GSK3A_RAT
ID GSK3A_RAT Reviewed; 483 AA.
AC P18265;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 1.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=Glycogen synthase kinase-3 alpha;
DE Short=GSK-3 alpha;
DE EC=2.7.11.26;
DE AltName: Full=Factor A;
DE Short=FA;
DE AltName: Full=Serine/threonine-protein kinase GSK3A;
DE EC=2.7.11.1;
GN Name=Gsk3a;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=2164470; DOI=10.1002/j.1460-2075.1990.tb07419.x;
RA Woodgett J.R.;
RT "Molecular cloning and expression of glycogen synthase kinase-3/factor A.";
RL EMBO J. 9:2431-2438(1990).
RN [2]
RP PHOSPHORYLATION AT TYR-279.
RX PubMed=8382613; DOI=10.1002/j.1460-2075.1993.tb05715.x;
RA Hughes K., Nikolakaki E., Plyte S.E., Totty N.F., Woodgett J.R.;
RT "Modulation of the glycogen synthase kinase-3 family by tyrosine
RT phosphorylation.";
RL EMBO J. 12:803-808(1993).
RN [3]
RP FUNCTION IN REGULATION OF PANCREATIC BETA-CELLS.
RX PubMed=17242403; DOI=10.1074/jbc.m609637200;
RA Mussmann R., Geese M., Harder F., Kegel S., Andag U., Lomow A., Burk U.,
RA Onichtchouk D., Dohrmann C., Austen M.;
RT "Inhibition of GSK3 promotes replication and survival of pancreatic beta
RT cells.";
RL J. Biol. Chem. 282:12030-12037(2007).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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. Requires primed phosphorylation of
CC the majority of its substrates. Contributes to insulin regulation of
CC glycogen synthesis by phosphorylating and inhibiting GYS1 activity and
CC hence glycogen synthesis (By similarity). Regulates glycogen metabolism
CC in liver, but not in muscle (By similarity). May also mediate the
CC development of insulin resistance by regulating activation of
CC transcription factors. In Wnt signaling, regulates the level and
CC transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates
CC amyloid precursor protein (APP) processing and the generation of APP-
CC derived amyloid plaques found in Alzheimer disease (By similarity). May
CC be involved in the regulation of replication in pancreatic beta-cells
CC (PubMed:17242403). Is necessary for the establishment of neuronal
CC polarity and axon outgrowth. Through phosphorylation of the anti-
CC apoptotic protein MCL1, may control cell apoptosis in response to
CC growth factors deprivation (By similarity). Acts as a regulator of
CC autophagy by mediating phosphorylation of KAT5/TIP60 under starvation
CC conditions, activating KAT5/TIP60 acetyltransferase activity and
CC promoting acetylation of key autophagy regulators, such as ULK1 and
CC RUBCNL/Pacer (By similarity). Negatively regulates extrinsic apoptotic
CC signaling pathway via death domain receptors. Promotes the formation of
CC an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death
CC receptors, including TNFRSF10B. The anti-apoptotic function is most
CC effective with weak apoptotic signals and can be overcome by stronger
CC stimulation (By similarity). {ECO:0000250|UniProtKB:P49840,
CC ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q2NL51,
CC ECO:0000269|PubMed:17242403}.
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:0000250|UniProtKB:Q2NL51};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-279. In
CC response to insulin, inhibited by phosphorylation at Ser-21 by
CC PKB/AKT1; phosphorylation at this site causes a conformational change,
CC preventing access of substrates to the active site. Inhibited by
CC lithium (By similarity). {ECO:0000250}.
CC -!- SUBUNIT: Monomer. Interacts with ARRB2, AXIN1 and CTNNB1/beta-catenin
CC (By similarity). Interacts with CTNND2 (By similarity). Interacts with
CC LMBR1L (By similarity). Interacts with DDX3X (By similarity). Interacts
CC with TNFRSF10B (By similarity). {ECO:0000250|UniProtKB:P49840}.
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 (By similarity). {ECO:0000250}.
CC -!- MISCELLANEOUS: Simultaneous silencing of GSK3A and GSK3B by RNAi
CC stimulates replication and promotes survival of INS-1E pancreatic beta
CC cells. {ECO:0000305|PubMed:17242403}.
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; X53427; CAA37518.1; -; mRNA.
DR PIR; S14707; TVRTKA.
DR RefSeq; NP_059040.1; NM_017344.1.
DR AlphaFoldDB; P18265; -.
DR SMR; P18265; -.
DR BioGRID; 248424; 2.
DR CORUM; P18265; -.
DR IntAct; P18265; 3.
DR STRING; 10116.ENSRNOP00000027677; -.
DR ChEMBL; CHEMBL1075224; -.
DR iPTMnet; P18265; -.
DR PhosphoSitePlus; P18265; -.
DR jPOST; P18265; -.
DR PaxDb; P18265; -.
DR PRIDE; P18265; -.
DR DNASU; 50686; -.
DR GeneID; 50686; -.
DR KEGG; rno:50686; -.
DR UCSC; RGD:620351; rat.
DR CTD; 2931; -.
DR RGD; 620351; Gsk3a.
DR VEuPathDB; HostDB:ENSRNOG00000020417; -.
DR eggNOG; KOG0658; Eukaryota.
DR InParanoid; P18265; -.
DR OMA; CLHAFFD; -.
DR OrthoDB; 990896at2759; -.
DR PhylomeDB; P18265; -.
DR BRENDA; 2.7.11.26; 5301.
DR PRO; PR:P18265; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Bgee; ENSRNOG00000020417; Expressed in frontal cortex and 18 other tissues.
DR ExpressionAtlas; P18265; baseline.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005874; C:microtubule; IDA:RGD.
DR GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
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:0004672; F:protein kinase activity; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; IPI:RGD.
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; ISO:RGD.
DR GO; GO:0050321; F:tau-protein kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0007568; P:aging; IDA:RGD.
DR GO; GO:0003214; P:cardiac left ventricle morphogenesis; ISO:RGD.
DR GO; GO:0016477; P:cell migration; ISO:RGD.
DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; ISO:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; ISO:RGD.
DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR GO; GO:0071285; P:cellular response to lithium ion; ISO:RGD.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; ISO:RGD.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0008286; P:insulin receptor signaling pathway; ISO:RGD.
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; ISO:RGD.
DR GO; GO:2000171; P:negative regulation of dendrite development; IMP:RGD.
DR GO; GO:0046325; P:negative regulation of glucose import; ISO:RGD.
DR GO; GO:1904227; P:negative regulation of glycogen synthase activity, transferring glucose-1-phosphate; ISO:RGD.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISO:RGD.
DR GO; GO:0032007; P:negative regulation of TOR signaling; ISO:RGD.
DR GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISO:RGD.
DR GO; GO:0071879; P:positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway; ISO:RGD.
DR GO; GO:0106071; P:positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISO:RGD.
DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; ISO:RGD.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:2000467; P:positive regulation of glycogen (starch) synthase activity; ISO:RGD.
DR GO; GO:0045823; P:positive regulation of heart contraction; ISO:RGD.
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; IMP:RGD.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; ISO:RGD.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISO:RGD.
DR GO; GO:1903955; P:positive regulation of protein targeting to mitochondrion; ISO:RGD.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0006349; P:regulation of gene expression by genomic imprinting; ISO:RGD.
DR GO; GO:0010975; P:regulation of neuron projection development; IBA:GO_Central.
DR GO; GO:0003073; P:regulation of systemic arterial blood pressure; ISO:RGD.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd14137; STKc_GSK3; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR039192; STKc_GSK3.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Carbohydrate metabolism; Glycogen metabolism;
KW Kinase; Neurogenesis; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase;
KW Signal transduction inhibitor; Transferase; Wnt signaling pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P49840"
FT CHAIN 2..483
FT /note="Glycogen synthase kinase-3 alpha"
FT /id="PRO_0000085979"
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 443..483
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 449..483
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 244
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 125..133
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 148
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:P49840"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
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:0000250|UniProtKB:P49840"
FT MOD_RES 77
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49840"
FT MOD_RES 97
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49840"
FT MOD_RES 279
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:8382613"
SQ SEQUENCE 483 AA; 51027 MW; A98DC1C5C7F7B716 CRC64;
MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV
GASSSGGGPS GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV TTVVATLGQG PERSQEVAYT
DIKVIGNGSF GVVYQARLAE TRELVAIKKV LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY
SSGEKKDELY LNLVLEYVPE TVYRVARHFT KAKLIIPIIY VKVYMYQLFR SLAYIHSQGV
CHRDIKPQNL LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS
IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN YTEFKFPQIK
AHPWTKVFKS RTPPEAIALC SSLLEYTPSS RLSPLEACAH SFFDELRSLG TQLPNNRPLP
PLFNFSPGEL SIQPSLNAIL IPPHLRSPSG PATLTSSSQA LTETQTGQDW QAPDATPTLT
NSS
