glycogen synthase kinases


Summary: A class of protein-serine-threonine kinases that was originally found as one of the three types of kinases that phosphorylate GLYCOGEN SYNTHASE. Glycogen synthase kinases along with CA(2+)-CALMODULIN DEPENDENT PROTEIN KINASES and CYCLIC AMP-DEPENDENT PROTEIN KINASES regulate glycogen synthase activity.

Top Publications

  1. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, et al. Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level. Genes Cells. 1998;3:395-403 pubmed
    ..Axin interacts with beta-catenin, GSK-3beta and APC, and negatively regulates the Wnt signalling pathway, presumably by regulating the level of beta-catenin. ..
  2. Stambolic V, Ruel L, Woodgett J. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol. 1996;6:1664-8 pubmed
    ..Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li+ action on development and differentiation. ..
  3. Seeling J, Miller J, Gil R, Moon R, White R, Virshup D. Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. Science. 1999;283:2089-91 pubmed
    ..B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby inhibit Wnt signaling. ..
  4. Wang Q, Fiol C, DePaoli Roach A, Roach P. Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. J Biol Chem. 1994;269:14566-74 pubmed
    ..Phosphorylation at different residues differentially controls enzyme activity, Ser/Thr phosphorylation causing inactivation and Tyr phosphorylation resulting in increased activity. ..
  5. Hedgepeth C, Deardorff M, Klein P. Xenopus axin interacts with glycogen synthase kinase-3 beta and is expressed in the anterior midbrain. Mech Dev. 1999;80:147-51 pubmed
    ..Xaxin also shows remarkably high expression in the anterior mesencephalon adjacent to the forebrain-midbrain boundary. ..
  6. Dajani R, Fraser E, Roe S, Young N, Good V, Dale T, et al. Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 2001;105:721-32 pubmed
  7. Hughes K, Nikolakaki E, Plyte S, Totty N, Woodgett J. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993;12:803-8 pubmed
    ..However, unlike MAP kinases, GSK-3 is highly phosphorylated on tyrosine and thus active in resting cells. ..
  8. D Amico M, Hulit J, Amanatullah D, Zafonte B, Albanese C, Bouzahzah B, et al. The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways. J Biol Chem. 2000;275:32649-57 pubmed
    ..We conclude that the cyclin D1 gene is regulated by the Wnt-1 and ILK signaling pathways and that ILK induction of cyclin D1 involves the CREB signaling pathway in mammary epithelial cells. ..
  9. Yamamoto H, Kishida S, Uochi T, Ikeda S, Koyama S, Asashima M, et al. Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. Mol Cell Biol. 1998;18:2867-75 pubmed
    ..These results indicate that Axil negatively regulates the Wnt signaling pathway by mediating GSK-3beta-dependent phosphorylation of beta-catenin, thereby inhibiting axis formation. ..

More Information


  1. Andoh T, Hirata Y, Kikuchi A. Yeast glycogen synthase kinase 3 is involved in protein degradation in cooperation with Bul1, Bul2, and Rsp5. Mol Cell Biol. 2000;20:6712-20 pubmed
    ..Furthermore, Rog1 is stabilized in the npi1 mutant, in which RSP5 expression levels are reduced. These results suggest that yeast GSK-3 regulates the stability of Rog1 in cooperation with Bul1, Bul2, and Rsp5. ..
  2. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 1997;16:3797-804 pubmed
    ..We show that ubiquitination of beta-catenin is greatly reduced in Wnt-expressing cells, providing the first evidence that the ubiquitin-proteasome degradation pathway may act downstream of GSK3beta in the regulation of beta-catenin. ..
  3. He X, Saint Jeannet J, Wang Y, Nathans J, Dawid I, Varmus H. A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science. 1997;275:1652-4 pubmed
    ..Wnt-5A/hFz5 signaling was antagonized by glycogen synthase kinase-3 and by the amino-terminal ectodomain of hFz5. These results identify hFz5 as a receptor for Wnt-5A. ..
  4. Fagotto F, Jho E, Zeng L, Kurth T, Joos T, Kaufmann C, et al. Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization. J Cell Biol. 1999;145:741-56 pubmed
    ..Coexpression of hemagglutinin-tagged Dishevelled (Dsh) revealed strong colocalization with Axin, suggesting that Dsh can interact with the Axin/APC/GSK3/beta-catenin complex, and may thus modulate its activity. ..
  5. Sakanaka C, Weiss J, Williams L. Bridging of beta-catenin and glycogen synthase kinase-3beta by axin and inhibition of beta-catenin-mediated transcription. Proc Natl Acad Sci U S A. 1998;95:3020-3 pubmed
    ..These findings suggest that Axin, by forming a complex with beta-catenin and glycogen synthase kinase-3beta, can block signaling stimulated by Wnt or by adenomatous polyposis coli mutations. ..
  6. Kadoya T, Kishida S, Fukui A, Hinoi T, Michiue T, Asashima M, et al. Inhibition of Wnt signaling pathway by a novel axin-binding protein. J Biol Chem. 2000;275:37030-7 pubmed
    ..These results suggest that Axam regulates the Wnt signaling pathway negatively by inhibiting the binding of Dvl to Axin. ..
  7. Coghlan M, Culbert A, Cross D, Corcoran S, Yates J, Pearce N, et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 2000;7:793-803 pubmed
    ..This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3...
  8. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science. 1996;272:1023-6 pubmed
    ..APC was a good substrate for GSK3 beta in vitro, and the phosphorylation sites were mapped to the central region of APC. Binding of beta-catenin to this region was dependent on phosphorylation by GSK3 beta. ..
  9. Cohen P, Frame S. The renaissance of GSK3. Nat Rev Mol Cell Biol. 2001;2:769-76 pubmed
    ..The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention. ..
  10. Woodgett J. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 1990;9:2431-8 pubmed
    ..Partial purification of GSK-3 activity from bovine brain results in the isolation of active alpha and beta proteins. The physiological importance of these two proteins in cellular signal transduction is discussed. ..
  11. Beals C, Sheridan C, Turck C, Gardner P, Crabtree G. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997;275:1930-4 pubmed
    ..Because GSK-3 responds to signals initiated by Wnt and other ligands, NF-AT family members could be effectors of these pathways. ..
  12. Cook D, Fry M, Hughes K, Sumathipala R, Woodgett J, Dale T. Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C. EMBO J. 1996;15:4526-36 pubmed
    ..These findings provide the first biochemical evidence in support of the genetically defined pathway from Wg to Zw3/Sgg, and suggest a previously uncharacterized role for a PKC upstream of GSK-3/Zw3 during Wnt/Wg signal transduction. ..
  13. Yost C, Torres M, Miller J, Huang E, Kimelman D, Moon R. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 1996;10:1443-54 pubmed
    ..These studies provide a basis for understanding the interaction between Xgsk-3 and beta-catenin in the establishment of the dorsal-ventral axis in early Xenopus embryos. ..
  14. Welsh G, Miyamoto S, Price N, Safer B, Proud C. T-cell activation leads to rapid stimulation of translation initiation factor eIF2B and inactivation of glycogen synthase kinase-3. J Biol Chem. 1996;271:11410-3 pubmed
    ..Since phosphorylation of eIF2B by GSK-3 appears to inhibit nucleotide exchange in vitro, this provides a potential mechanism by which eIF2B may be activated. ..
  15. Lucas J, Hernandez F, Gomez Ramos P, Moran M, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 2001;20:27-39 pubmed
  16. Stambolic V, Woodgett J. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J. 1994;303 ( Pt 3):701-4 pubmed
    ..Since p90rsk-1 is directly activated by mitogen-activated protein kinases, agonists of this pathway, such as insulin, repress GSK-3 function. ..
  17. Siegfried E, Chou T, Perrimon N. wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell. 1992;71:1167-79 pubmed
    ..Genetic epistasis experiments indicate that wg signaling operates by inactivating the zw3 repression of en autoactivation. In addition, we demonstrate that zw3 encodes the Drosophila homolog of mammalian glycogen synthase kinase-3. ..
  18. Liu C, Li Y, Semenov M, Han C, Baeg G, Tan Y, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 2002;108:837-47 pubmed
    ..Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes. ..
  19. Bienz M. APC: the plot thickens. Curr Opin Genet Dev. 1999;9:595-603 pubmed
    ..Recent experiments have shaped our understanding of how Axin and GSK3 function but the role of APC in this process remains elusive. ..
  20. Hedgepeth C, Conrad L, Zhang J, Huang H, Lee V, Klein P. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol. 1997;185:82-91 pubmed
    ..The mechanism by which myo-inositol inhibits both dominant negative GSK-3 beta and lithium remains uncertain. ..
  21. Dominguez I, Itoh K, Sokol S. Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos. Proc Natl Acad Sci U S A. 1995;92:8498-502 pubmed
    ..These results strongly suggest that XGSK-3 beta functions to inhibit dorsoventral axis formation in the embryo and provide evidence for conservation of the Wnt signaling pathway in Drosophila and vertebrates. ..
  22. Harwood A, Plyte S, Woodgett J, Strutt H, Kay R. Glycogen synthase kinase 3 regulates cell fate in Dictyostelium. Cell. 1995;80:139-48 pubmed
    ..We propose that cAMP acts through a common pathway that requires GSK-3 and determines the proportion of prespore and pstB cells. ..
  23. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. 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. EMBO J. 1998;17:1371-84 pubmed
    ..These results suggest that rAxin negatively regulates the Wnt signaling pathway by interacting with GSK-3beta and beta-catenin and mediating the signal from GSK-3beta to beta-catenin. ..
  24. Hart M, de los Santos R, Albert I, Rubinfeld B, Polakis P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol. 1998;8:573-81 pubmed
    ..Axin acts as a scaffold upon which APC, beta-catenin and GSK3 beta assemble to coordinate the regulation of beta-catenin signaling. ..
  25. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A. 1998;95:11211-6 pubmed
    ..ILK is thus a receptor-proximal effector for the Pi(3)K-dependent, extracellular matrix and growth factor mediated, activation of PKB/AKT, and inhibition of GSK-3. ..
  26. Cross D, Alessi D, Cohen P, Andjelkovich M, Hemmings B. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785-9 pubmed
    ..Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase. ..
  27. Cross D, Culbert A, Chalmers K, Facci L, Skaper S, Reith A. Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem. 2001;77:94-102 pubmed
  28. Lau K, Miller C, Anderton B, Shaw P. Expression analysis of glycogen synthase kinase-3 in human tissues. J Pept Res. 1999;54:85-91 pubmed
  29. He X, Saint Jeannet J, Woodgett J, Varmus H, Dawid I. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature. 1995;374:617-22 pubmed
    ..These results indicate that GSK-3 is required for ventral differentiation, and suggest that dorsal differentiation may involve the suppression of GSK-3 activity by a wingless/wnt-related signal. ..
  30. Diehl J, Cheng M, Roussel M, Sherr C. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12:3499-511 pubmed
    ..Therefore, phosphorylation and proteolytic turnover of cyclin D1 and its subcellular localization during the cell division cycle are linked through the action of GSK-3beta. ..
  31. Li X, Wang X, Guo Y, Deng N, Zheng P, Xu Q, et al. Regulation of endothelial nitric oxide synthase and asymmetric dimethylarginine by matrine attenuates isoproterenol-induced acute myocardial injury in rats. J Pharm Pharmacol. 2012;64:1107-18 pubmed publisher
    ..05). Our results suggested that matrine protects against isoproterenol-induced myocardial ischaemia via eNOS and ADMA pathway. ..
  32. Stulpinas A, Imbrasaite A, Kalvelytė A. Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells. Cell Biol Toxicol. 2012;28:103-14 pubmed publisher
    ..These findings could contribute to new approaches which will result in less toxicity and fewer side effects that are currently associated with the use of daunorubicin in cancer therapies. ..
  33. Kim L, Kimmel A. GSK3, a master switch regulating cell-fate specification and tumorigenesis. Curr Opin Genet Dev. 2000;10:508-14 pubmed
    ..Data from various systems now indicate more complex scenarios involving activating as well as inhibiting circuits, and the differential formation of multi-protein complexes that antagonistically affect GSK3 function. ..
  34. Welcker M, Singer J, Loeb K, Grim J, Bloecher A, Gurien West M, et al. Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation. Mol Cell. 2003;12:381-92 pubmed
    ..Thus, cyclin E turnover is controlled by multiple biological inputs and cannot be understood in terms of autophosphorylation alone. ..
  35. Kirschenbaum F, Hsu S, Cordell B, McCarthy J. Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J Biol Chem. 2001;276:30701-7 pubmed
    ..Overall, the results indicate that production of active NTF.CTF dimer is more complex than limited endoproteolysis of PS1 holoprotein and instead involves additional regulatory events. ..
  36. Culbert A, Brown M, Frame S, Hagen T, Cross D, Bax B, et al. GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity. FEBS Lett. 2001;507:288-94 pubmed
    ..By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and beta-catenin. ..
  37. Maiese K, Chong Z, Shang Y. Mechanistic insights into diabetes mellitus and oxidative stress. Curr Med Chem. 2007;14:1729-38 pubmed
    ..Further knowledge acquired in understanding the complexity of DM and its ability to impair cellular systems throughout the body will foster new strategies for the treatment of DM and its complications. ..
  38. Summers S, Kao A, Kohn A, Backus G, Roth R, Pessin J, et al. The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. J Biol Chem. 1999;274:17934-40 pubmed
    ..These data support the hypothesis that GSK3beta contributes to insulin regulation of glycogen synthesis, but is not responsible for the increase in glucose transport. ..
  39. Kaytor M, Orr H. The GSK3 beta signaling cascade and neurodegenerative disease. Curr Opin Neurobiol. 2002;12:275-8 pubmed
    ..How GSK3 acts in this regard is still open to debate, but it may involve both extracellular and nuclear apoptotic activities. ..
  40. Ostrakhovitch E, Lordnejad M, Schliess F, Sies H, Klotz L. Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species. Arch Biochem Biophys. 2002;397:232-9 pubmed
    ..Rather, both activation of Akt and generation of ROS are proposed to occur in parallel, regulating cell survival after a copper stress. ..
  41. Beitner Johnson D, Rust R, Hsieh T, Millhorn D. Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells. Cell Signal. 2001;13:23-7 pubmed
    ..Thus, hypoxia regulates both P13K-dependent and P13K-independent signaling pathways. Furthermore, activation of the P13K and Akt signaling pathways may be one mechanism by which cells adapt and survive under conditions of hypoxia. ..
  42. Mukai F, Ishiguro K, Sano Y, Fujita S. Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta. J Neurochem. 2002;81:1073-83 pubmed
  43. Ginger R, Dalton E, Ryves W, Fukuzawa M, Williams J, Harwood A. Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein. EMBO J. 2000;19:5483-91 pubmed
    ..It also raises the possibility of an analogous regulation of STAT nuclear export in higher eukaryotes. ..
  44. Koh S, Lee S, Kim M, Koh J, Lee S, An G, et al. T-DNA tagged knockout mutation of rice OsGSK1, an orthologue of Arabidopsis BIN2, with enhanced tolerance to various abiotic stresses. Plant Mol Biol. 2007;65:453-66 pubmed
    ..Therefore, we propose that stress-responsive OsGSK1 may have physiological roles in stress signal-transduction pathways and floral developmental processes. ..
  45. Sims Robinson C, Kim B, Rosko A, Feldman E. How does diabetes accelerate Alzheimer disease pathology?. Nat Rev Neurol. 2010;6:551-9 pubmed publisher
    ..An understanding of this complex interaction is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases. ..
  46. Okano J, Gaslightwala I, Birnbaum M, Rustgi A, Nakagawa H. Akt/protein kinase B isoforms are differentially regulated by epidermal growth factor stimulation. J Biol Chem. 2000;275:30934-42 pubmed
  47. Taei A, Hassani S, Eftekhari Yazdi P, Rezazadeh Valojerdi M, Nokhbatolfoghahai M, Masoudi N, et al. Enhanced generation of human embryonic stem cells from single blastomeres of fair and poor-quality cleavage embryos via inhibition of glycogen synthase kinase ? and Rho-associated kinase signaling. Hum Reprod. 2013;28:2661-71 pubmed publisher
    ..This study was financially supported by the National Elite Foundation and the Royan Institute for Stem Cell Biology and Technology. The authors have no conflict of interest to declare. ..
  48. Ferkey D, Kimelman D. Glycogen synthase kinase-3 beta mutagenesis identifies a common binding domain for GBP and Axin. J Biol Chem. 2002;277:16147-52 pubmed
    ..We use these mutations to examine the ability of GSK-3 to block eye development in Xenopus embryos and suggest that GSK-3 regulates eye development through a non-Wnt pathway. ..
  49. Fraser E, Young N, Dajani R, Franca Koh J, Ryves J, Williams R, et al. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. J Biol Chem. 2002;277:2176-85 pubmed
    ..Surprisingly, we find no genetic interaction between a non-Axin-binding GSK-3 mutant and T-cell factor activity, arguing that Axin interactions alone cannot explain the regulation of T-cell factor-mediated gene expression. ..
  50. Jackson G, Wiedau Pazos M, Sang T, Wagle N, Brown C, Massachi S, et al. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron. 2002;34:509-19 pubmed
    ..The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets. ..
  51. Aisa Y, Miyakawa Y, Nakazato T, Shibata H, Saito K, Ikeda Y, et al. Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and down-regulation of ERK pathways. Am J Hematol. 2005;78:7-14 pubmed
    ..These results demonstrate that fucoidan has direct anti-cancer effects on human HS-Sultan cells through caspase and ERK pathways. ..
  52. Dorn G, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest. 2005;115:527-37 pubmed
    ..Here we review recent developments in the area of these cardiotrophic kinases, highlighting the utility of animal models that are helping to identify molecular targets in the human condition. ..
  53. Auer K, Contessa J, Brenz Verca S, Pirola L, Rusconi S, Cooper G, et al. The Ras/Rac1/Cdc42/SEK/JNK/c-Jun cascade is a key pathway by which agonists stimulate DNA synthesis in primary cultures of rat hepatocytes. Mol Biol Cell. 1998;9:561-73 pubmed