Atlas of Genetics and Cytogenetics in Oncology and Haematology

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GSK3B (glycogen synthase kinase 3 beta)

Identity

Other namesEC 2.7.11.26
HGNC (Hugo) GSK3B
LocusID (NCBI) 2932
Location 3q13.33
Location_base_pair Starts at 119540802 and ends at 119813264 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Human: Nuclear receptor subfamily 1, group I, member 2 (NR1I2); GSK3B; G-protein coupled receptor 156 (GPR156).
Mouse: G-protein coupled receptor 156 (Gpr156); Gsk3b; Nuclear receptor subfamily 1, group I, member 2 (Nr1i2).

DNA/RNA

 
  A) Human GSK3B gene, isoform 1. B) Mouse Gsk3b gene. GSK3B is comprised of 12 exons in human and 11 exons in mouse. The ATG start codon is located within exon 1 and the TAG stop codon is found in exon 12 (Human) and 11 (Mouse). The sizes of exons for human gene 1-12 are 1071 bp, 191 bp, 85 bp, 110 bp, 130 bp, 106 bp, 97 bp, 95 bp, 38 bp, 186 bp, 98 bp and 604 bp, respectively. The sizes of exons for mouse gene 1-11 are 1613 bp, 193 bp, 83 bp, 110 bp, 130 bp, 106 bp, 97 bp, 95 bp, 186 bp, 98 bp and 5577 bp, respectively.
Description According to Entrez-Gene, human GSK3B maps to locus NC_000003.11. This gene contains 12 exons that encompass 266971 bp of genomic DNA. In mice, GSK3B maps to NC_000082.5 and contains 11 exons that span 157079 bp of DNA within the mouse genome.
Transcription Human GSK3B mRNA (NM_002193.3) consists of 7134 bp, and murine GSK3B mRNA (NM_019827) contains 8298 bp. Alternatively spliced transcript variants encoding different isoforms (1 and 2) have been found for human gene. Transcript variant 2 is missing an in-frame coding exon (9) compared to variant 1, resulting in a shorter isoform 2 lacking a 13 aa segment compared to isoform 1.
Pseudogene No pseudogene has been identified for GSK3B.

Protein

 
  GSK3B structure. GSK3B is a 46-47 kDa protein consisting of 433 and 420 amino acids in human and mouse respectively. The protein contains an N-terminal domain, a kinase domain and a C-terminal domain. Phosphorylation of Tyr216 located in the T-loop (activation site) facilitates substrate phosphorylation by GSK3B but is not strictly required for its kinase activity. Phosphorylation of GSK3B at Ser9 in N-terminal region leads to inhibition of its kinase activity. Binding domain (BD) includes GSK3B specific binding sites for substrates and protein complexes (e.g., p53).
Description Glycogen synthase kinase-3 beta (GSK3B) was named due to its ability to phosphorylate and inactivate glycogen synthase. GSK3B is a multifunctional serine/threonine kinase which has been implicated in multiple biological processes including embryonic development, cell differentiation, apoptosis and insulin response. GSK3B is a key component in neuronal functions and has been implicated in major diseases involving the central nervous system.
Expression GSK3B was originally isolated from the skeletal muscle but it is ubiquitously expressed in almost all the tissues. However, abundant expression is detected in brain tissue, especially in the neurons when compared to the astrocytes. The high level of expression in the brain is due to its vital role in the neuronal signaling. Dysregulation of GSK3B expression leads to various pathological conditions such as diabetes or insulin resistance, neuronal dysfunction and neuronal diseases.
Localisation GSK3B is generally considered a cytosolic protein; however, it is reported to be present in the nucleus and mitochondria. Nuclear and mitochondrial localization of GSK3B correlates with its higher kinase activity compared to cytosolic protein. Translocation and specific cellular localization of GSK3B determine its involvement in signaling pathways, regulate its interaction with substrates and participation in protein complex formation, and influence gene expression and transcription.
Function GSK3B is a multifunctional protein kinase which is implicated in a large number of cellular processes and diseases. GSK3B is regulated by serine (inhibitory) and tyrosine (activating) phosphorylation. More than 40 proteins have been reported to be phosphorylated by GSK3B. GSK3B substrates include metabolic and signaling proteins like glycogen synthase, Acetyl CoA carboxylase, Axin, Cyclin D1; structural proteins like Tau, neural cell adhesion protein (NCAM); transcription factors like beta-catenin, p53, Myc, NFkappaB, CREB and AP-1; apoptotic-related proteins like Bax and p53. GSK3B also regulates various cellular processes by binding to protein complexes.
Homology The GSK3B gene is conserved in human, chimpanzee, dog, cow, rat, chicken, zebrafish, fruit fly, mosquito, C. elegans, A. thaliana, rice, and P. falciparum.

Mutations

Germinal 1. Several rare sequence variants in GSK3B were identified in the case-control study of patients with probable Alzheimer disease (AD), familial frontotemporal dementia (FTD), primary progressive aphasia, and aged healthy subjects. An intronic polymorphism (IVS2-68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%).

2. GSK3beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Effect of rs334558 was studied on grey matter volumes of patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness.

Implicated in

Entity Ovarian cancer
Note Ovarian cancer is a leading cause of death from gynecological malignancies. GSK3B promotes ovarian cancer cell proliferation by regulating Cyclin D1. GSK3B-dependent increased Cyclin D1 expression in ovarian cancer cells supports a possibility that GSK3B is involved in ovarian tumor chemotherapy resistance. Therefore, it is possible that combination of traditional chemotherapy and GSK3B inhibitors would benefit ovarian cancer patient response.
  
Entity Prostate cancer
Note Androgen receptor (AR) regulates growth of normal and cancer prostate cells. AR phosphorylation status is associated with its transcriptional activation. GSK3B interacts directly with the AR, modulates AR signaling and plays important role in the control of the proliferation of normal and malignant androgen-regulated tissues. Therefore, pharmacological inhibitors designed to increase GSK3B activity could be useful in prostate cancer therapy.
  
Entity Pancreatic cancer
Note It was shown that pancreatic cancer cells contain a pool of active GSK3B, and that pharmacological inhibition of GSK3B kinase activity using small molecule inhibitors or genetic depletion of GSK3B by RNA interference leads to decreased cancer cell proliferation and survival. Hence GSK3B has potential as an important new target in the treatment of pancreatic cancer.
  
Entity Colorectal cancer
Note Colon cancer cell lines and colon cells from colorectal cancer patients have higher levels of GSK3B expression than their normal counterparts. Inhibition of GSK3B activity either by chemical inhibitors or by expression by RNA interference targeting GSK3B induced apoptosis and attenuation of proliferation of colon cancer cells in vitro. Hence GSK3B has a potential as therapeutic target in colorectal cancer.
  
Entity Neuroblastoma
Note Treatment of B65 neuroblastoma cell line with GSK3B inhibitors Lithium or SB415286 caused a decrease in cell proliferation that was associated with G2/M cell cycle arrest due to regulating the phosphorylation of Cdc2. Therefore, GSK3B and Cdc2 could be potential pharmacological targets in neuroblastoma.
  
Entity Glioblastoma
Note Glioblastoma is the most frequent malignant tumor of the brain and represents a subset of cancers that is mostly nonresponsive to currently available anticancer treatments. The current standard therapy for newly diagnosed glioblastoma consists of surgical resection of the tumor to the extent that is safe and feasible, followed by chemotherapy and irradiation. There has been an emerging paradigm for the combination of chemotherapy and molecular targeted therapy to improve therapeutic efficiency. Glioblastoma cells depend on deregulated GSK3B to survive, proliferate, and resist chemotherapy and radiation. Pretreatment with low-dose GSK3B inhibitor enhanced the cytocidal effect of ionizing radiation in glioblastoma cells. At the same time, GSK3B inhibitors have been shown to protect normal hippocampal neurons from radiation-induced apoptosis. Therefore, GSK3B inhibition provides dual benefits for the glioblastoma patients treated with radiation: by attenuating tumor proliferation and by protecting host brain tissue from degradation and allowing its repair.
  
Entity Insulin resistance and diabetes
Note Insulin resistance is caused by the inability of insulin sensitive tissues to respond to insulin and efficiently clear blood glucose. Insulin signaling involves autophosphorylation of the insulin receptor leading to the activation of PI3K which activates PKB (Akt). The activated PKB phosphorylates and inactivates GSK3B. Dysregulation of GSK3B results in impaired insulin signaling leading to diabetes. Inhibitors of GSK3B improve insulin signaling and maintain proper glucose levels.
  
Entity Alzheimer's disease
Note Alzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. The two neuropathologiocal features of Alzheimer's disease are neurofibrillary tangles and amyloid plaques. GSK3B has been implicated in both neuropathologies. In addition, presenilin 1 (PS1) have been linked to Alzheimer's disease. Presenilin 1 binds to and regulates GSK3B activity. Presenilin 1 mutations might compromise neuronal function by increasing GSK3B activity.
  
Entity Schizophrenia
Note Schizophrenia is a severe brain illness in which the disrupted in schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation. DISC1 is highly expressed in neural progenitor cells and required for embryonic brain development. DISC1 regulates beta-catenin turnover by inhibiting GSK3B activity. GSK3B inhibitors are able to normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function.
  
Entity Bipolar affective disorder
Note Patients with bipolar affective disorder have a history of experiencing manic episodes that are often interspersed with depression, and major depression is commonly referred to as mood disorders. Lithium, a known GSK3B inhibitor, is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder.
  

External links

Nomenclature
HGNC (Hugo)GSK3B   4617
Entrez_Gene (NCBI)GSK3B  2932  glycogen synthase kinase 3 beta
Cards
AtlasGSK3BID40761ch3q13
GeneCards (Weizmann)GSK3B
Ensembl (Hinxton)ENSG00000082701 [Gene_View]  chr3:119540802-119813264 [Contig_View]  GSK3B [Vega]
AceView (NCBI)GSK3B
Genatlas (Paris)GSK3B
SOURCE (Stanford)NM_001146156 NM_002093
Genomic and cartography
GoldenPath (UCSC)GSK3B  -  3q13.33   chr3:119540802-119813264 -  3q13.3   [Description]    (hg19-Feb_2009)
EnsemblGSK3B - 3q13.3 [CytoView]
Mapping of homologs : NCBIGSK3B [Mapview]
OMIM605004   
Gene and transcription
Genbank (Entrez)AB451356 AK290897 AY123976 BC000251 BC012760
RefSeq transcript (SRS)NM_001146156 NM_002093
RefSeq transcript (Entrez)NM_001146156 NM_002093
RefSeq genomic (SRS)AC_000135 NC_000003 NC_018914 NG_012922 NT_005612 NW_001838881 NW_004078013
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_012922 NT_005612 NW_001838881 NW_004078013
Consensus coding sequences : CCDS (NCBI)GSK3B
Cluster EST : UnigeneHs.445733 [ SRS ] Hs.445733 [ NCBI ]
CGAP (NCI)Hs.445733
Alternative Splicing : Fast-db (Paris)GSHG0021974
Alternative Splicing GalleryENSG00000082701
Gene ExpressionGSK3B [ NCBI-GEO ]   GSK3B [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP49841 (SRS) P49841 (Uniprot)
NextProtP49841
With graphics : InterProP49841
Splice isoforms : SwissVarP49841(Swissvar)
Domaine pattern : Prosite (SRS)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (SRS)Kinase-like_dom    Prot_kinase_cat_dom    Protein_kinase_ATP_BS    Ser/Thr_dual-sp_kinase_dom    Ser/Thr_kinase_AS   
Domains : Interpro (EBI)Kinase-like_dom    Prot_kinase_cat_dom    Protein_kinase_ATP_BS    Ser/Thr_dual-sp_kinase_dom    Ser/Thr_kinase_AS   
Related proteins : CluSTrP49841
Domain families : Pfam (SRS)Pkinase (PF00069)   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
DMDM2932
Blocks (Seattle)P49841
PDB (SRS)1GNG    1H8F    1I09    1J1B    1J1C    1O9U    1PYX    1Q3D    1Q3W    1Q41    1Q4L    1Q5K    1R0E    1UV5    2JDO    2JDR    2JLD    2O5K    2OW3    2UW9    2X39    2XH5    3CQU    3CQW    3DU8    3E87    3E88    3E8D    3F7Z    3F88    3GB2    3I4B    3L1S    3M1S    3PUP    3Q3B    3SAY    3SD0    3ZRK    3ZRL    3ZRM    4ACC    4ACD    4ACG    4ACH    4AFJ    4DIT    4EKK   
PDB (PDBSum)1GNG    1H8F    1I09    1J1B    1J1C    1O9U    1PYX    1Q3D    1Q3W    1Q41    1Q4L    1Q5K    1R0E    1UV5    2JDO    2JDR    2JLD    2O5K    2OW3    2UW9    2X39    2XH5    3CQU    3CQW    3DU8    3E87    3E88    3E8D    3F7Z    3F88    3GB2    3I4B    3L1S    3M1S    3PUP    3Q3B    3SAY    3SD0    3ZRK    3ZRL    3ZRM    4ACC    4ACD    4ACG    4ACH    4AFJ    4DIT    4EKK   
PDB (IMB)1GNG    1H8F    1I09    1J1B    1J1C    1O9U    1PYX    1Q3D    1Q3W    1Q41    1Q4L    1Q5K    1R0E    1UV5    2JDO    2JDR    2JLD    2O5K    2OW3    2UW9    2X39    2XH5    3CQU    3CQW    3DU8    3E87    3E88    3E8D    3F7Z    3F88    3GB2    3I4B    3L1S    3M1S    3PUP    3Q3B    3SAY    3SD0    3ZRK    3ZRL    3ZRM    4ACC    4ACD    4ACG    4ACH    4AFJ    4DIT    4EKK   
PDB (RSDB)1GNG    1H8F    1I09    1J1B    1J1C    1O9U    1PYX    1Q3D    1Q3W    1Q41    1Q4L    1Q5K    1R0E    1UV5    2JDO    2JDR    2JLD    2O5K    2OW3    2UW9    2X39    2XH5    3CQU    3CQW    3DU8    3E87    3E88    3E8D    3F7Z    3F88    3GB2    3I4B    3L1S    3M1S    3PUP    3Q3B    3SAY    3SD0    3ZRK    3ZRL    3ZRM    4ACC    4ACD    4ACG    4ACH    4AFJ    4DIT    4EKK   
Human Protein AtlasENSG00000082701
HPRD05418
IPIIPI00028570   IPI00216190   IPI01012997   
Protein Interaction databases
DIP (DOE-UCLA)P49841
IntAct (EBI)P49841
FunCoupENSG00000082701
REACTOMEGSK3B
Protein Interaction Database2932
BioGRIDGSK3B
InParanoidP49841
Interologous Interaction database P49841
IntegromeDBGSK3B
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GSK3B
SNP (GeneSNP Utah)GSK3B
SNP : HGBaseGSK3B
Genetic variants : HAPMAPGSK3B
Somatic Mutations in Cancer : COSMICGSK3B 
CONAN: Copy Number AnalysisGSK3B 
Mutations and Diseases : HGMDGSK3B
OMIM605004   
GENETests605004   
Disease Genetic AssociationGSK3B
Huge Navigator GSK3B [HugePedia]  GSK3B [HugeCancerGEM]
Genomic VariantsGSK3B  GSK3B [DGVbeta]
snp3D : Map Gene to Disease2932
General knowledge
Homologs : HomoloGeneGSK3B
Homology/Alignments : Family Browser (UCSC)GSK3B
Phylogenetic Trees/Animal Genes : TreeFamGSK3B
Catalytic activity : Enzyme2.7.11.26 [ Enzyme-Expasy ]   2.7.11.26 [ Enzyme-SRS ]   2.7.11.26 [ IntEnz-EBI ]   2.7.11.26 [ BRENDA ]   2.7.11.26 [ KEGG ]   
Chemical/Protein Interactions : CTD2932
Chemical/Pharm GKB GenePA29009
Clinical trialGSK3B
Cancer Resource (Charite)ENSG00000082701
Ontology : AmiGOre-entry into mitotic cell cycle  RNA polymerase II transcription factor binding  epithelial to mesenchymal transition  positive regulation of cell-matrix adhesion  p53 binding  protein serine/threonine kinase activity  protein serine/threonine kinase activity  integrin binding  protein binding  ATP binding  nucleus  nucleolus  cytoplasm  centrosome  cytosol  plasma membrane  glycogen metabolic process  regulation of gene expression by genetic imprinting  protein phosphorylation  protein export from nucleus  ER overload response  epidermal growth factor receptor signaling pathway  axon guidance  myoblast fusion  beta-catenin binding  fibroblast growth factor receptor signaling pathway  organ morphogenesis  response to lithium ion  positive regulation of peptidyl-threonine phosphorylation  kinase activity  kinase activity  cell migration  peptidyl-serine phosphorylation  protein kinase binding  hippocampus development  establishment of cell polarity  growth cone  ribonucleoprotein complex  beta-catenin destruction complex  beta-catenin destruction complex  negative regulation of protein complex assembly  positive regulation of protein complex assembly  ubiquitin protein ligase binding  negative regulation of protein binding  positive regulation of protein binding  positive regulation of Rac GTPase activity  regulation of microtubule-based process  positive regulation of peptidyl-serine phosphorylation  protein kinase A catalytic subunit binding  ionotropic glutamate receptor binding  protein localization to microtubule  intracellular signal transduction  response to drug  neuronal cell body  negative regulation of apoptotic process  dendritic spine  dendritic shaft  negative regulation of MAP kinase activity  hypermethylation of CpG island  canonical Wnt receptor signaling pathway involved in positive regulation of apoptotic process  membrane raft  fat cell differentiation  negative regulation of glycogen biosynthetic process  positive regulation of protein catabolic process  negative regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  positive regulation of protein export from nucleus  nerve growth factor receptor signaling pathway  phosphatidylinositol-mediated signaling  tau protein binding  regulation of neuronal synaptic plasticity  tau-protein kinase activity  negative regulation of dendrite morphogenesis  NF-kappaB binding  negative regulation of NFAT protein import into nucleus  canonical Wnt receptor signaling pathway  canonical Wnt receptor signaling pathway  superior temporal gyrus development  negative regulation of canonical Wnt receptor signaling pathway  negative regulation of type B pancreatic cell development  negative regulation of glycogen (starch) synthase activity  
Ontology : EGO-EBIre-entry into mitotic cell cycle  RNA polymerase II transcription factor binding  epithelial to mesenchymal transition  positive regulation of cell-matrix adhesion  p53 binding  protein serine/threonine kinase activity  protein serine/threonine kinase activity  integrin binding  protein binding  ATP binding  nucleus  nucleolus  cytoplasm  centrosome  cytosol  plasma membrane  glycogen metabolic process  regulation of gene expression by genetic imprinting  protein phosphorylation  protein export from nucleus  ER overload response  epidermal growth factor receptor signaling pathway  axon guidance  myoblast fusion  beta-catenin binding  fibroblast growth factor receptor signaling pathway  organ morphogenesis  response to lithium ion  positive regulation of peptidyl-threonine phosphorylation  kinase activity  kinase activity  cell migration  peptidyl-serine phosphorylation  protein kinase binding  hippocampus development  establishment of cell polarity  growth cone  ribonucleoprotein complex  beta-catenin destruction complex  beta-catenin destruction complex  negative regulation of protein complex assembly  positive regulation of protein complex assembly  ubiquitin protein ligase binding  negative regulation of protein binding  positive regulation of protein binding  positive regulation of Rac GTPase activity  regulation of microtubule-based process  positive regulation of peptidyl-serine phosphorylation  protein kinase A catalytic subunit binding  ionotropic glutamate receptor binding  protein localization to microtubule  intracellular signal transduction  response to drug  neuronal cell body  negative regulation of apoptotic process  dendritic spine  dendritic shaft  negative regulation of MAP kinase activity  hypermethylation of CpG island  canonical Wnt receptor signaling pathway involved in positive regulation of apoptotic process  membrane raft  fat cell differentiation  negative regulation of glycogen biosynthetic process  positive regulation of protein catabolic process  negative regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  positive regulation of protein export from nucleus  nerve growth factor receptor signaling pathway  phosphatidylinositol-mediated signaling  tau protein binding  regulation of neuronal synaptic plasticity  tau-protein kinase activity  negative regulation of dendrite morphogenesis  NF-kappaB binding  negative regulation of NFAT protein import into nucleus  canonical Wnt receptor signaling pathway  canonical Wnt receptor signaling pathway  superior temporal gyrus development  negative regulation of canonical Wnt receptor signaling pathway  negative regulation of type B pancreatic cell development  negative regulation of glycogen (starch) synthase activity  
Pathways : BIOCARTACell Cycle: G1/S Check Point [Genes]    Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages [Genes]    Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway [Genes]    Deregulation of CDK5 in Alzheimers Disease [Genes]    Sonic Hedgehog (Shh) Pathway [Genes]    Phosphoinositides and their downstream targets. [Genes]    ALK in cardiac myocytes [Genes]    Segmentation Clock [Genes]    Presenilin action in Notch and Wnt signaling [Genes]    NFAT and Hypertrophy of the heart (Transcription in the broken heart) [Genes]    Multi-step Regulation of Transcription by Pitx2 [Genes]    WNT Signaling Pathway [Genes]    Regulation of eIF2 [Genes]   
Pathways : KEGGCell cycleColorectal cancerInsulin signaling pathwayHedgehog signaling pathwayFocal adhesionAxon guidanceAlzheimer's diseaseWnt signaling pathwayB cell receptor signaling pathway
Other databases
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
PubGeneGSK3B
iHOPGSK3B

Bibliography

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REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2010Dinesh Kumar Thotala, Eugenia M Yazlovitskaya
Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University, SS1411 Medical Center North, 1161 21 Avenue S, Nashville, TN 37232, USA

Citation

This paper should be referenced as such :
Thotala DK, Yazlovitskaya EM . GSK3B (glycogen synthase kinase 3 beta). Atlas Genet Cytogenet Oncol Haematol. April 2010 .
URL : http://AtlasGeneticsOncology.org/Genes/GSK3BID40761ch3q13.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44931/1/04-2010-GSK3BID40761ch3q13.pdf   [ Bibliographic record ]

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