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The renaissance of GSK3

Nature Reviews Molecular Cell Biology volume 2, pages 769–776 (2001)Cite this article

Abstract

Glycogen synthase kinase 3 (GSK3) was initially described as a key enzyme involved in glycogen metabolism, but is now known to regulate a diverse array of cell functions. The study of the substrate specificity and regulation of GSK3 activity has been important in the quest for therapeutic intervention.

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Figure 1: The signalling pathway by which insulin inhibits GSK3 and contributes to the stimulation of glycogen and protein synthesis.
Figure 2: The unique substrate specificity of GSK3.
Figure 3: Comparison of the activation loops of GSK3β with the MAPK family member p38γ.
Figure 4: The molecular mechanism by which phosphorylation inhibits GSK3.
Figure 5: Several signalling pathways induce the inhibition of GSK3 by phosphorylating the same serine residue near the amino terminus.
Figure 6: The mechanism by which WNTs prevent the GSK3-catalysed phosphorylation of axin, APC and β-catenin.

References

  1. Van Schaftingen, E., Jett, M. F., Hue, L. & Hers, H. G. Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors. Proc. Natl Acad. Sci. USA 78, 3483?3486 (1981).

    Article  CAS  Google Scholar 

  2. Embi, N., Rylatt, D. B. & Cohen, P. Glycogen synthase kinase-3 from rabbit skeletal muscle; separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 107, 519?527 (1980).

    Article  CAS  Google Scholar 

  3. Parker, P. J. J., Caudwell, F. B. & Cohen, P. Glycogen synthase from rabbit skeletal muscle: effect of insulin on the state of phosphorylation of the seven phosphoserine residues in vivo. Eur. J. Biochem. 130, 227?234 (1983).

    Article  CAS  Google Scholar 

  4. Hughes, K., Ramakrishna, S., Benjamin, W. B. & Woodgett, J. R. Identification of multifunctional ATP-citrate lyase kinase as the α-isoform of glycogen synthase kinase-3. Biochem. J. 288, 309?314 (1992).

    Article  CAS  Google Scholar 

  5. Welsh, G. I. & Proud, C. G. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem. J. 294, 625?629 (1993).

    Article  CAS  Google Scholar 

  6. Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785?789 (1995).

    Article  CAS  Google Scholar 

  7. Alessi, D. R. et al. Characterisation of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261?269 (1997).

    Article  CAS  Google Scholar 

  8. Fiol, C. J., Mahrenholz, A. M., Wang, Y., Roeske, R. W. & Roach, P. J. Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. J. Biol. Chem. 262, 14042?14048 (1987).

    CAS  PubMed  Google Scholar 

  9. Frame, S., Cohen, P. & Biondi, R. M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321?1327 (2001).

    Article  CAS  Google Scholar 

  10. Dajani, R. et al. Crystal structure of glycogen synthase kinase 3β: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105, 721?732 (2001).

    Article  CAS  Google Scholar 

  11. ter Haar, E. et al. Structure of GSK3β reveals a primed phosphorylation mechanism. Nature Struct. Biol. 8, 593?596 (2001).

    Article  CAS  Google Scholar 

  12. Hughes, K., Nikolakaki, E., Plyte, S. E., Totty, N. F. & Woodgett, J. R. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12, 803?808 (1993).

    Article  CAS  Google Scholar 

  13. Stambolic, V. & Woodgett, J. R. Mitogen inactivation of glycogen synthase kinase-3β in intact cells via serine 9 phosphorylation. Biochem. J. 303, 701?704 (1994).

    Article  CAS  Google Scholar 

  14. Shaw, M. & Cohen, P. Role of protein kinase B and the MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells. FEBS Lett. 461, 120?124 (1999).

    Article  CAS  Google Scholar 

  15. Armstrong, J. L., Bonavaud, S. M., Toole, B. J. & Yeaman, S. J. Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J. Biol. Chem. 276, 952?956 (2001).

    Article  CAS  Google Scholar 

  16. Fang, X. et al. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc. Natl Acad. Sci. USA 97, 11960?11965 (2000).

    Article  CAS  Google Scholar 

  17. Li, M. et al. Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3β. Mol. Cell. Biol. 20, 9356?9363 (2000).

    Article  CAS  Google Scholar 

  18. Frame, S. & Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1?16 (2001).

    Article  CAS  Google Scholar 

  19. Alt, J. R., Cleveland, J. L., Hannink, M. & Diehl, J. A. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev. 14, 3102?3114 (2000).

    Article  CAS  Google Scholar 

  20. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499?3511 (1998).

    Article  CAS  Google Scholar 

  21. Sears, R. et al. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14, 2501?2514 (2000).

    Article  CAS  Google Scholar 

  22. Nikolakaki, E., Coffer, P. J., Hemelsoet, R., Woodgett, J. R. & Defize, L. H. Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells. Oncogene 8, 833?840 (1993).

    CAS  PubMed  Google Scholar 

  23. Sabbah, M., Courilleau, D., Mester, J. & Redeuilh, G. Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc. Natl Acad. Sci. USA 96, 11217?11222 (1999).

    Article  CAS  Google Scholar 

  24. Siegfried, E., Chou, T. B. & 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 71, 1167?1179 (1992).

    Article  CAS  Google Scholar 

  25. Pierce, S. B. & Kimelman, D. Regulation of Spemann organizer formation by the intracellular kinase Xgsk-3. Development 121, 755?765 (1995).

    CAS  PubMed  Google Scholar 

  26. He, X., Saint-Jeannet, J. P., Woodgett, J. R., Varmus, H. E. & Dawid, I. B. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature 374, 617?622 (1995).

    Article  CAS  Google Scholar 

  27. Kao, K. R., Masui, Y. & Elinson, R. P. Lithium-induced respecification of pattern in Xenopus laevis embryos. Nature 322, 371?373 (1986).

    Article  CAS  Google Scholar 

  28. Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455?8459 (1996).

    Article  CAS  Google Scholar 

  29. Stambolic, V., Ruel, L. & Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6, 1664?1668 (1996).

    Article  CAS  Google Scholar 

  30. Zeng, L. et al. The mouse fused locus encodes axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90, 181?192 (1997).

    Article  CAS  Google Scholar 

  31. Ikeda, S. et al. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3β and β-catenin and promotes GSK-3β-dependent phosphorylation of β-catenin. EMBO J. 17, 1371?1384 (1998).

    Article  CAS  Google Scholar 

  32. Hart, M. J., de los Santos, R., Albert, I. N., Rubinfeld, B. & Polakis, P. Downregulation of β-catenin by human axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr. Biol. 8, 573?581 (1998).

    Article  CAS  Google Scholar 

  33. Li, L. et al. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J. 18, 4233?4240 (1999).

    Article  CAS  Google Scholar 

  34. Yost, C. et al. GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93, 1031?1041 (1998).

    Article  CAS  Google Scholar 

  35. Ding, V. W., Chen, R. H. & McCormick, F. Differential regulation of glycogen synthase kinase 3β by insulin and Wnt signaling. J. Biol. Chem. 275, 32475?32481 (2000).

    Article  CAS  Google Scholar 

  36. Ruel, L., Stambolic, V., Ali, A., Manoukian, A. S. & Woodgett, J. R. Regulation of the protein kinase activity of Shaggy (Zeste-white3) by components of the Wingless pathway in Drosophila cells and embryos. J. Biol. Chem. 274, 21790?21796 (1999).

    Article  CAS  Google Scholar 

  37. Thomas, G. M. et al. A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and β-catenin. FEBS Lett. 458, 247?251 (1999).

    Article  CAS  Google Scholar 

  38. Hoeflich, K. P. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86?90 (2000).

    Article  CAS  Google Scholar 

  39. Eldar-Finkelman, H., Schreyer, S. A., Shinohara, M. M., LeBoeuf, R. C. & Krebs, E. G. Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes 48, 1662?1666 (1999).

    Article  CAS  Google Scholar 

  40. Coghlan, M. P. et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 7, 793?803 (2000).

    Article  CAS  Google Scholar 

  41. Lochhead, P. A., Coghlan, M., Rice, S. Q. J. & Sutherland, C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression. Diabetes 50, 1?10 (2001).

    Article  Google Scholar 

  42. Norman, P. Emerging fundamental themes in modern medicinal chemistry. Drug News Perspect. 14, 242?247 (2001).

    CAS  PubMed  Google Scholar 

  43. Yoshida, H. & Ihara, Y. Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. J. Neurochem. 61, 1183?1186 (1993).

    Article  CAS  Google Scholar 

  44. Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837?1851 (2000).

    CAS  Google Scholar 

  45. Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 18, 5931?5942 (1999).

    Article  CAS  Google Scholar 

  46. Woods, Y. et al. The kinase DYRK phosphorylates protein synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609?615 (2001).

    Article  CAS  Google Scholar 

  47. Pap, M. & Cooper, G. M. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J. Biol. Chem. 273, 19929?19932 (1998).

    Article  CAS  Google Scholar 

  48. Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. P. & Anderton, B. H. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 147, 58?62 (1992).

    Article  CAS  Google Scholar 

  49. Mandelkow, E. M. et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314, 315?321 (1992).

    Article  CAS  Google Scholar 

  50. Munoz-Montano, J. R., Moreno, F. J., Avila, J. & Diaz-Nido, J. Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett. 411, 183?188 (1997).

    Article  CAS  Google Scholar 

  51. Bramblett, G. T. et al. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089?1099 (1993).

    Article  CAS  Google Scholar 

  52. Cross, D. A. et al. Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J. Neurochem. 77, 94?102 (2001).

    Article  CAS  Google Scholar 

  53. Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signaling. Cell 103, 311?320 (2000).

    Article  CAS  Google Scholar 

  54. Weng, Q. P., Andrabi, K., Kozlowski, M. T., Grove, J. R. & Avruch, J. Multiple independent inputs are required for activation of the p70 S6 kinase. Mol. Cell. Biol. 15, 2333?2340 (1995).

    Article  CAS  Google Scholar 

  55. Kim, L. & Kimmel, A. R. GSK3, a master switch regulating cell-fate specification and tumorigenesis. Curr. Opin. Genet. Dev. 10, 508?514 (2000).

    Article  CAS  Google Scholar 

  56. Seidensticker, M. J. & Behrens, J. Biochemical interactions in the Wnt pathway. Biochim. Biophys. Acta 1495, 168?182 (2000).

    Article  CAS  Google Scholar 

  57. Williams, M. R. et al. The role of 3-phosphoinositide-depen-dent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr. Biol. 10, 439?448 (2000).

    Article  CAS  Google Scholar 

  58. Friedman, D. L. & Larner, J. Studies on UDPG-α-glucan transglucosylase III. Interconversion of two forms of muscle UDPG-α-glucan transglucosylase by a phosphorylation?dephosphorylation reaction sequence. Biochemistry 2, 669?675 (1963).

    Article  CAS  Google Scholar 

  59. Craig, J. W. & Larner, J. Influence of epinephrine and insulin on uridine diphosphate glucose-α-glucan transferase and phosphorylase in muscle. Nature 202, 971?973 (1964).

    Article  CAS  Google Scholar 

  60. Cohen, P. The hormonal control of glycogen metabolism in mammalian muscle by multivalent phosphorylation. 'The Fifteenth Colworth Medal Lecture'. Biochem. Soc. Trans. 7, 459?480 (1978).

    Article  Google Scholar 

  61. Woodgett, J. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9, 2431?2438 (1990).

    Article  CAS  Google Scholar 

  62. Boyle, W. J. et al. Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. Cell 64, 573?584 (1991).

    Article  CAS  Google Scholar 

  63. Sutherland, C. & Cohen, P. The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett. 338, 37?42 (1994).

    Article  CAS  Google Scholar 

  64. Cross, D. A. et al. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem. J. 303, 21?26 (1994).

    Article  CAS  Google Scholar 

  65. Yost, C. et al. The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10, 1443?1454 (1996).

    Article  CAS  Google Scholar 

  66. Rubinfeld, B. et al. Binding of GSK3β to the APC?β-catenin complex and regulation of complex assembly. Science 272, 1023?1026 (1996).

    Article  CAS  Google Scholar 

  67. Alessi, D. R. et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541?6551 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

Our research is supported by the UK Medical Research Council, Diabetes UK, The Royal Society, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, NovoNordisk and Pfizer. We apologize to the authors whose papers could not be referenced because of space restrictions.

Author information

Authors and Affiliations

  1. MRC Protein Phosphorylation Unit and Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, Scotland, DD1 5EH, UK

    Philip Cohen

  2. the Division of Signal Transduction Therapy, Scotland, DD1 5EH, UK

    Sheelagh Frame

Authors
  1. Philip Cohen
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  2. Sheelagh Frame
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Corresponding author

Correspondence to Philip Cohen.

Supplementary information

Related links

Related links

DATABASES

 FlyBase:

wingless

zeste-white 3

 InterPro:

PH

SH2

 Locuslink:

APC

axin

β-catenin

CDK4

CDK6

c-jun

CK2

c-myc

cyclin D1

DVL

DYRK

eIF2B

FRAT

frizzled

glycogen synthase

GSK3

IGF1

insulin

insulin receptor

IRS1

IRS2

MAPKAP-K1

mTOR

PDK1

6-phosphofructo-1-kinase

PI3K

PKA

PKB

retinoblastoma

S6K

Tau

WNTs

 OMIM:

Alzheimer's disease

NIDDM

 Swiss-Prot:

GBP

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Cohen, P., Frame, S. The renaissance of GSK3. Nat Rev Mol Cell Biol 2, 769–776 (2001). https://doi.org/10.1038/35096075

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