GSK3B - Glycogen synthase kinase-3 beta - human protein (Function)
 
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GSK3B »  Glycogen synthase kinase-3 beta   [ EC 2.7.11.26 ]  (GSK-3 beta)
 
Protein also known as:  Serine/threonine-protein kinase GSK3B [EC 2.7.11.1].
Gene name:  GSK3B
Entry whose protein(s) existence is based on evidence at protein level
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1 600 2
GENE REF ISO

Function

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Overview 
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. 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.  
15
  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524] silver  
  • IEAOrtholog Compara
Beta-catenin bindingdefinition[GO:0008013]  
1
  • IPIBHF-UCL
Integrin bindingdefinition[GO:0005178] silver  
  • IEAOrtholog Compara
Ionotropic glutamate receptor bindingdefinition[GO:0035255] silver  
  • IEAOrtholog Compara
Kinase activitydefinition[GO:0016301]  
1
  • IDAUniProtKB
NF-kappaB bindingdefinition[GO:0051059]  
1
  • IPIUniProtKB
P53 bindingdefinition[GO:0002039]  
1
  • IDAMGI
Protein bindingdefinition[GO:0005515]  
43
  • IPIIntAct
  • IPIBHF-UCL
  • IPIUniProtKB
  • IPIHGNC
Protein kinase A catalytic subunit bindingdefinition[GO:0034236]  
1
  • IPIBHF-UCL
Protein kinase bindingdefinition[GO:0019901]  
1
  • IPIUniProtKB
Protein serine/threonine kinase activitydefinition[GO:0004674]  
6
  • IDAUniProtKB
  • IDAMGI
  • IDABHF-UCL
  • ISSOrtholog Curator
RNA polymerase II transcription factor bindingdefinition[GO:0001085]  
1
  • IPIUniProtKB
Tau protein bindingdefinition[GO:0048156] silver  
  • IEAOrtholog Compara
Tau-protein kinase activitydefinition[GO:0050321]  
2
  • IDABHF-UCL
  • IDAUniProtKB
Ubiquitin protein ligase bindingdefinition[GO:0031625]  
1
  • IPIBHF-UCL
GO biological process 
Canonical Wnt signaling pathwaydefinition[GO:0060070]  
2
  • IDABHF-UCL
  • ICUniProtKB
Canonical Wnt signaling pathway involved in positive regulation of apoptotic processdefinition[GO:0044337] silver  
  • IEAOrtholog Compara
Cell migrationdefinition[GO:0016477] silver  
  • IEAOrtholog Compara
Cellular response to interleukin-3definition[GO:0036016]  
  • ISSOrtholog Curator
Cellular response to mechanical stimulusdefinition[GO:0071260] silver  
  • IEAOrtholog Compara
Circadian rhythmdefinition[GO:0007623]  
  • ISSOrtholog Curator
Epithelial to mesenchymal transitiondefinition[GO:0001837]  
1
  • IMPUniProtKB
ER overload responsedefinition[GO:0006983]  
1
  • IDAMGI
Establishment of cell polaritydefinition[GO:0030010] silver  
  • IEAOrtholog Compara
Extrinsic apoptotic signaling pathway in absence of liganddefinition[GO:0097192]  
  • ISSOrtholog Curator
Fat cell differentiationdefinition[GO:0045444] silver  
  • IEAOrtholog Compara
Glycogen metabolic processdefinition[GO:0005977]  
1
  • IDABHF-UCL
Hippocampus developmentdefinition[GO:0021766]  
1
  • IMPBHF-UCL
Hypermethylation of CpG islanddefinition[GO:0044027] silver  
  • IEAOrtholog Compara
Intracellular signal transductiondefinition[GO:0035556]  
1
  • IDAMGI
Myoblast fusiondefinition[GO:0007520] silver  
  • IEAOrtholog Compara
Negative regulation of apoptotic processdefinition[GO:0043066]  
1
  • IDAMGI
Negative regulation of canonical Wnt signaling pathwaydefinition[GO:0090090]  
1
  • TASUniProtKB
Negative regulation of cardiac muscle hypertrophydefinition[GO:0010614] silver  
  • IEAOrtholog Compara
Negative regulation of dendrite morphogenesisdefinition[GO:0050774] silver  
  • IEAOrtholog Compara
Negative regulation of glycogen (starch) synthase activitydefinition[GO:2000466]  
1
  • TASUniProtKB
Negative regulation of glycogen biosynthetic processdefinition[GO:0045719]  
1
  • TASUniProtKB
Negative regulation of MAP kinase activitydefinition[GO:0043407] silver  
  • IEAOrtholog Compara
Negative regulation of NFAT protein import into nucleusdefinition[GO:0051534]  
1
  • IMPUniProtKB
Negative regulation of protein bindingdefinition[GO:0032091]  
1
  • IDABHF-UCL
Negative regulation of protein complex assemblydefinition[GO:0031333]  
1
  • IMPBHF-UCL
Negative regulation of type B pancreatic cell developmentdefinition[GO:2000077]  
1
  • TASUniProtKB
Organ morphogenesisdefinition[GO:0009887] silver  
  • IEAOrtholog Compara
Peptidyl-serine phosphorylationdefinition[GO:0018105]  
3
  • IDAMGI
  • IDABHF-UCL
Positive regulation of cell-matrix adhesiondefinition[GO:0001954]  
1
  • IMPBHF-UCL
Positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathwaydefinition[GO:1901030]  
  • ISSOrtholog Curator
Positive regulation of peptidyl-serine phosphorylationdefinition[GO:0033138] silver  
  • IEAOrtholog Compara
Positive regulation of peptidyl-threonine phosphorylationdefinition[GO:0010800] silver  
  • IEAOrtholog Compara
Positive regulation of protein bindingdefinition[GO:0032092]  
  • ISSOrtholog Curator
Positive regulation of protein catabolic processdefinition[GO:0045732]  
1
  • ICBHF-UCL
Positive regulation of protein complex assemblydefinition[GO:0031334]  
1
  • IDABHF-UCL
Positive regulation of protein export from nucleusdefinition[GO:0046827]  
1
  • IDAMGI
Positive regulation of Rac GTPase activitydefinition[GO:0032855]  
1
  • IMPBHF-UCL
Positive regulation of stem cell differentiationdefinition[GO:2000738] silver  
  • IEAOrtholog Compara
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944] silver  
  • IEAOrtholog Compara
Protein export from nucleusdefinition[GO:0006611] silver  
  • IEAOrtholog Compara
Protein localization to microtubuledefinition[GO:0035372] silver  
  • IEAOrtholog Compara
Protein phosphorylationdefinition[GO:0006468]  
2
  • IDAUniProtKB
  • IDABHF-UCL
Re-entry into mitotic cell cycledefinition[GO:0000320] silver  
  • IEAOrtholog Compara
Regulation of gene expression by genetic imprintingdefinition[GO:0006349] silver  
  • IEAOrtholog Compara
Regulation of microtubule-based processdefinition[GO:0032886]  
1
  • IMPUniProtKB
Regulation of neuronal synaptic plasticitydefinition[GO:0048168] silver  
  • IEAOrtholog Compara
Response to drugdefinition[GO:0042493] silver  
  • IEAOrtholog Compara
Response to lithium iondefinition[GO:0010226] silver  
  • IEAOrtholog Compara
Superior temporal gyrus developmentdefinition[GO:0071109]  
1
  • IMPBHF-UCL
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reactions
EC 2.7.11.26: ATP + [tau protein] ADP + [tau protein] phosphate.  
  • CuratedUniProtKB
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
It is regulated in the following manner
Activated 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.  
4
  • CuratedUniProtKB
 
More information is available from:
Pathways 
According to KEGG, this protein belongs to the following pathways:
Alzheimer's disease  hsa05010+2932  
Axon guidance  hsa04360+2932  
B cell receptor signaling pathway  hsa04662+2932  
Basal cell carcinoma  hsa05217+2932  
Cell cycle  hsa04110+2932  
Chemokine signaling pathway  hsa04062+2932  
Colorectal cancer  hsa05210+2932  
Dopaminergic synapse  hsa04728+2932  
Endometrial cancer  hsa05213+2932  
ErbB signaling pathway  hsa04012+2932  
Focal adhesion  hsa04510+2932  
Hedgehog signaling pathway  hsa04340+2932  
Hepatitis C  hsa05160+2932  
HTLV-I infection  hsa05166+2932  
Influenza A  hsa05164+2932  
Insulin signaling pathway  hsa04910+2932  
Measles  hsa05162+2932  
Melanogenesis  hsa04916+2932  
Neurotrophin signaling pathway  hsa04722+2932  
Pathways in cancer  hsa05200+2932  
Prostate cancer  hsa05215+2932  
T cell receptor signaling pathway  hsa04660+2932  
Wnt signaling pathway  hsa04310+2932  
According to Reactome, this protein belongs to the following pathways:
Cellular responses to stress  REACT_120956  
Developmental Biology  REACT_111045  
Disease  REACT_116125  
Immune System  REACT_6900  
Signal Transduction  REACT_111102  
Note 
Higher expression and activity of GSK3B are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed19366350).  
2
  • CuratedUniProtKB
 

Keywords

Biological process 
Carbohydrate metabolism  definition   [KW-0119]
Differentiation  definition   [KW-0221]
Glycogen metabolism  definition   [KW-0321]
Neurogenesis  definition   [KW-0524]
Wnt signaling pathway  definition   [KW-0879]
Molecular function 
Developmental protein  definition   [KW-0217]
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Signal transduction inhibitor  definition   [KW-0734]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: GSK3B
GenomeRNAi: 2932
PRO: PR:P49841
Chemistry
GuidetoPHARMACOLOGY: 2030