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Gene Review

Gsk3b  -  glycogen synthase kinase 3 beta

Mus musculus

Synonyms: 7330414F15Rik, 8430431H08Rik, C86142, GSK-3, GSK-3 beta, ...
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Disease relevance of Gsk3b

  • Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the etiology of Alzheimer's disease and other tauopathies [1].
  • GSK-3beta and cyclin-dependent kinase 5 (Cdk5) are two pivotal kinases involved in Alzhermer's disease and other tauopathies. The relationship between these two kinases was unclear. A scaffold protein Axin was phosphorylated by Cdk5 in axons, and this phosphorylation led to GSK-3beta inactivation, hinting that Axin may link these two kinases in the etiology of tauopathies [2].
  • Cdk5 was known to indirectly inhibited GSK-3beta.
  • Using adenoviruses in lipopolysaccharide-stimulated mice, overexpression of GSK-3beta significantly decreased TNF-alpha expression in lung and heart tissues (38 and 15%, respectively), further confirming the anti-inflammatory role of GSK-3beta [3].
  • Here we show that disruption of the murine GSK-3beta gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-kappaB [4].
  • Inhibition of GSK3 or ablation of the GSK3beta gene ameliorated TLR2-induced peritonitis and arthritis [5].
  • Persistent phosphorylation of GSK-3beta could be critical for regulation of glycogen metabolism and cell growth in hepatoma cells [6].
  • GSK-3beta appears to control the progression of wound healing and fibrosis by modulating ET-1 levels [7].

Psychiatry related information on Gsk3b


High impact information on Gsk3b


Chemical compound and disease context of Gsk3b


Biological context of Gsk3b


Anatomical context of Gsk3b

  • NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC [22].
  • BDNF-, NT-3-induced inactivation of GSK-3beta in the growing axonal growth cone was mediated by the direct Axin-GSK-3beta interaction, which recruited GSK-3beta to the axonal tip and facilitated its inactivation by Akt [2].
  • Loss of glycogen synthase kinase 3beta (GSK-3beta) in mice results in embryonic lethality via hepatocyte apoptosis [23].
  • However, NF-kappaB DNA binding activity is reduced in GSK-3beta null cells and in cells treated with a pharmacological inhibitor of GSK-3 [23].
  • In this study, we used fibroblasts derived from GSK-3beta gene-deleted mice to understand the role of this kinase in TNF signaling [24].
  • Interestingly, neither endothelial cell survival nor NFkappaB-mediated expression of anti-apoptotic genes was affected by GSK-3beta overexpression [3].

Associations of Gsk3b with chemical compounds


Physical interactions of Gsk3b

  • Expression of a 59 amino acid GSK-3beta-binding region from Axin strongly activated transcription in the absence of an upstream signal [21].
  • Myc family transcription factors are destabilized by phosphorylation of a conserved amino-terminal GSK-3beta motif [29].
  • In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor [30].
  • IBU-PO (0.01-1 microM) inhibits glycogen-synthase-kinase-3beta (GSK-3beta) and stabilizes cytoplasmic beta-catenin reverting the silencing of the Wnt pathway caused by Abeta-toxicity and GSK-3beta overexpression [31].

Enzymatic interactions of Gsk3b

  • However, GSK-3 is also inhibited when it is phosphorylated by Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K) [32].
  • Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3beta [1].
  • Inhibition of GSK-3 beta leads to a decrease in a phosphorylated form of microtubule-associated protein-1B (MAP-1B), a protein involved in microtubule assembly, and a concomitant decrease in the level of stable microtubules [33].
  • D1-T286A, a cyclin D1 mutant that cannot be phosphorylated by GSK-3beta, remains nuclear throughout the cell cycle, a consequence of its reduced binding to CRM1 [34].
  • In addition, exercise returned the increased levels of phosphorylated GSK-3beta to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels [35].
  • GSK-3beta was inhibited indirectly by Cdk5 through a scaffold protein Axin [2].

Regulatory relationships of Gsk3b

  • In GSK3alpha/GSK3beta homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of beta-catenin and stimulation of Wnt-dependent transcription [19].
  • Here, we have explored mechanisms by which GSK-3beta may control NF-kappaB function [23].
  • Here we report that ILK controls tau phosphorylation via regulation of glycogen synthase kinase-3beta (GSK-3beta) activity in N1E-115 cells [36].
  • These results suggest that endogenously overproduced Abeta induces increased tau phosphorylation through activation of GSK-3, and that inactivation of PKC is at least one of the mechanisms involved in GSK-3 activation [37].
  • Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3 [38].
  • These data provide the first direct evidence that calpain promotes GSK-3 truncation in a way that has implications in signal transduction, and probably in pathological disorders such as Alzheimer disease [39].

Other interactions of Gsk3b

  • Additional experiments with LiCl as an inhibitor of GSK-3beta kinase activity indicate that the step affected by betaarr1 is upstream of GSK-3beta and most likely at the level of Dvl [40].
  • Therefore, GSK-3beta has profound effects on transcription in a gene-specific manner through a mechanism involving control of promoter-specific recruitment of NF-kappaB [23].
  • Expression of certain NF-kappaB-regulated genes, such as IkappaBalpha and macrophage inflammatory protein 2, is minimally affected by the absence of GSK-3beta [23].
  • Most surprisingly, TNF-induced Akt activation also required the presence of GSK-3beta [24].
  • ILK inactivation resulted in an increase in the active form but a decrease in the inactive form of GSK-3beta, which is a candidate kinase involved in PHF-tau formation [36].
  • The direct interaction between GSK-3beta and Axin was required for GSK-3beta inactivation [2].

Analytical, diagnostic and therapeutic context of Gsk3b

  • Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase [1].
  • The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy [41].
  • In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes [42].
  • Thus, BCR ligation initiates a PI 3-kinase/Akt/GSK-3 signaling pathway [43].
  • Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression [10].


  1. Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer's disease. Hernández, F., Pérez, M., Lucas, J.J., Mata, A.M., Bhat, R., Avila, J. J. Biol. Chem. (2004) [Pubmed]
  2. Cdk5-mediated phosphorylation of Axin directs axon formation during cerebral cortex development. Fang, W.Q., Ip, J.P., Li, R., Ng, Y.P., Lin, S.C., Chen, Y., Fu, A.K., Ip, N.Y. J. Neurosci. (2011) [Pubmed]
  3. Novel anti-inflammatory role for glycogen synthase kinase-3beta in the inhibition of tumor necrosis factor-alpha- and interleukin-1beta-induced inflammatory gene expression. Vines, A., Cahoon, S., Goldberg, I., Saxena, U., Pillarisetti, S. J. Biol. Chem. (2006) [Pubmed]
  4. Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Hoeflich, K.P., Luo, J., Rubie, E.A., Tsao, M.S., Jin, O., Woodgett, J.R. Nature (2000) [Pubmed]
  5. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Hu, X., Paik, P.K., Chen, J., Yarilina, A., Kockeritz, L., Lu, T.T., Woodgett, J.R., Ivashkiv, L.B. Immunity (2006) [Pubmed]
  6. Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells. Desbois-Mouthon, C., Blivet-Van Eggelpoël, M.J., Beurel, E., Boissan, M., Delélo, R., Cadoret, A., Capeau, J. Hepatology (2002) [Pubmed]
  7. GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1-dependent mechanism. Kapoor, M., Liu, S., Shi-wen, X., Huh, K., McCann, M., Denton, C.P., Woodgett, J.R., Abraham, D.J., Leask, A. J. Clin. Invest. (2008) [Pubmed]
  8. Lithium-mediated phosphorylation of glycogen synthase kinase-3beta involves PI3 kinase-dependent activation of protein kinase C-alpha. Kirshenboim, N., Plotkin, B., Shlomo, S.B., Kaidanovich-Beilin, O., Eldar-Finkelman, H. J. Mol. Neurosci. (2004) [Pubmed]
  9. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Beaulieu, J.M., Sotnikova, T.D., Yao, W.D., Kockeritz, L., Woodgett, J.R., Gainetdinov, R.R., Caron, M.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Chronic lithium administration to FTDP-17 tau and GSK-3beta overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. Engel, T., Goñi-Oliver, P., Lucas, J.J., Avila, J., Hernández, F. J. Neurochem. (2006) [Pubmed]
  11. Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei. Iwahana, E., Akiyama, M., Miyakawa, K., Uchida, A., Kasahara, J., Fukunaga, K., Hamada, T., Shibata, S. Eur. J. Neurosci. (2004) [Pubmed]
  12. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Trowbridge, J.J., Xenocostas, A., Moon, R.T., Bhatia, M. Nat. Med. (2006) [Pubmed]
  13. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., Brivanlou, A.H. Nat. Med. (2004) [Pubmed]
  14. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Phiel, C.J., Wilson, C.A., Lee, V.M., Klein, P.S. Nature (2003) [Pubmed]
  15. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. Bhat, R., Xue, Y., Berg, S., Hellberg, S., Ormö, M., Nilsson, Y., Radesäter, A.C., Jerning, E., Markgren, P.O., Borgegård, T., Nylöf, M., Giménez-Cassina, A., Hernández, F., Lucas, J.J., Díaz-Nido, J., Avila, J. J. Biol. Chem. (2003) [Pubmed]
  16. Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3. Clodfelder-Miller, B., De Sarno, P., Zmijewska, A.A., Song, L., Jope, R.S. J. Biol. Chem. (2005) [Pubmed]
  17. Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3beta activation. Li, H.J., Yin, H., Yao, Y.Y., Shen, B., Bader, M., Chao, L., Chao, J. Cardiovasc. Res. (2007) [Pubmed]
  18. Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: protection by mood stabilizers and imipramine. Roh, M.S., Eom, T.Y., Zmijewska, A.A., De Sarno, P., Roth, K.A., Jope, R.S. Biol. Psychiatry (2005) [Pubmed]
  19. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. McManus, E.J., Sakamoto, K., Armit, L.J., Ronaldson, L., Shpiro, N., Marquez, R., Alessi, D.R. EMBO J. (2005) [Pubmed]
  20. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S., Kikuchi, A. EMBO J. (1998) [Pubmed]
  21. Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. Smalley, M.J., Sara, E., Paterson, H., Naylor, S., Cook, D., Jayatilake, H., Fryer, L.G., Hutchinson, L., Fry, M.J., Dale, T.C. EMBO J. (1999) [Pubmed]
  22. NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC. Zhou, F.Q., Zhou, J., Dedhar, S., Wu, Y.H., Snider, W.D. Neuron (2004) [Pubmed]
  23. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Steinbrecher, K.A., Wilson, W., Cogswell, P.C., Baldwin, A.S. Mol. Cell. Biol. (2005) [Pubmed]
  24. Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. Takada, Y., Fang, X., Jamaluddin, M.S., Boyd, D.D., Aggarwal, B.B. J. Biol. Chem. (2004) [Pubmed]
  25. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules. Ciani, L., Krylova, O., Smalley, M.J., Dale, T.C., Salinas, P.C. J. Cell Biol. (2004) [Pubmed]
  26. Protein kinase B/Akt acts via glycogen synthase kinase 3 to regulate recycling of alpha v beta 3 and alpha 5 beta 1 integrins. Roberts, M.S., Woods, A.J., Dale, T.C., Van Der Sluijs, P., Norman, J.C. Mol. Cell. Biol. (2004) [Pubmed]
  27. Adiponectin Modulates the Glycogen Synthase Kinase-3{beta}/{beta}-Catenin Signaling Pathway and Attenuates Mammary Tumorigenesis of MDA-MB-231 Cells in Nude Mice. Wang, Y., Lam, J.B., Lam, K.S., Liu, J., Lam, M.C., Hoo, R.L., Wu, D., Cooper, G.J., Xu, A. Cancer Res. (2006) [Pubmed]
  28. GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. Lin, C.F., Chen, C.L., Chiang, C.W., Jan, M.S., Huang, W.C., Lin, Y.S. J. Cell. Sci. (2007) [Pubmed]
  29. The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors. Sjostrom, S.K., Finn, G., Hahn, W.C., Rowitch, D.H., Kenney, A.M. Dev. Cell (2005) [Pubmed]
  30. A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. Jing, H., Yen, J.H., Ganea, D. J. Biol. Chem. (2004) [Pubmed]
  31. The anti-inflammatory and cholinesterase inhibitor bifunctional compound IBU-PO protects from beta-amyloid neurotoxicity by acting on Wnt signaling components. Farías, G.G., Godoy, J.A., Vázquez, M.C., Adani, R., Meshulam, H., Avila, J., Amitai, G., Inestrosa, N.C. Neurobiol. Dis. (2005) [Pubmed]
  32. The B cell antigen receptor regulates the transcriptional activator beta-catenin via protein kinase C-mediated inhibition of glycogen synthase kinase-3. Christian, S.L., Sims, P.V., Gold, M.R. J. Immunol. (2002) [Pubmed]
  33. Wnt factors in axonal remodelling and synaptogenesis. Salinas, P.C. Biochem. Soc. Symp. (1999) [Pubmed]
  34. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Alt, J.R., Cleveland, J.L., Hannink, M., Diehl, J.A. Genes Dev. (2000) [Pubmed]
  35. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Konhilas, J.P., Watson, P.A., Maass, A., Boucek, D.M., Horn, T., Stauffer, B.L., Luckey, S.W., Rosenberg, P., Leinwand, L.A. Circ. Res. (2006) [Pubmed]
  36. Inactivation of integrin-linked kinase induces aberrant tau phosphorylation via sustained activation of glycogen synthase kinase 3beta in N1E-115 neuroblastoma cells. Ishii, T., Furuoka, H., Muroi, Y., Nishimura, M. J. Biol. Chem. (2003) [Pubmed]
  37. Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. Wang, Z.F., Li, H.L., Li, X.C., Zhang, Q., Tian, Q., Wang, Q., Xu, H., Wang, J.Z. J. Neurochem. (2006) [Pubmed]
  38. Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18. Kapadia, R.M., Guntur, A.R., Reinhold, M.I., Naski, M.C. Dev. Biol. (2005) [Pubmed]
  39. N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation. Goñi-Oliver, P., Lucas, J.J., Avila, J., Hernández, F. J. Biol. Chem. (2007) [Pubmed]
  40. beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Chen, W., Hu, L.A., Semenov, M.V., Yanagawa, S., Kikuchi, A., Lefkowitz, R.J., Miller, W.E. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  41. Glycogen synthase kinase-3 beta inhibition reduces secondary damage in experimental spinal cord trauma. Cuzzocrea, S., Genovese, T., Mazzon, E., Crisafulli, C., Di Paola, R., Muià, C., Collin, M., Esposito, E., Bramanti, P., Thiemermann, C. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  42. Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development. Liu, L., Rajareddy, S., Reddy, P., Jagarlamudi, K., Du, C., Shen, Y., Guo, Y., Boman, K., Lundin, E., Ottander, U., Selstam, G., Liu, K. J. Mol. Endocrinol. (2007) [Pubmed]
  43. The B cell antigen receptor activates the Akt (protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase. Gold, M.R., Scheid, M.P., Santos, L., Dang-Lawson, M., Roth, R.A., Matsuuchi, L., Duronio, V., Krebs, D.L. J. Immunol. (1999) [Pubmed]
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