Ca2+-Calmodulin-Dependent Protein Kinases and Protein Kinase C: Functional Similarities

  • Theodore G. Sotiroudis
  • Symeon M. Kyriakidis
  • Leonidas G. Baltas
  • Vasilis G. Zevgolis
  • Athanasios E. Evangelopoulos
Part of the NATO ASI Series book series (NATO ASI, volume 169)


Protein serine and threonine kinases can be classified into individual groups or subclasses on the basis of the type of regulation of their activities (Krebs, 1986). Two of the most intensively studied groups are Ca2+-regulated, i.e. the Ca2+/calmodulin (CaM)-dependent and the Ca2+-phospholipid (diacylglycerol)-dependent protein kinases. Of the enzymes belonging in the category of Ca2+/CaM-dependent kinases, myosin light chain kinases (MLCK) are distinguished by their high degree of substrate specificity and CaM dependency (Edelman et al, 1987). Phosphorylase kinase (PhK) another member of the same group is characterized by a broader substrate specificity. Its primary substrate is phosphorylase b but the enzyme may catalyze the phosphorylation of other proteins (Chan & Graves, 1984). In addition, a number of Ca2+/CaM-dependent multifunctional protein kinases (Ca2+/CaM PrK) identified in a variety of tissues shows a broad substrate specificity suggesting that such a group of CaM-dependent protein kinases may play important roles in the control of different cellular processes (Shenolikar et al, 1986). On the other hand, protein kinase C (PKC) is a multifunctional protein kinase identified by Nishizuka and co-workers as a Ca2+- and phospholipid-dependent protein kinase that plays a crucial role in the signal transduction for a variety of biologically active substances involved in cellular function and proliferation (Nishizuka, 1984). In the presence of limiting amounts of Ca2+ and phospholipids its activity is stimulated by sn-1,2-diacylglecerols or by phorbol esters (Nishizuka, 1984) and the kinase phosphorylates a broad range of cellular proteins (Kikkawa and Nishizuka, 1986).


Protein Kinase Sarcoplasmic Reticulum Myosin Light Chain Kinase Dependent Protein Kinase Broad Substrate Specificity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albert, K.A., Wu, W.C-S., Nairn, A.C. and Greengard, P., 1984, Inhibition of calcium/phospholipid-dependent protein phosphorylation, Proc. Natl. Acad. Sci. USA 81:3622.PubMedCrossRefGoogle Scholar
  2. Baltas, L.G., Zevgolis, V.G., Kyriakidis, S.M., Sotiroudis, T.G. and Evangelopoulos, A.E. in preparationGoogle Scholar
  3. Baudier, J. and Cole, R.D., 1987, Phosphorylation of tau proteins to a state like that in Alzheimer’s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids, J. Biol. Chem., 262:17577.PubMedGoogle Scholar
  4. Bazzi, M.D. and Nelsestuen, G.L., 1988, Constitutive activity of membrane-inserted protein kinase C., Biochem. Biophys. Res. Commun., 152:336.PubMedCrossRefGoogle Scholar
  5. Burn, P., 1988, Amphitropic proteins: A new class of membrane proteins, Treds Biochem. Sci. 13:79.CrossRefGoogle Scholar
  6. Castagna, M., Pavone, C., Bazgar, S., Couturier, A., Chevalier, M. and Fiszman, M., 1985, Phospholipid/Ca2+-dependent protein kinase, cell differentiation and tumor promotion, in: “Hormones and Cell Regulation” J.E. Dumont et al, eds, Elsevier Science Publishers BVGoogle Scholar
  7. Chan, K.-F.J. & Graves, D.J., 1984, Molecular properties of phosphorylase kinase, in: “Calcium & Cell Function” W.Y. Cheung, ed., Academic Press, New YorkGoogle Scholar
  8. Chauhan, V.P.S. and Brockerhoff, H., 1988, Phosphatidylinositoi,-4-5 biphosphate antecede diacylglycerol as activator for protein kinase C., FASEB J. 2:A349Google Scholar
  9. Cox, J.A., 1988, Interactive properties of calmodulin, Biochem. J., 249:621PubMedGoogle Scholar
  10. Dombradi, V.K., Silberman, S.R., Lee, E.Y.C., Caswell, A.H. & Brandt, N.R., 1984, The association of phosphorylase kinase with rabbit muscle T-tubules, Arch. Biochem. Biophys., 230:615PubMedCrossRefGoogle Scholar
  11. Edelman, A.M., Blumenthal, D.K. and Krebs, E.G., 1987, Protein serine-threonine kinases, Ann. Rev. Biochem., 56:567PubMedCrossRefGoogle Scholar
  12. Famulski, K.S. and Carafoli, E., 1984, Calmodulin-dependent protein phosphorylation and calcium uptake in rat liver microsames, Eur. J. Biochem., 141:15PubMedCrossRefGoogle Scholar
  13. Fujiki, H., Yamashita, K., Suganuma, M., Horiuchi, T., Taniguchi, N. and Makita, A., 1986, Involvement of sulfatide in activation of protein kinase C by tumor promoters, Biochem. Biophys. Res. Commun., 138:153PubMedCrossRefGoogle Scholar
  14. Gietzen, K., Sadorf, I. and Bader, H., 1981, A model for the regulation of the calmodulin-dependent enzymes erythrocyte Ca2+-transport ATPase and brain phosphodiesterase by activators and inhibitors, Biochem. J., 207:541Google Scholar
  15. Gschwendt, M., Horn, F., Kittstein, W. and Marks, F., 1983, Inhibition of the calcium-and phospholipid-dependent protein kinase activity from mouse brain cytosol by quercetin, Biochem. Biophys. Res. Commun., 117:444PubMedCrossRefGoogle Scholar
  16. Hanley, R.M., Means, A.R., Kemp, B.E. and Shenolikar, S., 1988, Mapping of calmodulin-binding domain of Ca2+/calmodulin-dependent protein kinase II from rat brain, Biochem. Biophys. Res. Commun., 152:122PubMedCrossRefGoogle Scholar
  17. Hannun, Y.A., Loomis, C.R., Merill, A.H. Jr and Bell, R.M., 1986, Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets, J. Biol. Chem., 261:12604PubMedGoogle Scholar
  18. Hannun, Y.A. and Bell, R.M., 1987, Lysosphingolipids inhibit protein kinase C: Implications for the sphingolipidoses, Science, 235:670PubMedCrossRefGoogle Scholar
  19. Hansson, A., Skoglund, G., Lassing, I., Lindberg, U. and Ingelman-Sundberg, M., 1988, Protein kinase C-dependent phosphorylation of profilin is specifically stimulated by Phosphatidylinositol biphosphate (PIP2), Biochem. Biophys. Res. Commun., 150:526.PubMedCrossRefGoogle Scholar
  20. Hessova, Z., Varsanyi, M. & Heilmeyer, L.M.G., Jr., 1985, Dual function of calmodulin (6) in phosphorylase kinase, Eur. J. Biochem., 146:107PubMedCrossRefGoogle Scholar
  21. Hörl, W.H., Jennissen, H.B. and Heilmeyer, L.M.G., Jr., 1978, Evidence for the participation of a Ca2+-dependent protein kinase and a protein phosphatase in the regulation of the Ca2+-transport ATPase of the sarcoplasmic reticulum. 1. Effect of inhibitors of the Ca2+-dependent protein kinase and protein phosphatase, Biochemistry, 17:759PubMedCrossRefGoogle Scholar
  22. Ito, M., Tanaka, T., Inagaki, M., Nakanishi, K. and Hidaka, H., 1986, N-(6-Phenylhexyl)-5-chloro-1-Naphthalenesulfonamide. A novel activator of protein kinase C., Biochemistry, 25:4179PubMedCrossRefGoogle Scholar
  23. Jett, M.-F., Schworer, C.M., Bass, M. and Soderling, T.R., 1987, Identification of membrane-bound calcium, calmodulin-dependent protein kinase II in canine heart, Arch. Biochem. Biophys., 255:354PubMedCrossRefGoogle Scholar
  24. Juckevich, J.C., Kuhn, D.M. and Lovenberg, W., 1983, Phosphorylation of brain cytosol proteins. Effects of phospholipids and calmodulin. J. Biol. Chem., 258:1950Google Scholar
  25. Kikkawa, V. and Nishizuka, Y., 1986, Protein kinase C., in: “The Enzymes”, P. Boyer and E.G. Krebs, eds, Academic Press, New YorkGoogle Scholar
  26. Kishimoto, A., Kajikawa, N., Siota, M. and Nishizuka, Y., 1983, Proteolytic activation of calmodulin-activated, phospholipid-dependent protein kinase by calcium-dependent neutral protease, J. Biol. Chem., 258:1156PubMedGoogle Scholar
  27. Kraft, A.S. and Anderson, W.B., 1983, Phorbol esters increase the amount of Ca2+ phospholipid-dependent protein kinase associated with plasma membrane, Nature, (London) 301:621PubMedCrossRefGoogle Scholar
  28. Krebs, E.G., 1986, The Enzymology of control by phosphorylation, in: “The Enzymes”, P. Boyer and E.G. Krebs, eds, Academic Press New YorkGoogle Scholar
  29. Kreutter, D., Kim, J.Y.H., Goldenring, J.R., Rasmussen, H., Ukomadu, C., DeLorenzo, R.J. and Yu, R.K., 1987, Regulation of protein kinase C activity by gangliosides, J. Biol. Chem., 262:1633PubMedGoogle Scholar
  30. Ktenas, T.B., Sotiroudis, T.G., Nikolaropoulos, S. and Evangelopoulos, A.E., 1985, Interaction of phosphorylase kinase with polymixins, Biochem. Biophys. Res. Commun., 133:891PubMedCrossRefGoogle Scholar
  31. Ktenas, T.B., Sotiroudis, T.G. and Evangelopoulos, A.E. in preparationGoogle Scholar
  32. Kuret, J. and Schulman, H., 1984, Purification and characterization of a Ca2+/calmodulin-dependent protein kinase from rat brain Biochemistry, 23:5495PubMedCrossRefGoogle Scholar
  33. Kyriakidis, S.M., Sotiroudis, T.G. and Evangelopoulos, A.E., 1986a, Stimulation of glycogen phosphorylase kinase with phospholipids, Biochem. Inter., 13:853Google Scholar
  34. Kyriakidis, S.M., Sotiroudis, T.G. and Evangelopoulos, A.E., 1986b, Interaction of flavonoids with rabbit muscle phosphorylase kinase, Biochim. Biophys. Acta, 871:121PubMedCrossRefGoogle Scholar
  35. Kyriakidis, S.M., Sotiroudis, T.G. and Evangelopoulos, A.E., 1988, Ca2+ and Mg2+-dependent association of phosphorylase kinase with human erythrocyte membranes, submitted for publicationGoogle Scholar
  36. Lindemann, J.P. and Watanabe, A.M., 1985, Phosphorylation of phospholamban in intact myocardium. Role of Ca2+-calmodulin-dependent mechanisms. J. Biol. Chem., 260:4516PubMedGoogle Scholar
  37. Lucas, T.J., Burgess, W.H., Prendergast, F.G., Lau, W. and Watterson, D.M., 1986, Calmodulin binding domains: Characterizarion of a phosphorylating and calmodulin binding site from myosin light chain kinase, Biochemistry, 25:1458CrossRefGoogle Scholar
  38. Mamoi, T., 1986, Activaton of protein kinase C by ganglioside GM3 in the presence of calcium and 12-o-tetradecanoylphorbol-13-acetate, Biochem. Biophys. Res. Commun., 138:865CrossRefGoogle Scholar
  39. Mazzei, G.J., Qi, D.-F., Schatzman, R.C., Raynor, R.L., Turner, R.S. and Kuo, J.F., 1983, Comparative abilities of lanthanide ions La3+ and Tb3+ to substitute for Ca2+ in regulating phospholipid-sensitive Ca2+-dependent kinase and myosin light chain kinase, Life Sci., 33:119PubMedCrossRefGoogle Scholar
  40. Mazzei, G.J., Girrard, P. and Kuo, J.F., 1984, Environmental pollutant Cd2+ biphasically and differentially regulates myosin light chain kinase and phospholipid/Ca2+-dependent protein kinase, FEBS Lett., 173:124PubMedCrossRefGoogle Scholar
  41. Meyer, T., Fabro, D., Eppenberger, U. and Matter, A., 1986, The lipohilic muramyltripeptide MTP-PE, a biological response modifier, is an activator of protein kinase C, Biochem. Biophys. Res. Commun., 140:1043PubMedCrossRefGoogle Scholar
  42. Murakami, K., Chan, S.Y. and Routtenberg, A., 1986, Protein kinase C activation by cis-fatty acid in the absence of Ca2+ and phospholipids, J. Biol. Chem., 261:15424PubMedGoogle Scholar
  43. Murakami, K., Whitley, M.K. and Routtenberg, A., 1987, Regulation of protein kinase C activity by cooperative interaction of Zn2+ and Ca2+, J. Biol. Chem., 262:13902PubMedGoogle Scholar
  44. Nairn, A.C., Hemmings, H.C., Jr. and Greengard, P., 1985, Protein kinases in the brain, Ann. Rev. Biochem., 54:931PubMedCrossRefGoogle Scholar
  45. Negami, A.I., Sasaki, H. and Yamamura, H., 1986, Activation of phosphorylase kinase through autophosphorylation by membrane component Phospholipids, Eur. J. Biochem., 157:597PubMedCrossRefGoogle Scholar
  46. Nikolaropoulos, S. and Sotiroudis, T.G., 1985, Phosphorylase kinase from chicken gizzard. Partial purification and characterization, Eur. J. Biochem., 151:467PubMedCrossRefGoogle Scholar
  47. Nishizuka, Y., 1984, The role of protein kinase C in cell-surface signal transduction and tumor promotion, Nature, 308:693PubMedCrossRefGoogle Scholar
  48. Nishizuka, Y., 1986, Studies and perspectives of protein kinase C, Science 233:305PubMedCrossRefGoogle Scholar
  49. Nishizuka, Y., 1988, The molecular heterogeneity of protein kinase C and its implications for cellular regulation, Nature, 334:661PubMedCrossRefGoogle Scholar
  50. Ono, Y., Fujii, T. Ogita, K., Kikkawa, U., Igarashi, K. and Nishizuka, Y., 1988, The structure, expression and properties of additional members of the protein kinase C family, J. Biol. Chem., 263:6927PubMedGoogle Scholar
  51. Parker, P.J. and Ullrich, A., 1987, Protein kinase C, J. Cell. Physiol. Suppl., 5:53PubMedCrossRefGoogle Scholar
  52. Pickett-Giese, C.A. & Walsh, D.A., 1986, Phosphorylase kinase, in: “The Enzymes”, P. Boyer & E.G. Krebs, eds, Academic Press, New YorkGoogle Scholar
  53. Sakai, K., Kobayashi, T., Komuvo, T., Nakamura, S., Mizuta, K., Sakanoue, Y., Hashimoto, E. and Yamamura, H., 1987, Non-requirement of calcium on protamine phosphorylation by calcium-activated, phospholipid dependent protein kinase, Biochem. Inter., 14:63Google Scholar
  54. Sato, H., Fukunaga, K., Araki, S., Ohtsuki, I. and Miyamoto, E., 1988, Identification of the multifunctional calmodulin-dependent protein kinase in the cytosol, sarcoplasmic reticulum and sarcolemma of rabbit skeletal muscle, Arch. Biochem. Biophys., 260:443PubMedCrossRefGoogle Scholar
  55. Schulman, H., 1984, Calcium—dependent protein kinases and neuronal function, Trends Pharmacol. Sci., 5:188CrossRefGoogle Scholar
  56. Shenolikar, S., Cohen, P.T.W., Cohen, P., Nairn, A.C. and Peryy, S.V., 1979, Role of calmodulin in the structure and regulation of phosphorylase kinase from rabbit skeletal muscle, Eur. J. Biochem., 100:329PubMedCrossRefGoogle Scholar
  57. Shenolikar, S., Lickteig, R., Hardie, D.G., Soderling, T.R., Hanley, R.M. and Kelly, P.T., 1986, Calmodulin-dependent multifunctional protein kinases. Evidence for isoenzyme forms in mammalian tissues, Eur. J. Biochem., 161:739PubMedCrossRefGoogle Scholar
  58. Singh, T., & Wang, J.H., 1979, Stimulation of glycogen phosphorylase kinase from rabbit skeletal muscle by organic solvents, J. Biol. Chem., 254:8466PubMedGoogle Scholar
  59. Sotiroudis, T.G., 1986, Lanthanide ions and Ca2+ are able to substitute for Ca2+ in regulating phosphorylase kinase, Biochem. Inter., 13:59Google Scholar
  60. Stull, J.T., Nunnally, M.H. and Michnoff, C.H., 1986, Calmodulin-dependent protein kinases, in: “The Enzymes”, P. Boyer and E.G. Krebs, eds, Academic Press, New YorkGoogle Scholar
  61. Takai, Y., Kishimoto, A., Iwasa, Y., Kawahara, Y., Mori, T. and Nishizuka, Y., 1979, Calcium-dependent activation of a multifunctional protein kinase by membrane phospholipids, J. Biol. Chem., 254:3692PubMedGoogle Scholar
  62. Tanaka, J. and Hidaka, H., 1980, Hydrophobic regions function in calmodulin enzyme(s) interactions, J. Biol. Chem., 255:11078PubMedGoogle Scholar
  63. Thieleczek, R., Behle, G., Behle, G., Messer, A., Varsanyi, M., Heilmeyer, L.M.G., Jr & Drenckhahn, D., 1987, Localization of phosphorylase kinase subunits at the sarcoplasmic reticulum of rabbit skeletal muscle by monoclonal and polyclonal antibodies, Eur. J. Cell Biol., 44:333PubMedGoogle Scholar
  64. Tuana, B.S. and MacLennan, D.H., 1984, Calmidazolium and compound 48/80 inhibit calmodulin-dependent Ca2+ uptake but not Ca2+-ATPase activity in skeletal muscle sarcoplasmic reticulum, J. Biol. Chem., 259:6979PubMedGoogle Scholar
  65. Wightman, P.D. and Raetz, C.R.H., 1984, The activation of protein kinase C by biologically active lipid moieties of lipopolysaccharide, J. Biol. Chem., 259:10048PubMedGoogle Scholar
  66. Wolf, M., LeVine III, H., May, S., Jr, Cuatrecasas, P. and Sahyoun, N., 1985, A model for intracellular translocation of protein kinase C involving synergism between Ca2+ and phosrbol esters, Nature, 317:546PubMedCrossRefGoogle Scholar
  67. Woodgett, J.R., Davison, M.T. and Cohen, P., 1983, The calmodulin-dependent glycogen synthase kinase from rabbit skeletal muscle. Purification subunit structure and substrate specificity, Eur. J. Biochem., 136:481PubMedCrossRefGoogle Scholar
  68. Zevgolis, V.G., Sotiroudis, T.G. and Evangelopoulos, A.E. in preparation.Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Theodore G. Sotiroudis
    • 1
  • Symeon M. Kyriakidis
    • 1
  • Leonidas G. Baltas
    • 1
  • Vasilis G. Zevgolis
    • 1
  • Athanasios E. Evangelopoulos
    • 1
  1. 1.The National Hellenic Research FoundationAthensGreece

Personalised recommendations