Summary

Name GSK3B
Full Name Glycogen synthase kinase-3 beta
Synonyms GSK-3 beta, Serine/threonine-protein kinase GSK3B, 2.7.11.1
Primary ID P49841
Links - -
Type protein
Relations 494
Pathways Adipogenesis, Alzheimer, Acute Myeloid Leukemia, AML_TRIPLETS, IBD_DENDRITIC CELLS, FLT3-ITD signaling, Cell cycle: G1/S phase transition, Cell cycle: G2/M phase transition, Sonic Hedgehog, IBD_IEC, Insulin Signaling, MTOR Signaling, Triple mutant AML, PI3K/AKT Signaling, WNT/FLT3, YAP/TAZ regulation
Inhibitors 3-[[6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenol; CHIR-98014; 3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one; CHIR 99021; 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione
Function Constitutively 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 (PubMed:19946213, PubMed:28903391). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (PubMed:18846110).

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Regulator Mechanism target score ℹ
+ GSK3Bdown-regulates img/direct_inhibition.png phosphorylation SNAI1 0.544
Publications: 14 Organism: Homo Sapiens
+ GSK3Bup-regulates img/direct-activation.png phosphorylation ESR1 0.336
Publications: 4 Organism: Homo Sapiens
+ GSK3Bdown-regulates quantity img/direct_inhibition.png phosphorylation FAAP20 0.2
Publications: 1 Organism: Homo Sapiens
+ GSK3Bdown-regulates quantity by destabilization img/direct_inhibition.png phosphorylation CDKN1A 0.395
Publications: 1 Organism: Homo Sapiens
Pathways:Acute Myeloid Leukemia, FLT3-ITD signaling, Cell cycle: G1/S phase transition, Cell cycle: G2/M phase transition
+ GSK3Bup-regulates img/direct-activation.png phosphorylation FBXO4 0.2
Publications: 1 Organism: Homo Sapiens
+ GSK3Bdown-regulates activity img/direct_inhibition.png phosphorylation MUC1 0.447
Publications: 1
+ GSK3Bup-regulates activity img/direct-activation.png phosphorylation CREB1 0.702
Publications: 1 Organism: Rattus Norvegicus
Pathways:Adipogenesis, FLT3-ITD signaling, PI3K/AKT Signaling
+ GSK3Bdown-regulates img/direct_inhibition.png phosphorylation CAMKK2 0.269
Publications: 3 Organism: Homo Sapiens
+ GSK3Bdown-regulates quantity by destabilization img/direct_inhibition.png phosphorylation PIAS1 0.325
Publications: 2 Organism: Mus Musculus
+ GSK3Bdown-regulates img/direct_inhibition.png phosphorylation PHLPP1 0.345
Publications: 1 Organism: Homo Sapiens
+ GSK3Bdown-regulates quantity by destabilization img/direct_inhibition.png phosphorylation PHLPP1 0.345
Publications: 2 Organism: Homo Sapiens
+ GSK3Bdown-regulates quantity by destabilization img/direct_inhibition.png phosphorylation TOP2A 0.342
Publications: 1 Organism: Homo Sapiens
+ GSK3Bdown-regulates quantity by destabilization img/direct_inhibition.png phosphorylation SPI1 0.2
Publications: 2 Organism: Homo Sapiens
Pathways:Acute Myeloid Leukemia
+ GSK3Bup-regulates activity img/direct-activation.png phosphorylation LRP6 0.805
Publications: 1 Organism: Homo Sapiens
Pathways:WNT/FLT3
+ GSK3Bup-regulates activity img/direct-activation.png phosphorylation USF2 0.281
Publications: 2 Organism: Homo Sapiens
+ GSK3B