Regulation of multifunctional Ca2+/calmodulin-dependent protein kinases by Ca2+/calmodulin-dependent protein kinase phosphatase.

We have recently reported a novel protein phosphatase which dephosphorylates and thereby deactivates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated through autophosphorylation (Ishida, A., Kameshita, I., and Fujisawa, H. (1998) J. Biol. Chem. 273, 1904-1910). In the present study, we show that this protein phosphatase also catalyzed dephosphorylation of Ca2+/calmodulin-dependent protein kinases I (CaMKI) and IV (CaMKIV) which had been phosphorylated and activated by Ca2+/calmodulin-dependent protein kinase kinase alpha, resulting in reversible deactivation of the enzymes. The fairly high degree of the substrate specificity of this protein phosphatase suggests that the physiological significance of the phosphatase may be the regulation of the three multifunctional Ca2+/calmodulin-dependent protein kinases, CaMKI, CaMKII, and CaMKIV, which are the key enzymes in a Ca(2+)-signaling system in the cell.