal; CPX-442; Beta-catenin destruction core complex, APC2-AXIN1-GSK3A variant. DR ComplexPortal; CPX-443; Beta-catenin destruction core complex, APC2-AXIN2-GSK3A variant. DR ELM; P49840; -. DR FunCoup; P49840; 1731. DR IntAct; P49840; 171. DR MINT; P49840; -. DR STRING; 9606.ENSP00000222330; -. DR BindingDB; P49840; -. DR ChEMBL; CHEMBL2850; -. DR DrugBank; DB01950; AR-AO-14418. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB16607; Lithium chloride. DR DrugBank; DB11913; LY-2090314. DR DrugBank; DB00313; Valproic acid. DR DrugCentral; P49840; -. DR GuidetoPHARMACOLOGY; 2029; -. DR GlyCosmos; P49840; 1 site, 1 glycan. DR GlyGen; P49840; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P49840; -. DR PhosphoSitePlus; P49840; -. DR SwissPalm; P49840; -. DR BioMuta; GSK3A; -. DR DMDM; 12644292; -. DR CPTAC; CPTAC-3040; -. DR jPOST; P49840; -. DR MassIVE; P49840; -. DR PaxDb; 9606-ENSP00000222330; -. DR PeptideAtlas; P49840; -. DR ProteomicsDB; 56150; -. DR Pumba; P49840; -. DR Antibodypedia; 3833; 1208 antibodies from 49 providers. DR DNASU; 2931; -. DR Ensembl; ENST00000222330.8; ENSP00000222330.3; ENSG00000105723.13. DR Ensembl; ENST00000453535.1; ENSP00000412663.1; ENSG00000105723.13. DR GeneID; 2931; -. DR KEGG; hsa:2931; -. DR MANE-Select; ENST00000222330.8; ENSP00000222330.3; NM_019884.3; NP_063937.2. DR UCSC; uc002otb.2; human. DR AGR; HGNC:4616; -. DR ClinPGx; PA29008; -. 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 OpenTargets; ENSG00000105723; -. DR VEuPathDB; HostDB:ENSG00000105723; -. DR eggNOG; KOG0658; Eukaryota. DR GeneTree; ENSGT00520000055635; -. DR InParanoid; P49840; -. DR OMA; CLHAFFD; -. DR OrthoDB; 272141at2759; -. DR PAN-GO; P49840; 10 GO annotations based on evolutionary models. DR PhylomeDB; P49840; -. DR BRENDA; 2.7.11.26; 2681. DR PathwayCommons; P49840; -. 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 Reactome; R-HSA-9683610; Maturation of nucleoprotein. DR Reactome; R-HSA-9694631; Maturation of nucleoprotein. DR SignaLink; P49840; -. DR SIGNOR; P49840; -. DR Agora; ENSG00000105723; -. DR BioGRID-ORCS; 2931; 21 hits in 1191 CRISPR screens. DR CD-CODE; 7FF4107C; Beta-Catenin Destruction Complex. DR CD-CODE; 8C2F96ED; Centrosome. 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 cortical plate and 213 other cell types or tissues. DR ExpressionAtlas; P49840; baseline and differential. 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: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:0106310; F:protein serine kinase activity; IEA:Ensembl. 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:0141068; P:autosome genomic imprinting; IEA:Ensembl. DR GO; GO:0160213; P:beta-arrestin-dependent dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISS:BHF-UCL. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0016477; P:cell migration; IEA:Ensembl. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; 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: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:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl. 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:0046325; P:negative regulation of D-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: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:0007399; P:nervous system development; IEA:UniProtKB-KW. 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: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; IBA:GO_Central. 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:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; IEA:Ensembl. 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:0070507; P:regulation of microtubule cytoskeleton organization; IBA:GO_Central. DR GO; GO:1901524; P:regulation of mitophagy; IMP:ParkinsonsUK-UCL. 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:0019082; P:viral protein processing; TAS:Reactome. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd14137; STKc_GSK3; 1. DR FunFam; 1.10.510.10:FF:000055; Glycogen synthase kinase-3 beta; 1. DR FunFam; 3.30.200.20:FF:000009; Glycogen synthase kinase-3 beta; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR050591; GSK-3. 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 PANTHER; PTHR24057; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1. DR PANTHER; PTHR24057:SF14; GLYCOGEN SYNTHASE KINASE-3 ALPHA; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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; KW Proteomics identification; Reference proteome; KW Serine/threonine-protein kinase; Signal transduction inhibitor; KW Transferase; Wnt signaling pathway. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|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 REGION 1..96 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 449..483 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..15 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 25..82 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 244 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 125..133 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 148 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 2 FT /note="N-acetylserine" FT /evidence="ECO:0007744|PubMed:19369195, FT ECO:0007744|PubMed:19413330" FT MOD_RES 2 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|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:0007744|PubMed:18691976" FT MOD_RES 77 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 97 FT /note="Phosphoserine" FT /evidence="ECO:0007744|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" FT STRAND 102..112 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 114..118 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 120..126 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 132..137 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 144..152 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 159..166 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 175..182 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 189..196 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 199..201 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 202..211 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 218..237 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 247..249 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 250..252 FT /evidence="ECO:0007829|PDB:7SXF" FT TURN 254..256 FT /evidence="ECO:0007829|PDB:7SXF" FT STRAND 259..261 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 264..266 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 283..285 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 288..291 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 300..315 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 325..336 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 341..347 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 349..351 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 364..366 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 374..383 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 388..390 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 394..398 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 401..403 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 404..407 FT /evidence="ECO:0007829|PDB:7SXF" FT TURN 414..416 FT /evidence="ECO:0007829|PDB:7SXG" FT HELIX 429..431 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 434..436 FT /evidence="ECO:0007829|PDB:7SXF" FT HELIX 437..440 FT /evidence="ECO:0007829|PDB:7SXF" 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 //