Full text data of GSK3A
GSK3A
[Confidence: low (only semi-automatic identification from reviews)]
Glycogen synthase kinase-3 alpha; GSK-3 alpha; 2.7.11.26 (Serine/threonine-protein kinase GSK3A; 2.7.11.1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Glycogen synthase kinase-3 alpha; GSK-3 alpha; 2.7.11.26 (Serine/threonine-protein kinase GSK3A; 2.7.11.1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P49840
ID GSK3A_HUMAN Reviewed; 483 AA.
AC P49840; O14959;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2000, sequence version 2.
DT 22-JAN-2014, entry version 139.
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;
GN Name=GSK3A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; 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.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA 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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP 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
RT insulin 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
RT that are modulated by Wnt.";
RL Eur. J. Neurosci. 24:3387-3392(2006).
RN [8]
RP REVIEW ON FUNCTION AND ENZYME 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
RT insulin resistance.";
RL Diabetes Res. Clin. Pract. 77:S49-S57(2007).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, AND MASS
RP SPECTROMETRY.
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
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP REVIEW ON FUNCTION AND ENZYME 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 [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-2; SER-77 AND SER-97, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [15]
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 [16]
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.,
RA Buerckstuemmer T., 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 [17]
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.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., 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
CC negative regulator in the hormonal control of glucose homeostasis,
CC Wnt signaling and regulation of transcription factors and
CC microtubules, by phosphorylating and inactivating glycogen
CC synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1.
CC Requires primed phosphorylation of the majority of its substrates.
CC Contributes to insulin regulation of glycogen synthesis by
CC phosphorylating and inhibiting GYS1 activity and hence glycogen
CC synthesis. Regulates glycogen metabolism in liver, but not in
CC muscle. May also mediate the development of insulin resistance by
CC regulating activation of transcription factors. In Wnt signaling,
CC regulates the level and transcriptional activity of nuclear
CC CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP)
CC processing and the generation of APP-derived amyloid plaques found
CC in Alzheimer disease. May be involved in the regulation of
CC replication in pancreatic beta-cells. Is necessary for the
CC establishment of neuronal polarity and axon outgrowth. Through
CC phosphorylation of the anti-apoptotic protein MCL1, may control
CC cell apoptosis in response to growth factors deprivation.
CC -!- CATALYTIC ACTIVITY: ATP + [tau protein] = ADP + [tau protein]
CC phosphate.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME 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
CC change, preventing access of substrates to the active site.
CC Inhibited by lithium.
CC -!- SUBUNIT: Monomer. Interacts with ARRB2 (By similarity). Interacts
CC with AXIN1 and CTNNB1/beta-catenin.
CC -!- INTERACTION:
CC O15169:AXIN1; NbExp=2; IntAct=EBI-1044067, EBI-710484;
CC O75398:DEAF1; NbExp=2; IntAct=EBI-1044067, EBI-718185;
CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-1044067, EBI-352572;
CC O75581:LRP6; NbExp=2; IntAct=EBI-1044067, EBI-910915;
CC -!- PTM: Phosphorylated by AKT1 at Ser-21: upon insulin-mediated
CC signaling, the activated PKB/AKT1 protein kinase phosphorylates
CC and desactivates GSK3A, resulting in the dephosphorylation and
CC activation of GYS1. Activated by phosphorylation at Tyr-279.
CC -!- MISCELLANEOUS: Higher expression and activity of GSK3A are found
CC in the skeletal muscle (vastus lateralis) of patients with type 2
CC diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B)
CC inhibitors have been identified and characterized in preclinical
CC models for treatments of type 2 diabetes (PubMed:19366350).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC
CC Ser/Thr protein kinase family. GSK-3 subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
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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 RefSeq; NP_063937.2; NM_019884.2.
DR UniGene; Hs.466828; -.
DR PDB; 2DFM; Model; -; A=98-449.
DR PDBsum; 2DFM; -.
DR ProteinModelPortal; P49840; -.
DR SMR; P49840; 99-446.
DR IntAct; P49840; 34.
DR MINT; MINT-1688290; -.
DR STRING; 9606.ENSP00000222330; -.
DR BindingDB; P49840; -.
DR ChEMBL; CHEMBL2850; -.
DR GuidetoPHARMACOLOGY; 2029; -.
DR PhosphoSite; P49840; -.
DR DMDM; 12644292; -.
DR PaxDb; P49840; -.
DR PeptideAtlas; P49840; -.
DR PRIDE; P49840; -.
DR DNASU; 2931; -.
DR Ensembl; ENST00000222330; ENSP00000222330; ENSG00000105723.
DR Ensembl; ENST00000453535; ENSP00000412663; ENSG00000105723.
DR GeneID; 2931; -.
DR KEGG; hsa:2931; -.
DR UCSC; uc002otb.1; human.
DR CTD; 2931; -.
DR GeneCards; GC19M042734; -.
DR HGNC; HGNC:4616; GSK3A.
DR HPA; CAB004422; -.
DR HPA; HPA028423; -.
DR MIM; 606784; gene.
DR neXtProt; NX_P49840; -.
DR PharmGKB; PA29008; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233017; -.
DR HOVERGEN; HBG014652; -.
DR InParanoid; P49840; -.
DR KO; K08822; -.
DR OMA; DELRCHG; -.
DR OrthoDB; EOG7TF78V; -.
DR PhylomeDB; P49840; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P49840; -.
DR ChiTaRS; GSK3A; human.
DR GeneWiki; GSK3A; -.
DR GenomeRNAi; 2931; -.
DR NextBio; 11615; -.
DR PRO; PR:P49840; -.
DR ArrayExpress; P49840; -.
DR Bgee; P49840; -.
DR CleanEx; HS_GSK3A; -.
DR Genevestigator; P49840; -.
DR GO; GO:0030877; C:beta-catenin destruction complex; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0050321; F:tau-protein kinase activity; TAS:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISS:BHF-UCL.
DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0005977; P:glycogen metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0090090; P:negative regulation of canonical Wnt receptor signaling pathway; TAS:UniProtKB.
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 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 cascade; 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:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0071879; P:positive regulation of adrenergic receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0030819; P:positive regulation of cAMP biosynthetic process; ISS:BHF-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; ISS:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; NAS:BHF-UCL.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0003073; P:regulation of systemic arterial blood pressure; ISS:BHF-UCL.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
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; Complete proteome; Diabetes mellitus;
KW Glycogen metabolism; Kinase; Neurogenesis; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Signal transduction inhibitor;
KW Transferase; Wnt signaling pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 483 Glycogen synthase kinase-3 alpha.
FT /FTId=PRO_0000085978.
FT DOMAIN 119 403 Protein kinase.
FT NP_BIND 125 133 ATP (By similarity).
FT COMPBIAS 3 83 Gly-rich.
FT ACT_SITE 244 244 Proton acceptor (By similarity).
FT BINDING 148 148 ATP (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 2 2 Phosphoserine.
FT MOD_RES 21 21 Phosphoserine; by PKB/AKT1.
FT MOD_RES 72 72 Phosphoserine.
FT MOD_RES 77 77 Phosphoserine.
FT MOD_RES 97 97 Phosphoserine.
FT MOD_RES 279 279 Phosphotyrosine (By similarity).
FT VARIANT 109 109 Q -> E (in dbSNP:rs35978177).
FT /FTId=VAR_051625.
FT VARIANT 461 461 L -> F (in dbSNP:rs35454502).
FT /FTId=VAR_040539.
FT CONFLICT 449 449 A -> S (in Ref. 1; AAA62432).
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
//
ID GSK3A_HUMAN Reviewed; 483 AA.
AC P49840; O14959;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-DEC-2000, sequence version 2.
DT 22-JAN-2014, entry version 139.
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;
GN Name=GSK3A;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; 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.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA 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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP 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
RT insulin 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
RT that are modulated by Wnt.";
RL Eur. J. Neurosci. 24:3387-3392(2006).
RN [8]
RP REVIEW ON FUNCTION AND ENZYME 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
RT insulin resistance.";
RL Diabetes Res. Clin. Pract. 77:S49-S57(2007).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, AND MASS
RP SPECTROMETRY.
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
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP REVIEW ON FUNCTION AND ENZYME 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 [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-2; SER-77 AND SER-97, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [15]
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 [16]
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.,
RA Buerckstuemmer T., 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 [17]
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.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., 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
CC negative regulator in the hormonal control of glucose homeostasis,
CC Wnt signaling and regulation of transcription factors and
CC microtubules, by phosphorylating and inactivating glycogen
CC synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1.
CC Requires primed phosphorylation of the majority of its substrates.
CC Contributes to insulin regulation of glycogen synthesis by
CC phosphorylating and inhibiting GYS1 activity and hence glycogen
CC synthesis. Regulates glycogen metabolism in liver, but not in
CC muscle. May also mediate the development of insulin resistance by
CC regulating activation of transcription factors. In Wnt signaling,
CC regulates the level and transcriptional activity of nuclear
CC CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP)
CC processing and the generation of APP-derived amyloid plaques found
CC in Alzheimer disease. May be involved in the regulation of
CC replication in pancreatic beta-cells. Is necessary for the
CC establishment of neuronal polarity and axon outgrowth. Through
CC phosphorylation of the anti-apoptotic protein MCL1, may control
CC cell apoptosis in response to growth factors deprivation.
CC -!- CATALYTIC ACTIVITY: ATP + [tau protein] = ADP + [tau protein]
CC phosphate.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME 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
CC change, preventing access of substrates to the active site.
CC Inhibited by lithium.
CC -!- SUBUNIT: Monomer. Interacts with ARRB2 (By similarity). Interacts
CC with AXIN1 and CTNNB1/beta-catenin.
CC -!- INTERACTION:
CC O15169:AXIN1; NbExp=2; IntAct=EBI-1044067, EBI-710484;
CC O75398:DEAF1; NbExp=2; IntAct=EBI-1044067, EBI-718185;
CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-1044067, EBI-352572;
CC O75581:LRP6; NbExp=2; IntAct=EBI-1044067, EBI-910915;
CC -!- PTM: Phosphorylated by AKT1 at Ser-21: upon insulin-mediated
CC signaling, the activated PKB/AKT1 protein kinase phosphorylates
CC and desactivates GSK3A, resulting in the dephosphorylation and
CC activation of GYS1. Activated by phosphorylation at Tyr-279.
CC -!- MISCELLANEOUS: Higher expression and activity of GSK3A are found
CC in the skeletal muscle (vastus lateralis) of patients with type 2
CC diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B)
CC inhibitors have been identified and characterized in preclinical
CC models for treatments of type 2 diabetes (PubMed:19366350).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC
CC Ser/Thr protein kinase family. GSK-3 subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -----------------------------------------------------------------------
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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 RefSeq; NP_063937.2; NM_019884.2.
DR UniGene; Hs.466828; -.
DR PDB; 2DFM; Model; -; A=98-449.
DR PDBsum; 2DFM; -.
DR ProteinModelPortal; P49840; -.
DR SMR; P49840; 99-446.
DR IntAct; P49840; 34.
DR MINT; MINT-1688290; -.
DR STRING; 9606.ENSP00000222330; -.
DR BindingDB; P49840; -.
DR ChEMBL; CHEMBL2850; -.
DR GuidetoPHARMACOLOGY; 2029; -.
DR PhosphoSite; P49840; -.
DR DMDM; 12644292; -.
DR PaxDb; P49840; -.
DR PeptideAtlas; P49840; -.
DR PRIDE; P49840; -.
DR DNASU; 2931; -.
DR Ensembl; ENST00000222330; ENSP00000222330; ENSG00000105723.
DR Ensembl; ENST00000453535; ENSP00000412663; ENSG00000105723.
DR GeneID; 2931; -.
DR KEGG; hsa:2931; -.
DR UCSC; uc002otb.1; human.
DR CTD; 2931; -.
DR GeneCards; GC19M042734; -.
DR HGNC; HGNC:4616; GSK3A.
DR HPA; CAB004422; -.
DR HPA; HPA028423; -.
DR MIM; 606784; gene.
DR neXtProt; NX_P49840; -.
DR PharmGKB; PA29008; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233017; -.
DR HOVERGEN; HBG014652; -.
DR InParanoid; P49840; -.
DR KO; K08822; -.
DR OMA; DELRCHG; -.
DR OrthoDB; EOG7TF78V; -.
DR PhylomeDB; P49840; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P49840; -.
DR ChiTaRS; GSK3A; human.
DR GeneWiki; GSK3A; -.
DR GenomeRNAi; 2931; -.
DR NextBio; 11615; -.
DR PRO; PR:P49840; -.
DR ArrayExpress; P49840; -.
DR Bgee; P49840; -.
DR CleanEx; HS_GSK3A; -.
DR Genevestigator; P49840; -.
DR GO; GO:0030877; C:beta-catenin destruction complex; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0050321; F:tau-protein kinase activity; TAS:UniProtKB.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISS:BHF-UCL.
DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0097192; P:extrinsic apoptotic signaling pathway in absence of ligand; ISS:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0005977; P:glycogen metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0090090; P:negative regulation of canonical Wnt receptor signaling pathway; TAS:UniProtKB.
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 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 cascade; 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:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0071879; P:positive regulation of adrenergic receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0030819; P:positive regulation of cAMP biosynthetic process; ISS:BHF-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; ISS:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; NAS:BHF-UCL.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0003073; P:regulation of systemic arterial blood pressure; ISS:BHF-UCL.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
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; Complete proteome; Diabetes mellitus;
KW Glycogen metabolism; Kinase; Neurogenesis; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Signal transduction inhibitor;
KW Transferase; Wnt signaling pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 483 Glycogen synthase kinase-3 alpha.
FT /FTId=PRO_0000085978.
FT DOMAIN 119 403 Protein kinase.
FT NP_BIND 125 133 ATP (By similarity).
FT COMPBIAS 3 83 Gly-rich.
FT ACT_SITE 244 244 Proton acceptor (By similarity).
FT BINDING 148 148 ATP (By similarity).
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 2 2 Phosphoserine.
FT MOD_RES 21 21 Phosphoserine; by PKB/AKT1.
FT MOD_RES 72 72 Phosphoserine.
FT MOD_RES 77 77 Phosphoserine.
FT MOD_RES 97 97 Phosphoserine.
FT MOD_RES 279 279 Phosphotyrosine (By similarity).
FT VARIANT 109 109 Q -> E (in dbSNP:rs35978177).
FT /FTId=VAR_051625.
FT VARIANT 461 461 L -> F (in dbSNP:rs35454502).
FT /FTId=VAR_040539.
FT CONFLICT 449 449 A -> S (in Ref. 1; AAA62432).
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
//
MIM
606784
*RECORD*
*FIELD* NO
606784
*FIELD* TI
*606784 GLYCOGEN SYNTHASE KINASE 3-ALPHA; GSK3A
*FIELD* TX
DESCRIPTION
Glycogen synthase kinase 3-alpha (GSK3A; EC 2.7.1.37) is a
read moremultifunctional protein serine kinase homologous to Drosophila 'shaggy'
(zeste-white3) that is implicated in the control of several regulatory
proteins, including glycogen synthase (see GYS1, 138570) and
transcription factors (e.g., JUN, 165160). It also plays a role in the
WNT (164820) and PI3K (see PIK3CG, 601232) signaling pathways (see
review by Ali et al. (2001)).
CLONING
Woodgett (1990) cloned rat Gsk3a and Gsk3b (605004). The deduced
483-amino acid Gsk3a protein is 93% identical overall and 99% identical
in the kinase catalytic domain to the human protein (GenBank GENBANK
AAA62432). SDS-PAGE analysis showed expression of the 51-kD rat protein
as predicted from the primary sequence. Northern blot analysis revealed
wide expression of a 2.5-kb transcript in rat tissues. Western blot
analysis, however, showed that expression is variable, suggesting
differential modes of transcriptional and translational regulation.
GENE FUNCTION
Hughes et al. (1993) showed that under resting conditions GSK3A and its
homologs are highly phosphorylated at tyr279 in the phosphorylation
loop. Constitutive phosphorylation of this tyrosine is important for
kinase activity. Dephosphorylation of tyr279 after mitogen activation is
accompanied by kinase inactivation. Fang et al. (2000) found that PKA
(see 188830) as well as PI3K-activated PKB (AKT1; 164730) inactivate
GSK3A by phosphorylation at ser21.
Yost et al. (1998) characterized the GSK3 binding activities of FRAT1
(602503) and FRAT2 (605006), which inhibit the phosphorylation of CTNNB1
(116806) and positively regulate the WNT signaling pathway.
Fang et al. (2002) demonstrated that lysophosphatidic acid primarily
utilizes a PKC (see 176960)-dependent pathway to modulate GSK3 and that
certain growth factors (e.g., PDGFB, 190040), which control GSK3 mainly
through PIK3-PKB, are able to regulate GSK3 through an alternative,
redundant phospholipase-C-gamma (see 600220)-PKC pathway.
Alzheimer disease (AD; 104300) is associated with increased production
and aggregation of amyloid-beta-40 and -42 peptides into plaques. Phiel
et al. (2003) showed that GSK3A is required for maximal production of
the beta-amyloid-40 and -42 peptides generated from the amyloid
precursor protein (APP; 104760) by presenilin (PSEN1; 104311)-dependent
gamma-secretase cleavage. In vitro, lithium, a GSK3A inhibitor, blocked
the production of the beta-amyloid peptides by interfering with the
gamma-secretase step. In mice expressing familial AD-associated
mutations in APP and PSEN1, lithium reduced the levels of beta-amyloid
peptides. Phiel et al. (2003) noted that GSK3A also phosphorylates the
tau protein (MAPT; 157140), the principal component of neurofibrillary
tangles in AD, and suggested that inhibition of GSK3A may offer a new
therapeutic approach to AD.
Maurer et al. (2006) found that Gsk3 phosphorylated mouse Mcl1 (159552)
at a conserved GSK3 phosphorylation site, and this phosphorylation led
to increased ubiquitylation and degradation of Mcl1. In mouse pre-B
lymphocytic cells, Il3 (147740) withdrawal or Pi3 kinase inhibition
induced phosphorylation of Mcl1, and Akt or inhibition of Gsk3 activity
prevented Mcl1 phosphorylation. Mcl1 with a mutation of the
phosphorylation site showed enhanced stability upon Il3 withdrawal and
conferred increased resistance to apoptosis compared with wildtype Mcl1.
Maurer et al. (2006) concluded that control of MCL1 stability by GSK3
regulates apoptosis by growth factors, PI3 kinase, and AKT.
Zeng et al. (2005) provided biochemical and genetic evidence for a dual
kinase mechanism for LRP6 (603507) phosphorylation and activation. GSK3,
which is known for its inhibitory role in Wnt signaling through the
promotion of beta-catenin (116806) phosphorylation and degradation,
mediates the phosphorylation and activation of LRP6. Zeng et al. (2005)
showed that Wnt induces sequential phosphorylation of LRP6 by GSK3 and
casein kinase-1 (see 600505), and this dual phosphorylation promotes the
engagement of LRP6 with the scaffolding protein Axin (603816). Zeng et
al. (2005) further showed that a membrane-associated form of GSK3, in
contrast to the cytosolic GSK3, stimulates Wnt signaling and Xenopus
axis duplication. Zeng et al. (2005) concluded that their results
identified 2 key kinases mediating Wnt coreceptor activation, revealed
an unexpected and intricate logic of Wnt/beta-catenin signaling, and
illustrated GSK3 as a genuine switch that dictates both on and off
states of this pivotal regulatory pathway.
Natural killer (NK) cells from individuals with X-linked
lymphoproliferative syndrome (XLP; 308240) exhibit functional defects
when stimulated through the NK cell receptor, 2B4 (CD244; 605554), most
likely due to aberrant intracellular signaling initiated by mutations in
the gene encoding the adaptor molecule SAP (SH2D1A; 300490). Aoukaty and
Tan (2005) found that NK cells from individuals with XLP failed to
phosphorylate GSK3A and GSK3B after stimulation of 2B4. Lack of GSK3
phosphorylation inactivated GSK3 and prevented accumulation of the
transcriptional coactivator beta-catenin in the cytoplasm and its
subsequent translocation to the nucleus. Aoukaty and Tan (2005)
identified VAV1 (164875), RAC1 (602048), RAF1 (164760), MEK2 (MAP2K2;
601263), ERK1 (MAPK3; 601795), and ERK3 (MAPK6; 602904) as proteins
potentially involved in mediating the signaling pathway between 2B4 and
GSK3/CTNNB and found that some of these elements were aberrant in XLP NK
cells. Aoukaty and Tan (2005) concluded that GSK3 and beta-catenin
mediate signaling of 2B4 in NK cells and that dysfunction of some of the
elements in the transduction pathway between 2B4 and GSK3/beta-catenin
may result in diminished IFNG (147570) secretion and cytotoxic function
of NK cells in XLP patients.
Lohi et al. (2005) showed that laforin is a GSK3 ser9 phosphatase, and
therefore capable of inactivating GYS1. Laforin also interacted with
malin (NHLRC1; 608072), which acts as an E3 ubiquitin ligase binding
GYS1. The authors proposed that laforin, in response to appearance of
polyglucosans, directs 2 negative feedback pathways:
polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity and
polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal
degradation.
Wang et al. (2008) reported pharmacologic, physiologic, and genetic
studies that demonstrated an oncogenic requirement for GSK3 in the
maintenance of a specific subtype of poor prognosis human leukemia,
genetically defined by mutations of the MLL (159555) protooncogene. In
contrast to its previously characterized roles in suppression of
neoplasia-associated signaling pathways, GSK3 paradoxically supports MLL
leukemia cell proliferation and transformation by a mechanism that
ultimately involves destabilization of the cyclin-dependent kinase
inhibitor p27(KIP1) (600778). Inhibition of GSK3 in a preclinical murine
model of MLL leukemia provided promising evidence of efficacy and
earmarked GSK3 as a candidate cancer drug target.
GSK3A and GSK3B form a cytoplasmic destruction complex with APC (611731)
and AXIN that mediates the phosphorylation of a wide range of proteins,
leading to their ubiquitination and subsequent degradation in
proteasomes. The activity of the destruction complex is inhibited by the
WNT signaling pathway. Using human and mouse cells and Xenopus oocytes,
Taelman et al. (2010) showed that WNT signaling triggered sequestration
of GSK3 from the cytosol into multivesicular bodies and thereby
inhibited protein degradation by sequestering GSK3 from cytosolic
substrates. Addition of WNT3A (606359) reduced endogenous cytosolic GSK3
activity, and endocytosed WNT3A colocalized with GSK3 in acidic
endosomal vesicles. Depletion of GSK3A and GSK3B in HEK293 cells
protected the same range of proteins as WNT3A treatment. Depletion of
the endosomal sorting proteins HRS (HGS; 604375) or VPS4 (see 609982)
also reduced GSK3 endocytosis and inhibited WNT signaling. The GSK3
substrate beta-catenin was required for endocytosis of the
GSK3-containing complex, as was the kinase activity of GSK3. Taelman et
al. (2010) concluded that rising beta-catenin levels during WNT
signaling function in a positive-feedback loop by facilitating GSK3
sequestration, allowing newly translated beta-catenin to accumulate in
the nucleus.
Lin et al. (2012) reported that GSK3, when deinhibited by default in
cells deprived of growth factors, activates acetyltransferase TIP60
(601409) through phosphorylating TIP60 serine at codon 86. This directly
acetylates and stimulates the protein kinase ULK1 (603168), which is
required for autophagy. Cells engineered to express TIP60(S86A) that
cannot be phosphorylated by GSK3 could not undergo serum
deprivation-induced autophagy. An acetylation-defective mutant of ULK1
failed to rescue autophagy in Ulk-null mouse embryonic fibroblasts.
Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy
when deprived of serum but not glucose. Lin et al. (2012) concluded that
their findings uncovered an activating pathway that integrates protein
phosphorylation and acetylation to connect growth factor deprivation to
autophagy.
Kim et al. (2013) reported that WNT signaling is governed by
phosphorylation regulation of the axin (603816) scaffolding function.
Phosphorylation by GSK3 kept axin activated (open) for beta-catenin
(116806) interaction and poised for engagement of LRP6 (603507).
Formation of the WNT-induced LRP6-axin signaling complex promoted axin
dephosphorylation by protein phosphatase-1 (see 176875) and inactivated
(closed) axin through an intramolecular interaction. Inactivation of
axin diminished its association with beta-catenin and LRP6, thereby
inhibiting beta-catenin phosphorylation and enabling activated LRP6 to
selectively recruit active axin for inactivation reiteratively.
MAPPING
Using somatic cell hybrid and FISH analysis, Hansen et al. (1997) mapped
the GSK3A gene to chromosome 19q13.1-q13.2, a locus distinct from that
for GSK3B at 3q13.3-q21.
MOLECULAR GENETICS
By RT-PCR and SSCP analysis, Hansen et al. (1997) detected only silent
polymorphisms in the 2 GSK3 isoforms in diabetes mellitus type II
(NIDDM; 125853) patients and their first-degree relatives. Based on this
finding and mapping data, the authors concluded that GSK3 is unlikely to
be involved in the pathogenesis of NIDDM.
ANIMAL MODEL
By expressing GSK3A and GSK3B and kinase-dead mutants, generated by
altering 2 consecutive lysine residues, in frog eggs, He et al. (1995)
showed that the dominant-negative mutants induced dorsal differentiation
whereas the wildtype forms caused ventral differentiation. The authors
suggested that dorsal differentiation involves the suppression of GSK3
activity by a Wnt-related signal.
Jia et al. (2002) reported that in addition to the role of Gsk3 proteins
as inhibitory components of the Wnt pathway, they also inhibit the
'hedgehog' (Hh) pathway (see SHH, 600725) in Drosophila. Gsk3
phosphorylates 'cubitus interruptus' (Ci; see GLI3, 165240) after a
primed phosphorylation by PKA, causing hyperphosphorylation of Ci and
thus targeting it for proteolytic processing. In contrast, Hh opposes Ci
proteolysis by promoting its dephosphorylation.
Trowbridge et al. (2006) showed that hematopoietic repopulation by
hematopoietic stem cells (HSC) can be augmented by administration of a
GSK3 inhibitor to recipient mice transplanted with mouse or human HSCs.
The results suggested that the use of GSK3 inhibitors may provide a
potent and unique clinical approach to directly enhance HSC repopulation
in vivo.
*FIELD* RF
1. Ali, A.; Hoeflich, K. P.; Woodgett, J. R.: Glycogen synthase kinase-3
: properties, functions, and regulation. Chem. Rev. 101: 2527-2540,
2001.
2. Aoukaty, A.; Tan, R.: Role for glycogen synthase kinase-3 in NK
cell cytotoxicity and X-linked lymphoproliferative disease. J. Immun. 174:
4551-4558, 2005.
3. Fang, X.; Yu, S.; Tanyi, J. L.; Lu, Y.; Woodgett, J. R.; Mills,
G. B.: Convergence of multiple signaling cascades at glycogen synthase
kinase 3: edg receptor-mediated phosphorylation and inactivation by
lysophosphatidic acid through a protein kinase C-dependent intracellular
pathway. Molec. Cell. Biol. 22: 2099-2110, 2002.
4. Fang, X.; Yu, S. X.; Lu, Y.; Bast, R. C., Jr.; Woodgett, J. R.;
Mills, G. B.: Phosphorylation and inactivation of glycogen synthase
kinase 3 by protein kinase A. Proc. Nat. Acad. Sci. 97: 11960-11965,
2000.
5. Hansen, L.; Arden, K. C.; Rasmussen, S. B.; Viars, C. S.; Vestergaard,
H.; Hansen, T.; Moller, A. M.; Woodgett, J. R.; Pedersen, O.: Chromosomal
mapping and mutational analysis of the coding region of the glycogen
synthase kinase-3-alpha and beta isoforms in patients with NIDDM. Diabetologia 40:
940-946, 1997.
6. He, X.; Saint-Jeannet, J.-P.; Woodgett, J. R.; Varmus, H. E.; Dawid,
I. B.: Glycogen synthase kinase-3 and dorsoventral patterning in
Xenopus embryos. Nature 374: 617-622, 1995. Note: Erratum: Nature
375: 253 only, 1995.
7. Hughes, K.; Nikolakaki, E.; Plyte, S. E.; Totty, N. F.; Woodgett,
J. R.: Modulation of the glycogen synthase kinase-3 family by tyrosine
phosphorylation. EMBO J. 12: 803-808, 1993.
8. Jia, J.; Amanai, K.; Wang, G.; Tang, J.; Wang, B.; Jiang, J.:
Shaggy/GSK3 antagonizes hedgehog signaling by regulating cubitus interruptus. Nature 416:
548-552, 2002.
9. Kim, S.-E.; Huang, H.; Zhao, M.; Zhang, X.; Zhang, A.; Semonov,
M. V.; MacDonald, B. T.; Zhang, X.; Abreu, J. G.; Peng, L.; He, X.
: Wnt stabilization of beta-catenin reveals principles for morphogen
receptor-scaffold assemblies. Science 340: 867-870, 2013.
10. Lin, S.-Y.; Li, T. Y.; Liu, Q.; Zhang, C.; Li, X.; Chen, Y.; Zhang,
S.-M.; Lian, G.; Liu, Q.; Ruan, K.; Wang, Z.; Zhang, C.-S.; Chien,
K.-Y.; Wu, J.; Li, Q.; Han, J.; Lin, S.-C.: GSK3-TIP60-ULK1 signaling
pathway links growth factor deprivation to autophagy. Science 336:
477-481, 2012. Note: Erratum: Science 337: 799 only, 2012.
11. Lohi, H.; Ianzano, L.; Zhao, X.-C.; Chan, E. M.; Turnbull, J.;
Scherer, S. W.; Ackerley, C. A.; Minassian, B. A.: Novel glycogen
synthase kinase 3 and ubiquitination pathways in progressive myoclonus
epilepsy. Hum. Molec. Genet. 14: 2727-2736, 2005.
12. Maurer, U.; Charvet, C.; Wagman, A. S.; Dejardin, E.; Green, D.
R.: Glycogen synthase kinase-3 regulates mitochondrial outer membrane
permeabilization and apoptosis by destabilization of MCL-1. Molec.
Cell 21: 749-760, 2006.
13. Phiel, C. J.; Wilson, C. A.; Lee, V. M.-Y.; Klein, P. S.: GSK-3-alpha
regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423:
435-439, 2003.
14. Taelman, V. F.; Dobrowolski, R.; Plouhinec, J.-L.; Fuentealba,
L. C.; Vorwald, P. P.; Gumper, I.; Sabatini, D. D.; De Robertis, E.
M.: Wnt signaling requires sequestration of glycogen synthase kinase
3 inside multivesicular endosomes. Cell 143: 1136-1148, 2010.
15. Trowbridge, J. J.; Xenocostas, A.; Moon, R. T.; Bhatia, M.: Glycogen
synthase kinase-3 is an in vivo regulator of hematopoietic stem cell
repopulation. Nature Med. 12: 89-98, 2006.
16. Wang, Z.; Smith, K. S.; Murphy, M.; Piloto, O.; Somervaille, T.
C. P.; Cleary, M. L.: Glycogen synthase kinase 3 in MLL leukaemia
maintenance and targeted therapy. Nature 455: 1205-1209, 2008.
17. Woodgett, J. R.: Molecular cloning and expression of glycogen
synthase kinase-3/factor A. EMBO J. 9: 2431-2438, 1990.
18. Yost, C.; Farr, G. H., III; Pierce, S. B.; Ferkey, D. M.; Chen,
M. M.; Kimelman, D.: GBP, an inhibitor of GSK-3, is implicated in
Xenopus development and oncogenesis. Cell 93: 1031-1041, 1998.
19. Zeng, X.; Tamai, K.; Doble, B.; Li, S.; Huang, H.; Habas, R.;
Okamura, H.; Woodgett, J.; He, X.: A dual-kinase mechanism for Wnt
co-receptor phosphorylation and activation. Nature 438: 873-877,
2005.
*FIELD* CN
Ada Hamosh - updated: 06/25/2013
Ada Hamosh - updated: 9/20/2012
Patricia A. Hartz - updated: 3/9/2011
Ada Hamosh - updated: 12/31/2008
George E. Tiller - updated: 12/10/2008
Paul J. Converse - updated: 10/20/2006
Ada Hamosh - updated: 5/26/2006
Patricia A. Hartz - updated: 4/10/2006
Victor A. McKusick - updated: 2/16/2006
Cassandra L. Kniffin - updated: 5/21/2003
*FIELD* CD
Paul J. Converse: 3/25/2002
*FIELD* ED
alopez: 06/25/2013
terry: 3/14/2013
alopez: 3/5/2013
alopez: 9/25/2012
terry: 9/20/2012
mgross: 6/6/2011
terry: 3/9/2011
alopez: 12/31/2008
wwang: 12/17/2008
wwang: 12/10/2008
mgross: 10/24/2006
mgross: 10/20/2006
alopez: 6/7/2006
terry: 5/26/2006
mgross: 4/12/2006
terry: 4/10/2006
alopez: 3/13/2006
terry: 2/16/2006
cwells: 11/10/2003
carol: 5/21/2003
ckniffin: 5/16/2003
alopez: 4/12/2002
alopez: 3/26/2002
alopez: 3/25/2002
*RECORD*
*FIELD* NO
606784
*FIELD* TI
*606784 GLYCOGEN SYNTHASE KINASE 3-ALPHA; GSK3A
*FIELD* TX
DESCRIPTION
Glycogen synthase kinase 3-alpha (GSK3A; EC 2.7.1.37) is a
read moremultifunctional protein serine kinase homologous to Drosophila 'shaggy'
(zeste-white3) that is implicated in the control of several regulatory
proteins, including glycogen synthase (see GYS1, 138570) and
transcription factors (e.g., JUN, 165160). It also plays a role in the
WNT (164820) and PI3K (see PIK3CG, 601232) signaling pathways (see
review by Ali et al. (2001)).
CLONING
Woodgett (1990) cloned rat Gsk3a and Gsk3b (605004). The deduced
483-amino acid Gsk3a protein is 93% identical overall and 99% identical
in the kinase catalytic domain to the human protein (GenBank GENBANK
AAA62432). SDS-PAGE analysis showed expression of the 51-kD rat protein
as predicted from the primary sequence. Northern blot analysis revealed
wide expression of a 2.5-kb transcript in rat tissues. Western blot
analysis, however, showed that expression is variable, suggesting
differential modes of transcriptional and translational regulation.
GENE FUNCTION
Hughes et al. (1993) showed that under resting conditions GSK3A and its
homologs are highly phosphorylated at tyr279 in the phosphorylation
loop. Constitutive phosphorylation of this tyrosine is important for
kinase activity. Dephosphorylation of tyr279 after mitogen activation is
accompanied by kinase inactivation. Fang et al. (2000) found that PKA
(see 188830) as well as PI3K-activated PKB (AKT1; 164730) inactivate
GSK3A by phosphorylation at ser21.
Yost et al. (1998) characterized the GSK3 binding activities of FRAT1
(602503) and FRAT2 (605006), which inhibit the phosphorylation of CTNNB1
(116806) and positively regulate the WNT signaling pathway.
Fang et al. (2002) demonstrated that lysophosphatidic acid primarily
utilizes a PKC (see 176960)-dependent pathway to modulate GSK3 and that
certain growth factors (e.g., PDGFB, 190040), which control GSK3 mainly
through PIK3-PKB, are able to regulate GSK3 through an alternative,
redundant phospholipase-C-gamma (see 600220)-PKC pathway.
Alzheimer disease (AD; 104300) is associated with increased production
and aggregation of amyloid-beta-40 and -42 peptides into plaques. Phiel
et al. (2003) showed that GSK3A is required for maximal production of
the beta-amyloid-40 and -42 peptides generated from the amyloid
precursor protein (APP; 104760) by presenilin (PSEN1; 104311)-dependent
gamma-secretase cleavage. In vitro, lithium, a GSK3A inhibitor, blocked
the production of the beta-amyloid peptides by interfering with the
gamma-secretase step. In mice expressing familial AD-associated
mutations in APP and PSEN1, lithium reduced the levels of beta-amyloid
peptides. Phiel et al. (2003) noted that GSK3A also phosphorylates the
tau protein (MAPT; 157140), the principal component of neurofibrillary
tangles in AD, and suggested that inhibition of GSK3A may offer a new
therapeutic approach to AD.
Maurer et al. (2006) found that Gsk3 phosphorylated mouse Mcl1 (159552)
at a conserved GSK3 phosphorylation site, and this phosphorylation led
to increased ubiquitylation and degradation of Mcl1. In mouse pre-B
lymphocytic cells, Il3 (147740) withdrawal or Pi3 kinase inhibition
induced phosphorylation of Mcl1, and Akt or inhibition of Gsk3 activity
prevented Mcl1 phosphorylation. Mcl1 with a mutation of the
phosphorylation site showed enhanced stability upon Il3 withdrawal and
conferred increased resistance to apoptosis compared with wildtype Mcl1.
Maurer et al. (2006) concluded that control of MCL1 stability by GSK3
regulates apoptosis by growth factors, PI3 kinase, and AKT.
Zeng et al. (2005) provided biochemical and genetic evidence for a dual
kinase mechanism for LRP6 (603507) phosphorylation and activation. GSK3,
which is known for its inhibitory role in Wnt signaling through the
promotion of beta-catenin (116806) phosphorylation and degradation,
mediates the phosphorylation and activation of LRP6. Zeng et al. (2005)
showed that Wnt induces sequential phosphorylation of LRP6 by GSK3 and
casein kinase-1 (see 600505), and this dual phosphorylation promotes the
engagement of LRP6 with the scaffolding protein Axin (603816). Zeng et
al. (2005) further showed that a membrane-associated form of GSK3, in
contrast to the cytosolic GSK3, stimulates Wnt signaling and Xenopus
axis duplication. Zeng et al. (2005) concluded that their results
identified 2 key kinases mediating Wnt coreceptor activation, revealed
an unexpected and intricate logic of Wnt/beta-catenin signaling, and
illustrated GSK3 as a genuine switch that dictates both on and off
states of this pivotal regulatory pathway.
Natural killer (NK) cells from individuals with X-linked
lymphoproliferative syndrome (XLP; 308240) exhibit functional defects
when stimulated through the NK cell receptor, 2B4 (CD244; 605554), most
likely due to aberrant intracellular signaling initiated by mutations in
the gene encoding the adaptor molecule SAP (SH2D1A; 300490). Aoukaty and
Tan (2005) found that NK cells from individuals with XLP failed to
phosphorylate GSK3A and GSK3B after stimulation of 2B4. Lack of GSK3
phosphorylation inactivated GSK3 and prevented accumulation of the
transcriptional coactivator beta-catenin in the cytoplasm and its
subsequent translocation to the nucleus. Aoukaty and Tan (2005)
identified VAV1 (164875), RAC1 (602048), RAF1 (164760), MEK2 (MAP2K2;
601263), ERK1 (MAPK3; 601795), and ERK3 (MAPK6; 602904) as proteins
potentially involved in mediating the signaling pathway between 2B4 and
GSK3/CTNNB and found that some of these elements were aberrant in XLP NK
cells. Aoukaty and Tan (2005) concluded that GSK3 and beta-catenin
mediate signaling of 2B4 in NK cells and that dysfunction of some of the
elements in the transduction pathway between 2B4 and GSK3/beta-catenin
may result in diminished IFNG (147570) secretion and cytotoxic function
of NK cells in XLP patients.
Lohi et al. (2005) showed that laforin is a GSK3 ser9 phosphatase, and
therefore capable of inactivating GYS1. Laforin also interacted with
malin (NHLRC1; 608072), which acts as an E3 ubiquitin ligase binding
GYS1. The authors proposed that laforin, in response to appearance of
polyglucosans, directs 2 negative feedback pathways:
polyglucosan-laforin-GSK3-GYS1 to inhibit GYS1 activity and
polyglucosan-laforin-malin-GYS1 to remove GYS1 through proteasomal
degradation.
Wang et al. (2008) reported pharmacologic, physiologic, and genetic
studies that demonstrated an oncogenic requirement for GSK3 in the
maintenance of a specific subtype of poor prognosis human leukemia,
genetically defined by mutations of the MLL (159555) protooncogene. In
contrast to its previously characterized roles in suppression of
neoplasia-associated signaling pathways, GSK3 paradoxically supports MLL
leukemia cell proliferation and transformation by a mechanism that
ultimately involves destabilization of the cyclin-dependent kinase
inhibitor p27(KIP1) (600778). Inhibition of GSK3 in a preclinical murine
model of MLL leukemia provided promising evidence of efficacy and
earmarked GSK3 as a candidate cancer drug target.
GSK3A and GSK3B form a cytoplasmic destruction complex with APC (611731)
and AXIN that mediates the phosphorylation of a wide range of proteins,
leading to their ubiquitination and subsequent degradation in
proteasomes. The activity of the destruction complex is inhibited by the
WNT signaling pathway. Using human and mouse cells and Xenopus oocytes,
Taelman et al. (2010) showed that WNT signaling triggered sequestration
of GSK3 from the cytosol into multivesicular bodies and thereby
inhibited protein degradation by sequestering GSK3 from cytosolic
substrates. Addition of WNT3A (606359) reduced endogenous cytosolic GSK3
activity, and endocytosed WNT3A colocalized with GSK3 in acidic
endosomal vesicles. Depletion of GSK3A and GSK3B in HEK293 cells
protected the same range of proteins as WNT3A treatment. Depletion of
the endosomal sorting proteins HRS (HGS; 604375) or VPS4 (see 609982)
also reduced GSK3 endocytosis and inhibited WNT signaling. The GSK3
substrate beta-catenin was required for endocytosis of the
GSK3-containing complex, as was the kinase activity of GSK3. Taelman et
al. (2010) concluded that rising beta-catenin levels during WNT
signaling function in a positive-feedback loop by facilitating GSK3
sequestration, allowing newly translated beta-catenin to accumulate in
the nucleus.
Lin et al. (2012) reported that GSK3, when deinhibited by default in
cells deprived of growth factors, activates acetyltransferase TIP60
(601409) through phosphorylating TIP60 serine at codon 86. This directly
acetylates and stimulates the protein kinase ULK1 (603168), which is
required for autophagy. Cells engineered to express TIP60(S86A) that
cannot be phosphorylated by GSK3 could not undergo serum
deprivation-induced autophagy. An acetylation-defective mutant of ULK1
failed to rescue autophagy in Ulk-null mouse embryonic fibroblasts.
Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy
when deprived of serum but not glucose. Lin et al. (2012) concluded that
their findings uncovered an activating pathway that integrates protein
phosphorylation and acetylation to connect growth factor deprivation to
autophagy.
Kim et al. (2013) reported that WNT signaling is governed by
phosphorylation regulation of the axin (603816) scaffolding function.
Phosphorylation by GSK3 kept axin activated (open) for beta-catenin
(116806) interaction and poised for engagement of LRP6 (603507).
Formation of the WNT-induced LRP6-axin signaling complex promoted axin
dephosphorylation by protein phosphatase-1 (see 176875) and inactivated
(closed) axin through an intramolecular interaction. Inactivation of
axin diminished its association with beta-catenin and LRP6, thereby
inhibiting beta-catenin phosphorylation and enabling activated LRP6 to
selectively recruit active axin for inactivation reiteratively.
MAPPING
Using somatic cell hybrid and FISH analysis, Hansen et al. (1997) mapped
the GSK3A gene to chromosome 19q13.1-q13.2, a locus distinct from that
for GSK3B at 3q13.3-q21.
MOLECULAR GENETICS
By RT-PCR and SSCP analysis, Hansen et al. (1997) detected only silent
polymorphisms in the 2 GSK3 isoforms in diabetes mellitus type II
(NIDDM; 125853) patients and their first-degree relatives. Based on this
finding and mapping data, the authors concluded that GSK3 is unlikely to
be involved in the pathogenesis of NIDDM.
ANIMAL MODEL
By expressing GSK3A and GSK3B and kinase-dead mutants, generated by
altering 2 consecutive lysine residues, in frog eggs, He et al. (1995)
showed that the dominant-negative mutants induced dorsal differentiation
whereas the wildtype forms caused ventral differentiation. The authors
suggested that dorsal differentiation involves the suppression of GSK3
activity by a Wnt-related signal.
Jia et al. (2002) reported that in addition to the role of Gsk3 proteins
as inhibitory components of the Wnt pathway, they also inhibit the
'hedgehog' (Hh) pathway (see SHH, 600725) in Drosophila. Gsk3
phosphorylates 'cubitus interruptus' (Ci; see GLI3, 165240) after a
primed phosphorylation by PKA, causing hyperphosphorylation of Ci and
thus targeting it for proteolytic processing. In contrast, Hh opposes Ci
proteolysis by promoting its dephosphorylation.
Trowbridge et al. (2006) showed that hematopoietic repopulation by
hematopoietic stem cells (HSC) can be augmented by administration of a
GSK3 inhibitor to recipient mice transplanted with mouse or human HSCs.
The results suggested that the use of GSK3 inhibitors may provide a
potent and unique clinical approach to directly enhance HSC repopulation
in vivo.
*FIELD* RF
1. Ali, A.; Hoeflich, K. P.; Woodgett, J. R.: Glycogen synthase kinase-3
: properties, functions, and regulation. Chem. Rev. 101: 2527-2540,
2001.
2. Aoukaty, A.; Tan, R.: Role for glycogen synthase kinase-3 in NK
cell cytotoxicity and X-linked lymphoproliferative disease. J. Immun. 174:
4551-4558, 2005.
3. Fang, X.; Yu, S.; Tanyi, J. L.; Lu, Y.; Woodgett, J. R.; Mills,
G. B.: Convergence of multiple signaling cascades at glycogen synthase
kinase 3: edg receptor-mediated phosphorylation and inactivation by
lysophosphatidic acid through a protein kinase C-dependent intracellular
pathway. Molec. Cell. Biol. 22: 2099-2110, 2002.
4. Fang, X.; Yu, S. X.; Lu, Y.; Bast, R. C., Jr.; Woodgett, J. R.;
Mills, G. B.: Phosphorylation and inactivation of glycogen synthase
kinase 3 by protein kinase A. Proc. Nat. Acad. Sci. 97: 11960-11965,
2000.
5. Hansen, L.; Arden, K. C.; Rasmussen, S. B.; Viars, C. S.; Vestergaard,
H.; Hansen, T.; Moller, A. M.; Woodgett, J. R.; Pedersen, O.: Chromosomal
mapping and mutational analysis of the coding region of the glycogen
synthase kinase-3-alpha and beta isoforms in patients with NIDDM. Diabetologia 40:
940-946, 1997.
6. He, X.; Saint-Jeannet, J.-P.; Woodgett, J. R.; Varmus, H. E.; Dawid,
I. B.: Glycogen synthase kinase-3 and dorsoventral patterning in
Xenopus embryos. Nature 374: 617-622, 1995. Note: Erratum: Nature
375: 253 only, 1995.
7. Hughes, K.; Nikolakaki, E.; Plyte, S. E.; Totty, N. F.; Woodgett,
J. R.: Modulation of the glycogen synthase kinase-3 family by tyrosine
phosphorylation. EMBO J. 12: 803-808, 1993.
8. Jia, J.; Amanai, K.; Wang, G.; Tang, J.; Wang, B.; Jiang, J.:
Shaggy/GSK3 antagonizes hedgehog signaling by regulating cubitus interruptus. Nature 416:
548-552, 2002.
9. Kim, S.-E.; Huang, H.; Zhao, M.; Zhang, X.; Zhang, A.; Semonov,
M. V.; MacDonald, B. T.; Zhang, X.; Abreu, J. G.; Peng, L.; He, X.
: Wnt stabilization of beta-catenin reveals principles for morphogen
receptor-scaffold assemblies. Science 340: 867-870, 2013.
10. Lin, S.-Y.; Li, T. Y.; Liu, Q.; Zhang, C.; Li, X.; Chen, Y.; Zhang,
S.-M.; Lian, G.; Liu, Q.; Ruan, K.; Wang, Z.; Zhang, C.-S.; Chien,
K.-Y.; Wu, J.; Li, Q.; Han, J.; Lin, S.-C.: GSK3-TIP60-ULK1 signaling
pathway links growth factor deprivation to autophagy. Science 336:
477-481, 2012. Note: Erratum: Science 337: 799 only, 2012.
11. Lohi, H.; Ianzano, L.; Zhao, X.-C.; Chan, E. M.; Turnbull, J.;
Scherer, S. W.; Ackerley, C. A.; Minassian, B. A.: Novel glycogen
synthase kinase 3 and ubiquitination pathways in progressive myoclonus
epilepsy. Hum. Molec. Genet. 14: 2727-2736, 2005.
12. Maurer, U.; Charvet, C.; Wagman, A. S.; Dejardin, E.; Green, D.
R.: Glycogen synthase kinase-3 regulates mitochondrial outer membrane
permeabilization and apoptosis by destabilization of MCL-1. Molec.
Cell 21: 749-760, 2006.
13. Phiel, C. J.; Wilson, C. A.; Lee, V. M.-Y.; Klein, P. S.: GSK-3-alpha
regulates production of Alzheimer's disease amyloid-beta peptides. Nature 423:
435-439, 2003.
14. Taelman, V. F.; Dobrowolski, R.; Plouhinec, J.-L.; Fuentealba,
L. C.; Vorwald, P. P.; Gumper, I.; Sabatini, D. D.; De Robertis, E.
M.: Wnt signaling requires sequestration of glycogen synthase kinase
3 inside multivesicular endosomes. Cell 143: 1136-1148, 2010.
15. Trowbridge, J. J.; Xenocostas, A.; Moon, R. T.; Bhatia, M.: Glycogen
synthase kinase-3 is an in vivo regulator of hematopoietic stem cell
repopulation. Nature Med. 12: 89-98, 2006.
16. Wang, Z.; Smith, K. S.; Murphy, M.; Piloto, O.; Somervaille, T.
C. P.; Cleary, M. L.: Glycogen synthase kinase 3 in MLL leukaemia
maintenance and targeted therapy. Nature 455: 1205-1209, 2008.
17. Woodgett, J. R.: Molecular cloning and expression of glycogen
synthase kinase-3/factor A. EMBO J. 9: 2431-2438, 1990.
18. Yost, C.; Farr, G. H., III; Pierce, S. B.; Ferkey, D. M.; Chen,
M. M.; Kimelman, D.: GBP, an inhibitor of GSK-3, is implicated in
Xenopus development and oncogenesis. Cell 93: 1031-1041, 1998.
19. Zeng, X.; Tamai, K.; Doble, B.; Li, S.; Huang, H.; Habas, R.;
Okamura, H.; Woodgett, J.; He, X.: A dual-kinase mechanism for Wnt
co-receptor phosphorylation and activation. Nature 438: 873-877,
2005.
*FIELD* CN
Ada Hamosh - updated: 06/25/2013
Ada Hamosh - updated: 9/20/2012
Patricia A. Hartz - updated: 3/9/2011
Ada Hamosh - updated: 12/31/2008
George E. Tiller - updated: 12/10/2008
Paul J. Converse - updated: 10/20/2006
Ada Hamosh - updated: 5/26/2006
Patricia A. Hartz - updated: 4/10/2006
Victor A. McKusick - updated: 2/16/2006
Cassandra L. Kniffin - updated: 5/21/2003
*FIELD* CD
Paul J. Converse: 3/25/2002
*FIELD* ED
alopez: 06/25/2013
terry: 3/14/2013
alopez: 3/5/2013
alopez: 9/25/2012
terry: 9/20/2012
mgross: 6/6/2011
terry: 3/9/2011
alopez: 12/31/2008
wwang: 12/17/2008
wwang: 12/10/2008
mgross: 10/24/2006
mgross: 10/20/2006
alopez: 6/7/2006
terry: 5/26/2006
mgross: 4/12/2006
terry: 4/10/2006
alopez: 3/13/2006
terry: 2/16/2006
cwells: 11/10/2003
carol: 5/21/2003
ckniffin: 5/16/2003
alopez: 4/12/2002
alopez: 3/26/2002
alopez: 3/25/2002