GSK3B (glycogen synthase kinase 3 beta)

2010-04-01   Dinesh 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




Atlas Image
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.


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.


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.


No pseudogene has been identified for GSK3B.


Atlas Image
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).


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.


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.


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.


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.


The GSK3B gene is conserved in human, chimpanzee, dog, cow, rat, chicken, zebrafish, fruit fly, mosquito, C. elegans, A. thaliana, rice, and P. falciparum.



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 name
Ovarian cancer
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 name
Prostate cancer
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 name
Pancreatic cancer
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 name
Colorectal cancer
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 name
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 name
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 name
Insulin resistance and diabetes
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 name
Alzheimers disease
Alzheimers disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. The two neuropathologiocal features of Alzheimers disease are neurofibrillary tangles and amyloid plaques. GSK3B has been implicated in both neuropathologies. In addition, presenilin 1 (PS1) have been linked to Alzheimers disease. Presenilin 1 binds to and regulates GSK3B activity. Presenilin 1 mutations might compromise neuronal function by increasing GSK3B activity.
Entity name
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 name
Bipolar affective disorder
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.


Pubmed IDLast YearTitleAuthors
201133582010Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-β activity.Benedetti F et al
151893332004Glycogen synthase kinase 3: a drug target for CNS therapies.Bhat RV et al
167885732006Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cells.Cao Q et al
151738372004GSK3 inhibitors: development and therapeutic potential.Cohen P et al
114407152001Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition.Dajani R et al
192655512009GSK3 beta N-terminus binding to p53 promotes its acetylation.Eom TY et al
175041182007Glycogen synthase kinase-3 beta; a new target in pancreatic cancer?Garcea G et al
151024362004The glamour and gloom of glycogen synthase kinase-3.Jope RS et al
104862031999Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter.Lau KF et al
195386892009The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis.Machado-Vieira R et al
193038462009Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.Mao Y et al
121117502002Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation.Martinez A et al
155592492004Pharmacological inhibitors of glycogen synthase kinase 3.Meijer L et al
191881592009Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma.Miyashita K et al
157816152005Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells.Ougolkov AV et al
186247662009A molecular study of pathways involved in the inhibition of cell proliferation in neuroblastoma B65 cells by the GSK-3 inhibitors lithium and SB-415286.Pizarro JG et al
188523542008Association of GSK3B with Alzheimer disease and frontotemporal dementia.Schaffer BA et al
160431252005Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation.Shakoori A et al
191798042009Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: inhibitors of the Wnt/beta-catenin signaling pathway as novel anticancer drugs.Takahashi-Yanaga F et al
201172912010A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.Thotala DK et al
151786912004Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells.Wang L et al
171458622006Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation.Yazlovitskaya EM et al

Other Information

Locus ID:

NCBI: 2932
MIM: 605004
HGNC: 4617
Ensembl: ENSG00000082701


dbSNP: 2932
ClinVar: 2932
TCGA: ENSG00000082701


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
ErbB signaling pathwayKEGGko04012
Cell cycleKEGGko04110
mTOR signaling pathwayKEGGko04150
Wnt signaling pathwayKEGGko04310
Hedgehog signaling pathwayKEGGko04340
Axon guidanceKEGGko04360
Focal adhesionKEGGko04510
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Insulin signaling pathwayKEGGko04910
Alzheimer's diseaseKEGGko05010
Colorectal cancerKEGGko05210
Endometrial cancerKEGGko05213
Prostate cancerKEGGko05215
Basal cell carcinomaKEGGko05217
ErbB signaling pathwayKEGGhsa04012
Cell cycleKEGGhsa04110
mTOR signaling pathwayKEGGhsa04150
Wnt signaling pathwayKEGGhsa04310
Hedgehog signaling pathwayKEGGhsa04340
Axon guidanceKEGGhsa04360
Focal adhesionKEGGhsa04510
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
Insulin signaling pathwayKEGGhsa04910
Alzheimer's diseaseKEGGhsa05010
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Endometrial cancerKEGGhsa05213
Prostate cancerKEGGhsa05215
Basal cell carcinomaKEGGhsa05217
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Influenza AKEGGko05164
Influenza AKEGGhsa05164
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Thyroid hormone signaling pathwayKEGGhsa04919
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Wnt signalingKEGGhsa_M00677
Wnt signalingKEGGM00677
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by AKT1 E17K in CancerREACTOMER-HSA-5674400
Signaling by WNT in cancerREACTOMER-HSA-4791275
truncated APC mutants destabilize the destruction complexREACTOMER-HSA-4839744
APC truncation mutants have impaired AXIN bindingREACTOMER-HSA-5467337
AXIN mutants destabilize the destruction complex, activating WNT signalingREACTOMER-HSA-4839735
AXIN missense mutants destabilize the destruction complexREACTOMER-HSA-5467340
AMER1 mutants destabilize the destruction complexREACTOMER-HSA-4839748
Truncations of AMER1 destabilize the destruction complexREACTOMER-HSA-5467348
phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complexREACTOMER-HSA-4839743
S45 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358751
T41 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358752
S37 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358749
S33 mutants of beta-catenin aren't phosphorylatedREACTOMER-HSA-5358747
Misspliced GSK3beta mutants stabilize beta-cateninREACTOMER-HSA-5339716
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
AKT phosphorylates targets in the cytosolREACTOMER-HSA-198323
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by WntREACTOMER-HSA-195721
Degradation of beta-catenin by the destruction complexREACTOMER-HSA-195253
Beta-catenin phosphorylation cascadeREACTOMER-HSA-196299
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Disassembly of the destruction complex and recruitment of AXIN to the membraneREACTOMER-HSA-4641262
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog 'off' stateREACTOMER-HSA-5610787
GLI3 is processed to GLI3R by the proteasomeREACTOMER-HSA-5610785
Degradation of GLI2 by the proteasomeREACTOMER-HSA-5610783
Gene ExpressionREACTOMER-HSA-74160
Epigenetic regulation of gene expressionREACTOMER-HSA-212165
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
CRMPs in Sema3A signalingREACTOMER-HSA-399956
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to heat stressREACTOMER-HSA-3371556
Regulation of HSF1-mediated heat shock responseREACTOMER-HSA-3371453
Insulin resistanceKEGGhsa04931
Positive epigenetic regulation of rRNA expressionREACTOMER-HSA-5250913
B-WICH complex positively regulates rRNA expressionREACTOMER-HSA-5250924
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA447199Bipolar DisorderDiseaseClinicalAnnotationassociatedPD21047205, 21781277, 23021822
PA447321Depressive Disorder, MajorDiseaseClinicalAnnotationassociatedPD18195729
PA450243lithiumChemicalClinicalAnnotation, Literature, MultilinkAnnotationassociatedPD21047205, 21781277, 23021822, 24885933


Pubmed IDYearTitleCitations
160070922005Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.394
165431452006Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.350
206480612010GSK3 signalling in neural development.267
170723032006A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells.254
173871462007Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization.180
184513032008Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.169
186064912009Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy.148
145360782003Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation.146
156319892005Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition.138
127965052003Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3.134


Dinesh Kumar Thotala ; Eugenia M Yazlovitskaya

GSK3B (glycogen synthase kinase 3 beta)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: