Protein Kinase C — Structural Studies

  • Peter J. Parker
  • Richard Marais
  • Mona Bajaj
  • Fiona Mitchell
  • Peter King
  • Sue Young
  • Axel Ullrich
  • Silvia Stabel
Part of the Advances in Experimental Medicine and Biology book series (NATO ASI F, volume 231)


Protein kinase C was first reported by Nishizuka and colleagues. This group identified a histone kinase activity that was irreversibly activated by mM concentrations of Ca2+ (Takai et al., 1977), an effect shown to be due to proteolysis of the holoenzyme by contaminating Ca2+-activated neutral protease (Inoue et al., 1977). Reversible activation was subsequently shown to occur in response to Ca2+ (~10-5M) and anionic phospholipid, phosphatidylserine being the most effective (Takai et al., 1979). Furthermore, activation could be effected at physiological Ca2+ concentrations (~10-6M) if the neutral lipid diacylglycerol was also present (Kishimoto et al., 1980). These characteristics of protein kinase C have led to the operational definition of the enzyme as a Ca2+/phospholipid dependent protein kinase.


Protein Kinase Epidermal Growth Factor Receptor Phorbol Ester Dependent Protein Kinase Human Fetal Brain 
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  1. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U. and Nishizuka, Y. (1982) Direct activation of calcium-activated, phospholipid dependent protein kinase by tumour-promoting phorbol esters. J. Biol. Chem. 257 7847–7851.PubMedGoogle Scholar
  2. Cochet, C., Gill, G.N., Meisenhelder, J., Cooper, J.A. and Hunter, T. (1984) C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity. J. Biol. Chem. 259 2553–2558.PubMedGoogle Scholar
  3. Coussens, L., Parker, P.J., Rhee, L., Yang-Feng, T.L., Chen, E., Waterfield, M.D. and Ullrich, A. (1986) Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signalling pathways. Science 233 859–866.PubMedCrossRefGoogle Scholar
  4. Coussens, L., Rhee, L., Parker, P.J. and Ullrich, A. (1987). Alternative splicing increases the diversity of the human protein kinase C family. In Press.Google Scholar
  5. Davis, R.J., Ganong, B.R., Bell, R.M. and Czech, M.P. (1985) Structural requirements for diacylglycerols to mimic tumour-promoting phorbol diester action on the epidermal growth factor receptor. J. Biol. Chem. 260 5315–5322.PubMedGoogle Scholar
  6. Downward, J., Waterfield, M.D. and Parker, PJ. (1985) Autophosphorylation and protein kinase C phosphorylation of the epidermal growth factor receptor. J. Biol. Chem 260 14538–14546.PubMedGoogle Scholar
  7. Fujiki, H., Tanaka, Y., Miyake, R., Kikkawa, U., Nishizuka, Y. and Sugimura, T. (1984) Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumour promoters: teleocidin and debromoaplysiatoxin. Biochem. Biophys. Res. Commun. 120 339–343.PubMedCrossRefGoogle Scholar
  8. Hoshijima, M., Kikuchi, A., Tanimoto, T., Kaibuchi, K. and Takai, Y. (1986) Formation of a phorbol ester-binding fragment from protein kinase C by proteolytic digestion. Cancer Res. 46 3000–3004.PubMedGoogle Scholar
  9. Huang, K.P. and Huang, F. (1986) Conversion of protein kinase C from a Ca2+-dependent to an independent form of phorbol ester-binding protein by digestion with trypsin. Biochem. Biophys. Res. Commun. 139 320–326.PubMedCrossRefGoogle Scholar
  10. Inoue, M., Kishimoto, A., Takai, Y. and Nishizuka, Y. (1977) Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. J. Biol. Chem. 252 7610–7616.PubMedGoogle Scholar
  11. Irvine, R.F. and Moor, R.M. (1986) Microinjection of inositol 1,3,4,5-tetrakisphosphate activates sea urchin eggs by a mechanism dependent on external Ca2+. Biochem. J. 240 917–920.PubMedGoogle Scholar
  12. Ishikawa, F., Takaku, F., Nagao, M. and Sugimura, T. (1986) Cysteine-rich regions conserved in amino-terminal halves of raf gene family products and protein kinase C. Jpn. J. Cancer Res. 22 1183–1187.Google Scholar
  13. Jeffrey, A.M. and Liskamp, R.M.J. (1986) Computer-assisted molecular modelling of tumour promoters: rationale for the activity of phorbol esters, teleocidin B and aphysiatoxin. Proc. Natl. Acad. Sci. USA 83 241 – 245.PubMedCrossRefGoogle Scholar
  14. Jeng, A.Y., Sharkey, N.A. and Blumberg, P.M. (1986) Purification of stable protein kinase C from mouse brain cytosol by specific ligand elution using fast protein liquid chromatography. Cancer Res. 46 1966–1971.PubMedGoogle Scholar
  15. Kikkawa, U., Takai, Y., Minakuchi, R., Inohara, S. and Nishizuka, Y. (1982) Calcium-activated, phospholipid-dependent protein kinase from rat brain. J. Biol. Chem. 252 13341–13348.Google Scholar
  16. Kikkawa, U., Go, M., Koumoto, J. and Nishizuka, Y. (1986) Rapid purification of protein kinase C by high performance liquid chromatography. Biochem Biophys. Res. Commun. 135 636–643.Google Scholar
  17. Kishimoto, A., Takai, Y., Mori, T., Kikkawa, U. and Nishizuka, Y. (1980) Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover. J. Biol. Chem. 255 2273–2276.PubMedGoogle Scholar
  18. Knopf, J.L., Lee, M.H., Schultzman, L.A., Kriz, R.W., Loomis, CR., Hewick, R.M. and Bell, R.M. (1986) Cloning and expression of multiple protein kinase C cDNAs. Cell 46 491–502.PubMedCrossRefGoogle Scholar
  19. Kuo, J.F., Anderson, R.G.G., Wise, B.C., Mackerlova, L., Salomonsson, I., Bracken, N.L., Katoh, N., Shoji, M. and Wrenn, R.W. (1980) Calciumdependent protein kinase: Widespread occurrence in various tissues and phyla of the animal kingdom and comparison of effects of phospholipid, calmodulin and trifluoperazine. Proc. Natl. Acad. Sci. 77 7039–7043.PubMedCrossRefGoogle Scholar
  20. Leach, K.L. James, M.L. and Blumberg, P.M. (1983) Characterisation of a specific phorbol ester aporeceptor in mouse brain cytosol. Proc. Natl. Acad. Sci. 80 607–610.CrossRefGoogle Scholar
  21. Lee, M-H. and Bell, R.M. (1986) The lipid binding, regulatory domain of protein kinase C. J. Biol. Chem. 261 14876–14870.Google Scholar
  22. Minakuchi, R., Takai, Y., Yu, B. and Nishizuka, Y. (1981) Widespread occurrence of calcium-activated, phospholipid-dependent protein kinase in mammalian tissues. J. Biochem. 89 1651–1654.PubMedGoogle Scholar
  23. Miyake, R., Tanaka, Y., Kaibuchi, K., Kikkawa, U. and Nishizuka, Y. (1984) Activation of protein kinase C by non-phorbol tumour prometer, mezerin. Biochem. Biophys. Res. Commun. 121 649–656.PubMedCrossRefGoogle Scholar
  24. Nishizuka, Y. (1986) Studies and perspectives of protein kinase C. Science 233 305–312.PubMedCrossRefGoogle Scholar
  25. Ohno, S., Kawasaki, H., Imajoh, S., Suzuki, K., Inagaki, M., Yokokura, H., Sakoh, T. and Hidaka, H. (1987) Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325 161–166.PubMedCrossRefGoogle Scholar
  26. Ono, Y., Kurokawa, T., Fujii, T., Kawahara, K., Igarashi, K., Kikkawa, U., Ogita, K. and Nishizuka, Y. (1986) Two types of complementary cDNAs of rat brain protein kinase C; heterogeneity determined by alternative splicing. FEBS. Letts. 206 347–352.CrossRefGoogle Scholar
  27. Parker, P.J., Stabel, S. and Waterfield, M.D. (1984) Purification to homogeneity of protein kinase C from bovine brain — identity with the phorbol ester receptor. EMBO J. 3 953–959.PubMedGoogle Scholar
  28. Parker, P.J., Coussens, L., Totty, N., Rhee, L., Young, S., Chen, E., Stabel, S., Waterfield, M.D. and Ullrich, A. (1986) The complete primary structure of protein kinase C — the major phorbol ester receptor. Science 233 853–859.PubMedCrossRefGoogle Scholar
  29. Parker, P.J. and Ullrich, A. (1987) Protein kinase C: Structure and function. J. Cell. Physiol. In Press.Google Scholar
  30. Rosenthal, A., Rhee, L., Yadegari, R., Paro, R., Ullrich, A. and Goeddel, D.V. (1987) Structure and nucleotide sequence of a Drosophila melanogaster protein kinase C gene. EMBO J. 6. 433–441.PubMedGoogle Scholar
  31. Sando, J.J. and Young, M.C. (1983) Identification of high-affinity phorbol ester receptor in cytosol of EL4 thymoma cells: requirement for calcium, magnesium and phospholipids. Proc. Natl. Acad. Sci. USA 80 2642–2646.PubMedCrossRefGoogle Scholar
  32. Shoyab, M. (1984) Isolation and characterisation of a specific receptor for biologically active phorbol and ingenol esters. Arch. Biochem Biophys. 236 435–440.CrossRefGoogle Scholar
  33. Stabel, S., Rodriguez-Pena, A., Young, S., Rozengurt, E. and Parker, P. Quantitation of protein kinase C by immunoblot — expression in different cell lines and response to phorbol esters (1987) J. Cell. Physiol. 130 111–117.PubMedCrossRefGoogle Scholar
  34. Streb, H., Irvine, R.F., Berridge, M.J. and Schultz, I. (1984) Release of Ca2+ from a non-mitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306 67–69.CrossRefGoogle Scholar
  35. Takai, Y., Kishimoto, A., Inoue, M. and Nishizuka, Y. (1977) Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues: 1. purification and characterisation of an active enzyme from bovine cerebellum. J. Biol. Chem. 252 7603–7609.PubMedGoogle Scholar
  36. Takai, Y., Kishimoto, A., Kikkawa, IL, Mori, T. and Nishizuka, Y. (1979) Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids. J. Biol. Chem. 254 3692–3695.PubMedGoogle Scholar
  37. Uchida, T. and Filburn, C.R. (1984) Affinity chromatography of protein kinase C-phorbol ester receptor on polyacrylamide-immobilized phosphatidylserine. J. Biol. Chem. 259 12311–12314.PubMedGoogle Scholar
  38. Wender, P.A., Koehler, K.F., Sharkey, N.A., DeirAquila, M.L. and Blumberg, P.M. (1986) Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs. Proc. Natl. Acad. Sci. 83 4214–4218.PubMedCrossRefGoogle Scholar
  39. Wolf, M., Sahyoun, N., Levine, H. and Cautrecasas, P. (1984) Protein kinase C: rapid enzyme purification and substrate dependence of the diacylglycerol effect. Biochem. Biophys. Res. Commun. 122 1268–1275.PubMedCrossRefGoogle Scholar
  40. Young, S., Parker, P., Ullrich, A. and Stabel, S. (1987) Down-regulation of protein kinase C is effected through increased proteolysis. Biochem. J. In Press.Google Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Peter J. Parker
    • 1
  • Richard Marais
    • 1
  • Mona Bajaj
    • 1
  • Fiona Mitchell
    • 1
  • Peter King
    • 1
  • Sue Young
    • 2
  • Axel Ullrich
    • 3
  • Silvia Stabel
    • 1
  1. 1.Ludwig Institute for Cancer ResearchLondonEngland
  2. 2.Imperial Cancer Research FundLondonEngland
  3. 3.Genentech Inc.South San FranciscoUSA

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