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The origins of protein phosphorylation

Abstract

The reversible phosphorylation of proteins is central to the regulation of most aspects of cell function but, even after the first protein kinase was identified, the general significance of this discovery was slow to be appreciated. Here I review the discovery of protein phosphorylation and give a personal view of the key findings that have helped to shape the field as we know it today.

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Figure 1: The glycogenolytic cascade in mammalian skeletal muscle.

References

  1. MacKintosh, C., Beattie, K. A., Klumpp, S., Cohen, P. & Codd, G. A. FEBS Lett 264, 187–192 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Cori, G. T. & Green, A. A. J. Biol. Chem. 151, 31–38 (1943).

    CAS  Google Scholar 

  3. Burnett, G. & Kennedy, E. P. J. Biol. Chem. 211, 969–980 (1954).

    CAS  PubMed  Google Scholar 

  4. Fischer, E. H. & Krebs, E. G. J. Biol. Chem. 216, 121–132 (1955).

    CAS  PubMed  Google Scholar 

  5. Krebs, E. G. & Fischer, E. H. Biochim. Biophys. Acta 20, 150–157 (1956).

    Article  CAS  PubMed  Google Scholar 

  6. Sutherland, E. W. & Wosilait, W. D. Nature 175, 169–170 (1955).

    Article  CAS  PubMed  Google Scholar 

  7. Fischer, E. H., Graves, D. J., Crittenden, E. R. S. & Krebs, E. G. J. Biol. Chem. 234, 1698–1704 (1959).

    CAS  PubMed  Google Scholar 

  8. Ingebritsen, T. S. & Cohen, P. Eur. J. Biochem. 132, 255–261 (1983).

    Article  CAS  PubMed  Google Scholar 

  9. Robison, G. A., Butcher, R. W. & Sutherland, E. W. Cyclic AMP Academic Press, London (1971).

    Google Scholar 

  10. Walsh, D. A., Perkins, J. P. & Krebs E. G. J. Biol. Chem. 243, 3763–3765 (1968).

    CAS  PubMed  Google Scholar 

  11. Bishop, J. S. & Larner, J. Biochim. Biophys. Acta 171, 374–377 (1969).

    Article  CAS  PubMed  Google Scholar 

  12. Soderling, T. R. et al. J. Biol. Chem. 245, 6617–6628 (1970).

    Google Scholar 

  13. Heilmeyer, L. M. G. Jr, Meyer, F., Haschke, R. H. & Fischer, E. H. J. Biol. Chem. 245, 6649–6656 (1970).

    CAS  PubMed  Google Scholar 

  14. Brostrom, C. O., Hunkeler, F. L. & Krebs, E. G. J.Biol. Chem. 246, 1961–1967 (1971).

    CAS  PubMed  Google Scholar 

  15. Cohen, P., Burchell, A., Foulkes, J. G. & Cohen, P. T. W. FEBS Lett. 92, 287–292 (1978).

    Article  CAS  PubMed  Google Scholar 

  16. Linn, T. C., Pettit, F. H. & Reed, L. J. Proc. Natl Acad. Sci. USA 62, 234–241 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Corbin, J. D., Reimann, E. M., Walsh, D. A. & Krebs, E. G. J. Biol. Chem. 245, 4849–4851 (1970).

    CAS  PubMed  Google Scholar 

  18. Ljungstrom, O., Hjelmqvist, G. & Engstrom, L. Biochim. Biophys. Acta 358, 289–298 (1974).

    Article  Google Scholar 

  19. Kuo, J. F. & Greengard, P. Proc. Natl Acad. Sci. USA 64, 1349–1355 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. England, P. J. FEBS Lett. 50, 57–60 (1975).

    Article  CAS  PubMed  Google Scholar 

  21. Tada, M., Kirschberger, M. A. & Katz, A. M. J. Biol. Chem. 250, 2640–2647 (1975).

    CAS  PubMed  Google Scholar 

  22. Langan, T. A. Proc. Natl Acad. Sci. USA 64, 1276–1283 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dabrowska, R., Sherry, J. M. F., Aromatorio, D. K. & Hartshorne, D. J. Biochemistry 17, 253–258 (1978).

    Article  CAS  PubMed  Google Scholar 

  24. Schulman, H. & Greengard, P. Nature 271, 478–479 (1978).

    Article  CAS  PubMed  Google Scholar 

  25. McGuinness, T. L., Lai, Y., Greengard, P., Woodgett, J. R. & Cohen, P. FEBS Lett. 163, 329–334 (1983).

    Article  CAS  PubMed  Google Scholar 

  26. Kishimoto, A., Takai, Y., Mori, T., Kikkawa, U. & Nisdhizuka, Y. J. Biol. Chem. 255, 2273–2276 (1980).

    CAS  PubMed  Google Scholar 

  27. Stewart, A. A., Ingebritsen, T. S., Manalan, A., Klee, C. B. & Cohen, P. FEBS Lett. 137, 80–84 (1982).

    Article  CAS  PubMed  Google Scholar 

  28. Liu, J., Farmer, J. D., Lane, W. S., Friedman, J., Weissman, I. & Schreiber, S. L. Cell 66, 807–815 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Daile, P. & Carnegie, P. R. & Young, J. D. Nature 257, 416–418 (1975).

    Article  CAS  PubMed  Google Scholar 

  30. Zetterqvist, O., Ragnarsson, U., Humble, E., Berglund, L. & Engstrom, L. Biochem. Biophys. Res. Commun. 70, 696–703 (1976).

    Article  CAS  PubMed  Google Scholar 

  31. Kemp, B. E., Benjamini, E. & Krebs, E. G. Proc. Natl. Acad. Sci. USA 73, 1038–1042 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shoji, S. et al. Proc. Natl Acad. Sci. USA 78, 848–851 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nurse, P. Trends Genet. 1, 51–55 (1985).

    Article  CAS  Google Scholar 

  34. Cohen, P. Trends Biochem. Sci. 1, 38–40 (1976).

    Article  CAS  Google Scholar 

  35. Nakielny, S., Campbell, D. G. & Cohen, P. Eur. J. Biochem. 199, 713–722 (1991).

    Article  CAS  PubMed  Google Scholar 

  36. Stralfors, P., Hiraga, A. & Cohen, P. Eur. J. Biochem. 149, 295–303 (1985).

    Article  CAS  PubMed  Google Scholar 

  37. Bregman, D. B., Bhattacharyya, N, and Rubin, C. S. J. Biol. Chem. 266, 4648–4656 (1989).

    Google Scholar 

  38. Colledge, M. & Scott, M. D. Trends Cell Biol. 9, 216–221 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Collett, M. S. & Erikson, R. L. Proc. Natl Acad. Sci. USA 75, 2021–2024 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hunter, T. & Sefton, B. M. Proc. Natl Acad. Sci. USA 77, 1311–1315 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ushiro, H. & Cohen, S. J. Biol. Chem. 255, 8363–8365 (1980).

    CAS  PubMed  Google Scholar 

  42. Kasuga, M., Karlsson, F. A. & Kahn, C. R. Science 215, 185–187 (1982).

    Article  CAS  PubMed  Google Scholar 

  43. Sadowski, I., Stone, J. C. & Pawson, T. Mol. Cell. Biol. 6, 4396–4408 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Anderson, A., Koch, C. A., Grey, L., Ellis, C., Moran, M. F. & Pawson, T. Science 250, 979–982 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Tonks, N. K., Diltz, C. D. & Fischer, E. H. J. Biol. Chem. 263, 6722–6730 (1988).

    CAS  PubMed  Google Scholar 

  46. Tonks, N. K., Charbonneau, H., Diltz, C. D., Fischer, E. H. & Walsh, K. A. Biochemistry 27, 8695–8701 (1988).

    Article  CAS  PubMed  Google Scholar 

  47. Wilkes, A. F., Harpur, A. G., Kurban, R. R., Ralph, S. J., Zürcher, G. & Ziemiecki, A. Mol. Cell. Biol. 11, 2057–2065(1991).

    Article  Google Scholar 

  48. Wilks, A. F. & Harpur, A. G. Bioessays 16, 313–320 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Ray, L. B. & Sturgill, T. W. Proc. Natl Acad. Sci. USA 84, 1502–1506 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Anderson, N., Maller, J. L., Tonks, N. K. & Sturgill, T. W. Nature 343, 651–653 (1990).

    Article  CAS  PubMed  Google Scholar 

  51. Ahn, N. G., Seger, R., Bratlien, R. L., Diltz, C. D., Tonks, N. K. & Krebs, E. G. J. Biol. Chem. 266, 4220–4227 (1991).

    CAS  PubMed  Google Scholar 

  52. Gomez, N. & Cohen, P. Nature 353, 170–173 (1991).

    Article  CAS  PubMed  Google Scholar 

  53. Leevers, S. J. & Marshall, C. J. EMBO J. 11, 569–574 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Whitman, M., Downes, C. P., Keeler, M., Keller, T. & Cantley, L. C. Nature 332, 644–646 (1988).

    Article  CAS  PubMed  Google Scholar 

  55. Traynor-Kaplan, A. E., Harris, A. L., Thompson, B. L., Taylor, P. & Sklar, L. A. Nature 334, 353–356 (1988).

    Article  CAS  PubMed  Google Scholar 

  56. Toker, A. & Cantley, L. C. Nature 387, 673–676 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. J. Biol. Chem. 269, 5241–5248 (1994).

    CAS  PubMed  Google Scholar 

  58. Ui, M., Okada, T., Hazeki, K. & Hazeki, O. Trends Biochem. Sci. 20, 303–307 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Franke, T. F. et al. Cell 81, 727–736 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Burgering, B. M. Th and Coffer, P. J. Nature 376, 599–602 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Cross, D. A. E., Alessi, D. R., Cohen, P., Anjelkovic, M. & Hemmings, B. A. Nature 378, 785–788 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Alessi, D. R. et al. Curr. Biol. 7, 261–269 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Cohen, P. Nature 296, 613–620 (1982).

    Article  CAS  PubMed  Google Scholar 

  64. Smith, D. L., Chen, C-C, Bruegger, B. B., Holtz, S. L., Halpern, R. M. & Smith, R. A. Biochemistry 13, 3780–3785 (1974).

    Article  CAS  PubMed  Google Scholar 

  65. Swanson, R. V., Alex, L.A. & Simon, M. I. Trends Biochem. Sci. 19, 439–518 (1994).

    Article  Google Scholar 

  66. Levy-Favatier, F., Delpech, M. & Kruh, J. Eur. J. Biochem. 166, 617–621 (1987).

    Article  CAS  PubMed  Google Scholar 

  67. Khandelwahl, R. M., Mattoo, R. L. & Waygood, E. B. FEBS Lett. 162, 127–132 (1983).

    Article  Google Scholar 

  68. Cohen, P. Nature Rev. Drug Disc. 1, 309–315 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This perspective is a personal account of some of the important events in protein phosphorylation research that have taken place over the past 50 years or more. I apologize to the scientists whose many important discoveries that could not be included or referenced in this article because of space restrictions. The work carried out in my laboratory is supported by the UK Medical Research Council, The Royal Society of London, Diabetes U.K., The Louis Jeantet Foundation, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, NovoNordisk and Pfizer.

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Cohen, P. The origins of protein phosphorylation. Nat Cell Biol 4, E127–E130 (2002). https://doi.org/10.1038/ncb0502-e127

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