GSK3A_HUMAN
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 03-AUG-2022, entry version 210.
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=ATP + L-seryl-[tau protein] = ADP + H(+) + O-phospho-L-seryl-
CC [tau protein]; 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=ATP + L-threonyl-[tau protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[tau protein]; 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; 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=3; IntAct=EBI-1044067, EBI-710484;
CC P49840; O75398: DEAF1; NbExp=3; IntAct=EBI-1044067, EBI-718185;
CC P49840; Q92837: FRAT1; NbExp=3; IntAct=EBI-1044067, EBI-3934879;
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; Q14596: NBR1; NbExp=5; 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 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}.
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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 AlphaFoldDB; P49840; -.
DR SMR; P49840; -.
DR BioGRID; 109186; 258.
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; 126.
DR MINT; P49840; -.
DR STRING; 9606.ENSP00000222330; -.
DR BindingDB; P49840; -.
DR ChEMBL; CHEMBL2850; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; P49840; -.
DR GuidetoPHARMACOLOGY; 2029; -.
DR GlyGen; P49840; 1 site, 1 O-linked glycan (1 site).
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; 1230 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 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 VEuPathDB; HostDB:ENSG00000105723; -.
DR eggNOG; KOG0658; Eukaryota.
DR GeneTree; ENSGT00520000055635; -.
DR InParanoid; P49840; -.
DR OMA; CLHAFFD; -.
DR OrthoDB; 990896at2759; -.
DR PhylomeDB; P49840; -.
DR TreeFam; TF101104; -.
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 BioGRID-ORCS; 2931; 18 hits in 1114 CRISPR screens.
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 211 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:0106310; F:protein serine kinase activity; IEA:RHEA.
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: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: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: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:0007399; P:nervous system development; IEA:UniProtKB-KW.
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 genomic 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: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 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 Acetylation; Alzheimer disease; ATP-binding; Carbohydrate metabolism;
KW Diabetes mellitus; Glycogen metabolism; Kinase; Neurogenesis;
KW Nucleotide-binding; Phosphoprotein; 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 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"
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
