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MGP001344

UniProt Annotations

Entry Information
Gene Nameglycogen synthase kinase 3 beta
Protein EntryGSK3B_HUMAN
UniProt IDP49841
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; Synonyms=GSK-3beta1; IsoId=P49841-1; Sequence=Displayed; Name=2; Synonyms=GSK-3beta2, neuron-specific; IsoId=P49841-2; Sequence=VSP_004790; Note=May play a specific role in axon growth and neurite outgrowth. Reduced binding to AXIN1, reduced ability to phosphorylate MAPT/TAU. {ECO:0000269|PubMed:20067585};
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
Catalytic ActivityATP + [tau protein] = ADP + [tau protein] phosphate.
Enzyme RegulationActivated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 and RPS6KA3; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium. {ECO:0000269|PubMed:11749387, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:19366350, ECO:0000269|PubMed:8524413}.
FunctionConstitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. {ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20932480, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:8397507, ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}.
InteractionP31749:AKT1; NbExp=3; IntAct=EBI-373586, EBI-296087; P31751:AKT2; NbExp=2; IntAct=EBI-373586, EBI-296058; O15169:AXIN1; NbExp=32; IntAct=EBI-373586, EBI-710484; O35625:Axin1 (xeno); NbExp=5; IntAct=EBI-373586, EBI-2365912; Q14DJ8:Axin1 (xeno); NbExp=2; IntAct=EBI-373586, EBI-4312125; Q96G01:BICD1; NbExp=7; IntAct=EBI-373586, EBI-1104509; P35222:CTNNB1; NbExp=15; IntAct=EBI-373586, EBI-491549; Q5VWQ8:DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-2871881; Q5VWQ8-2:DAB2IP; NbExp=2; IntAct=EBI-373586, EBI-9543020; Q9NYF0:DACT1; NbExp=3; IntAct=EBI-373586, EBI-3951744; O75398:DEAF1; NbExp=2; IntAct=EBI-373586, EBI-718185; Q811T9:Disc1 (xeno); NbExp=4; IntAct=EBI-373586, EBI-2298259; P13807:GYS1; NbExp=3; IntAct=EBI-373586, EBI-740553; O75581:LRP6; NbExp=4; IntAct=EBI-373586, EBI-910915; Q5S007:LRRK2; NbExp=7; IntAct=EBI-373586, EBI-5323863; P63085:Mapk1 (xeno); NbExp=2; IntAct=EBI-373586, EBI-397697; P10636:MAPT; NbExp=2; IntAct=EBI-373586, EBI-366182; P10636-8:MAPT; NbExp=9; IntAct=EBI-373586, EBI-366233; Q8N4C6:NIN; NbExp=3; IntAct=EBI-373586, EBI-1164022; P17612:PRKACA; NbExp=5; IntAct=EBI-373586, EBI-476586; Q01201:RELB; NbExp=4; IntAct=EBI-373586, EBI-357837; Q15797:SMAD1; NbExp=2; IntAct=EBI-373586, EBI-1567153; O95863:SNAI1; NbExp=5; IntAct=EBI-373586, EBI-1045459; P37840:SNCA; NbExp=2; IntAct=EBI-373586, EBI-985879; Q6J9G0:STYK1; NbExp=2; IntAct=EBI-373586, EBI-6424915; P04637:TP53; NbExp=3; IntAct=EBI-373586, EBI-366083; Q14134:TRIM29; NbExp=2; IntAct=EBI-373586, EBI-702370; O95071:UBR5; NbExp=8; IntAct=EBI-373586, EBI-358329; P63104:YWHAZ; NbExp=4; IntAct=EBI-373586, EBI-347088; Q8IX07:ZFPM1; NbExp=2; IntAct=EBI-373586, EBI-3942619;
MiscellaneousHigher expression and activity of GSK3B are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350). {ECO:0000305|PubMed:10868943, ECO:0000305|PubMed:19366350}.
PtmMono-ADP-ribosylation by PARP10 negatively regulates kinase activity.
PtmPhosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216. {ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:18669648, ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:8250835}.
SimilarityBelongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm. Nucleus. Cell membrane. Note=The phosphorylated form shows localization to cytoplasm and cell membrane. The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosphorylated form to the cell membrane.
SubunitMonomer. Interacts with ARRB2, DISC1 and ZBED3 (By similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction. Interacts with and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with SGK3. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA. Interacts with the CLOCK-ARNTL/BMAL1 heterodimer. Interacts with the ARNTL/BMAL1. {ECO:0000250, ECO:0000269|PubMed:11004522, ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:15752768, ECO:0000269|PubMed:16428445, ECO:0000269|PubMed:17318175, ECO:0000269|PubMed:19493954, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20080667, ECO:0000269|PubMed:9731200, ECO:0000269|PubMed:9819408}.
Tissue SpecificityExpressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain. {ECO:0000269|PubMed:21029237}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/GSK3BID40761ch3q13.html";
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