GSK3B_SPECI
ID GSK3B_SPECI Reviewed; 420 AA.
AC Q5YJC2;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 1.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=Glycogen synthase kinase-3 beta;
DE Short=GSK-3 beta;
DE EC=2.7.11.26 {ECO:0000250|UniProtKB:P49841};
DE AltName: Full=Serine/threonine-protein kinase GSK3B;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:P49841};
GN Name=GSK3B;
OS Spermophilus citellus (European suslik) (Citellus citellus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Sciuromorpha; Sciuridae;
OC Xerinae; Marmotini; Spermophilus.
OX NCBI_TaxID=9997;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Stieler J.T., Strijkstra A.M.;
RT "Molecular cloning of Spermophilus citellus glycogen synthase kinase 3
RT beta.";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
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 EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN,
CC NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of
CC the majority of its substrates. In skeletal muscle, contributes to
CC insulin regulation of glycogen synthesis by phosphorylating and
CC inhibiting GYS1 activity and hence glycogen synthesis. May also mediate
CC the development of insulin resistance by regulating activation of
CC transcription factors. Regulates protein synthesis by controlling the
CC activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as
CC glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex
CC with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-
CC terminus of CTNNB1 leading to its degradation mediated by
CC ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-
CC binding domain, thereby reducing its affinity for DNA. Phosphorylates
CC NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC
CC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby
CC opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-
CC 548', decreasing significantly MAPT/TAU ability to bind and stabilize
CC microtubules. MAPT/TAU is the principal component of neurofibrillary
CC tangles in Alzheimer disease. Plays an important role in ERBB2-
CC dependent stabilization of microtubules at the cell cortex (By
CC similarity). Phosphorylates MACF1, inhibiting its binding to
CC microtubules which is critical for its role in bulge stem cell
CC migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1)
CC at the transcriptional level and is required for the NF-kappa-B-
CC mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively
CC regulates replication in pancreatic beta-cells, resulting in apoptosis,
CC loss of beta-cells and diabetes. Through phosphorylation of the anti-
CC apoptotic protein MCL1, may control cell apoptosis in response to
CC growth factors deprivation (By similarity). Phosphorylates MUC1 in
CC breast cancer cells, decreasing the interaction of MUC1 with
CC CTNNB1/beta-catenin. Is necessary for the establishment of neuronal
CC polarity and axon outgrowth (By similarity). Phosphorylates MARK2,
CC leading to inhibition of its activity (By similarity). Phosphorylates
CC SIK1 at 'Thr-182', leading to sustainment of its activity.
CC Phosphorylates ZC3HAV1 which enhances its antiviral activity.
CC Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and
CC proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell
CC activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and
CC stabilizes it by protecting it from proteasomal degradation. Regulates
CC the circadian clock via phosphorylation of the major clock components
CC including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-
CC 427' and targets it for proteasomal degradation. Phosphorylates
CC ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination
CC and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4'
CC which positively regulates its activity. Phosphorylates MYCN in
CC neuroblastoma cells which may promote its degradation (By similarity).
CC Regulates the circadian rhythmicity of hippocampal long-term
CC potentiation and ARNTL/BMLA1 and PER2 expression (By similarity). Acts
CC as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60
CC under starvation conditions, activating KAT5/TIP60 acetyltransferase
CC activity and promoting acetylation of key autophagy regulators, such as
CC ULK1 and RUBCNL/Pacer. 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. Phosphorylates E2F1, promoting the interaction between
CC E2F1 and USP11, stabilizing E2F1 and promoting its activity (By
CC similarity). {ECO:0000250|UniProtKB:P18266,
CC ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q9WV60}.
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 Evidence={ECO:0000250|UniProtKB:P49841};
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; Evidence={ECO:0000250|UniProtKB:P49841};
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:P49841};
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:0000250|UniProtKB:P49841};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Tyr-216. In
CC response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1;
CC phosphorylation at this site causes a conformational change, preventing
CC access of substrates to the active site. Inhibited by lithium (By
CC similarity). {ECO:0000250}.
CC -!- SUBUNIT: Monomer (By similarity). Interacts with DAB2IP (via C2
CC domain); the interaction stimulates GSK3B kinase activation (By
CC similarity). Interacts (via C2 domain) with PPP2CA (By similarity).
CC Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE1 and
CC ZBED3 (By similarity). Interacts with AXIN1; the interaction mediates
CC hyperphosphorylation of CTNNB1 leading to its ubiquitination and
CC destruction (By similarity). Interacts with and phosphorylates SNAI1
CC (By similarity). Interacts with DNM1L (via a C-terminal domain) (By
CC similarity). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1
CC and GSK3B (By similarity). Interacts with SGK3 (By similarity).
CC Interacts with the CLOCK-ARNTL/BMAL1 heterodimer (By similarity).
CC Interacts with the ARNTL/BMAL1 (By similarity). Interacts with CTNND2
CC (By similarity). The complex composed, at least, of APC, CTNNB1 and
CC GSK3B interacts with JPT1; the interaction requires the inactive form
CC of GSK3B (phosphorylated at 'Ser-9') (By similarity). Forms a complex
CC composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP
CC interaction; facilitates PKA-induced phosphorylation and regulates
CC GSK3B activity (By similarity). Interacts with GSKIP (By similarity).
CC Interacts with GID8 (By similarity). Interacts with PIWIL2 (By
CC similarity). Interacts with LMBR1L (By similarity). Interacts with
CC DDX3X (By similarity). Interacts with BIRC2 (By similarity). Interacts
CC with TNFRSF10B; TNFRSF10B stimulation inhibits GSK3B kinase activity
CC (By similarity). {ECO:0000250|UniProtKB:P18266,
CC ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q9WV60}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P49841}. Nucleus
CC {ECO:0000250|UniProtKB:P49841}. Cell membrane
CC {ECO:0000250|UniProtKB:P49841}. Note=The phosphorylated form shows
CC localization to cytoplasm and cell membrane. The MEMO1-RHOA-DIAPH1
CC signaling pathway controls localization of the phosphorylated form to
CC the cell membrane (By similarity). {ECO:0000250|UniProtKB:P49841}.
CC -!- PTM: Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling,
CC the activated PKB/AKT1 and RPS6KA3 protein kinases phosphorylate and
CC deactivate GSK3B, resulting in the dephosphorylation and activation of
CC GYS1. Activated by phosphorylation at Tyr-216 (By similarity).
CC Inactivated by phosphorylation at Ser-9 (By similarity).
CC {ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q9WV60}.
CC -!- PTM: Mono-ADP-ribosylation by PARP10 negatively regulates kinase
CC activity. {ECO:0000250|UniProtKB:P49841}.
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; AY392021; AAS59774.1; -; mRNA.
DR AlphaFoldDB; Q5YJC2; -.
DR SMR; Q5YJC2; -.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016301; F:kinase activity; ISS:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0050321; F:tau-protein kinase activity; ISS:UniProtKB.
DR GO; GO:0036016; P:cellular response to interleukin-3; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0001837; P:epithelial to mesenchymal transition; ISS:UniProtKB.
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:0070885; P:negative regulation of calcineurin-NFAT signaling cascade; ISS:UniProtKB.
DR GO; GO:0051093; P:negative regulation of developmental process; IEA:UniProt.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISS:UniProtKB.
DR GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0045724; P:positive regulation of cilium assembly; ISS:UniProtKB.
DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISS:UniProtKB.
DR GO; GO:1903566; P:positive regulation of protein localization to cilium; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0032886; P:regulation of microtubule-based process; ISS:UniProtKB.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd14137; STKc_GSK3; 1.
DR InterPro; IPR033573; GSK3B.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR039192; STKc_GSK3.
DR PANTHER; PTHR24057:SF8; PTHR24057:SF8; 1.
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 2: Evidence at transcript level;
KW ADP-ribosylation; ATP-binding; Biological rhythms; Carbohydrate metabolism;
KW Cell membrane; Cytoplasm; Developmental protein; Differentiation;
KW Glycogen metabolism; Kinase; Membrane; Neurogenesis; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Serine/threonine-protein kinase;
KW Signal transduction inhibitor; Transferase; Wnt signaling pathway.
FT CHAIN 1..420
FT /note="Glycogen synthase kinase-3 beta"
FT /id="PRO_0000250495"
FT DOMAIN 56..340
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..35
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 387..420
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..25
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 62..70
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 85
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 9
FT /note="Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3"
FT /evidence="ECO:0000250|UniProtKB:P49841"
FT MOD_RES 216
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P49841"
FT MOD_RES 389
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9WV60"
FT MOD_RES 390
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P49841"
SQ SEQUENCE 420 AA; 46744 MW; 5F5243CA7D9EA549 CRC64;
MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK
VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG
EKKDVVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR
DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDV
WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP
WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF
NFTTQELSSN PPLATILIPP HARIQAAAST PTNATAASDA NAGDRGQTNN AAFASASNST
