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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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. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed24391509).  
17
  • UniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
1
  • UniProtKB KW
Beta-catenin bindingdefinition[GO:0008013]  
1
  • BHF-UCL
Kinase activitydefinition[GO:0016301]  
2
  • UniProtKB
NF-kappaB bindingdefinition[GO:0051059]  
1
  • UniProtKB
P53 bindingdefinition[GO:0002039]  
1
  • MGI
Protein bindingdefinition[GO:0005515]  
49
  • IntAct
  • UniProtKB
  • HGNC
  • BHF-UCL
Protein kinase A catalytic subunit bindingdefinition[GO:0034236]  
1
  • BHF-UCL
Protein kinase bindingdefinition[GO:0019901]  
1
  • UniProtKB
Protein serine/threonine kinase activitydefinition[GO:0004674]  
7
  • UniProtKB
  • MGI
  • BHF-UCL
  • Ortholog Curator
RNA polymerase II transcription factor bindingdefinition[GO:0001085]  
1
  • UniProtKB
Tau-protein kinase activitydefinition[GO:0050321]  
2
  • BHF-UCL
  • UniProtKB
Ubiquitin protein ligase bindingdefinition[GO:0031625]  
1
  • BHF-UCL
GO biological process 
Canonical Wnt signaling pathwaydefinition[GO:0060070]  
2
  • BHF-UCL
  • UniProtKB
Canonical Wnt signaling pathway involved in positive regulation of apoptotic processdefinition[GO:0044337] silver  
1
  • Ortholog Compara
Cell migrationdefinition[GO:0016477] silver  
1
  • Ortholog Compara
Cellular response to interleukin-3definition[GO:0036016]  
1
  • Ortholog Curator
Circadian rhythmdefinition[GO:0007623]  
1
  • Ortholog Curator
Epithelial to mesenchymal transitiondefinition[GO:0001837]  
1
  • UniProtKB
ER overload responsedefinition[GO:0006983]  
1
  • MGI
Extrinsic apoptotic signaling pathway in absence of liganddefinition[GO:0097192]  
1
  • Ortholog Curator
Fat cell differentiationdefinition[GO:0045444] silver  
1
  • Ortholog Compara
Glycogen metabolic processdefinition[GO:0005977]  
1
  • BHF-UCL
Hippocampus developmentdefinition[GO:0021766]  
1
  • BHF-UCL
Hypermethylation of CpG islanddefinition[GO:0044027] silver  
1
  • Ortholog Compara
Intracellular signal transductiondefinition[GO:0035556]  
1
  • MGI
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stressdefinition[GO:0070059] silver  
1
  • Ortholog Compara
Myoblast fusiondefinition[GO:0007520] silver  
1
  • Ortholog Compara
Negative regulation of apoptotic processdefinition[GO:0043066]  
1
  • MGI
Negative regulation of canonical Wnt signaling pathwaydefinition[GO:0090090]  
1
  • UniProtKB
Negative regulation of cardiac muscle hypertrophydefinition[GO:0010614] silver  
1
  • Ortholog Compara
Negative regulation of glycogen (starch) synthase activitydefinition[GO:2000466]  
1
  • UniProtKB
Negative regulation of glycogen biosynthetic processdefinition[GO:0045719]  
1
  • UniProtKB
Negative regulation of neuron maturationdefinition[GO:0014043] silver  
1
  • Ortholog Compara
Negative regulation of neuron projection developmentdefinition[GO:0010977] silver  
1
  • Ortholog Compara
Negative regulation of NFAT protein import into nucleusdefinition[GO:0051534]  
1
  • UniProtKB
Negative regulation of protein bindingdefinition[GO:0032091]  
1
  • BHF-UCL
Negative regulation of protein complex assemblydefinition[GO:0031333]  
1
  • BHF-UCL
Negative regulation of protein localization to nucleusdefinition[GO:1900181]  
1
  • Ortholog Curator
Negative regulation of type B pancreatic cell developmentdefinition[GO:2000077]  
1
  • UniProtKB
Organ morphogenesisdefinition[GO:0009887] silver  
1
  • Ortholog Compara
Peptidyl-serine phosphorylationdefinition[GO:0018105]  
3
  • MGI
  • BHF-UCL
Positive regulation of axon extensiondefinition[GO:0045773] silver  
1
  • Ortholog Compara
Positive regulation of cell-matrix adhesiondefinition[GO:0001954]  
1
  • BHF-UCL
Positive regulation of GTPase activitydefinition[GO:0043547]  
1
  • BHF-UCL
Positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathwaydefinition[GO:1901030]  
1
  • Ortholog Curator
Positive regulation of peptidyl-serine phosphorylationdefinition[GO:0033138] silver  
1
  • Ortholog Compara
Positive regulation of peptidyl-threonine phosphorylationdefinition[GO:0010800] silver  
1
  • Ortholog Compara
Positive regulation of proteasomal ubiquitin-dependent protein catabolic processdefinition[GO:0032436] silver  
1
  • Ortholog Compara
Positive regulation of protein bindingdefinition[GO:0032092]  
1
  • Ortholog Curator
Positive regulation of protein catabolic processdefinition[GO:0045732]  
1
  • BHF-UCL
Positive regulation of protein complex assemblydefinition[GO:0031334]  
1
  • BHF-UCL
Positive regulation of protein export from nucleusdefinition[GO:0046827]  
1
  • MGI
Positive regulation of stem cell differentiationdefinition[GO:2000738] silver  
1
  • Ortholog Compara
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944] silver  
1
  • Ortholog Compara
Protein autophosphorylationdefinition[GO:0046777]  
1
  • UniProtKB
Protein export from nucleusdefinition[GO:0006611] silver  
1
  • Ortholog Compara
Protein localization to microtubuledefinition[GO:0035372] silver  
1
  • Ortholog Compara
Protein phosphorylationdefinition[GO:0006468]  
2
  • UniProtKB
  • BHF-UCL
Re-entry into mitotic cell cycledefinition[GO:0000320] silver  
1
  • Ortholog Compara
Regulation of gene expression by genetic imprintingdefinition[GO:0006349] silver  
1
  • Ortholog Compara
Regulation of microtubule-based processdefinition[GO:0032886]  
1
  • UniProtKB
Superior temporal gyrus developmentdefinition[GO:0071109]  
1
  • BHF-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.  
1
  • UniProtKB
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
1
  • UniProtKB
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.  
5
  • UniProtKB
 
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:
AKT phosphorylates targets in the cytosol  R-HSA-198323  
APC truncation mutants have impaired AXIN binding  R-HSA-5467337  
AXIN missense mutants destabilize the destruction complex  R-HSA-5467340  
Beta-catenin phosphorylation cascade  R-HSA-196299  
Constitutive Signaling by AKT1 E17K in Cancer  R-HSA-5674400  
CRMPs in Sema3A signaling  R-HSA-399956  
Degradation of beta-catenin by the destruction complex  R-HSA-195253  
Degradation of GLI2 by the proteasome  R-HSA-5610783  
Disassembly of the destruction complex and recruitment of AXIN to the membrane  R-HSA-4641262  
GLI3 is processed to GLI3R by the proteasome  R-HSA-5610785  
Misspliced GSK3beta mutants stabilize beta-catenin  R-HSA-5339716  
Regulation of HSF1-mediated heat shock response  R-HSA-3371453  
S33 mutants of beta-catenin aren't phosphorylated  R-HSA-5358747  
S37 mutants of beta-catenin aren't phosphorylated  R-HSA-5358749  
S45 mutants of beta-catenin aren't phosphorylated  R-HSA-5358751  
T41 mutants of beta-catenin aren't phosphorylated  R-HSA-5358752  
Truncations of AMER1 destabilize the destruction complex  R-HSA-5467348  
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).  
3
  • UniProtKB
 

Keywords

Biological process 
Biological rhythms  definition   [KW-0090]
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