Regulatory Mechanisms Governing Protein Kinase C Signaling

Abstract

Protein kinase C (PKC) is an extensive isozyme family that plays critical roles in cell growth regulation and differentiation and in specialized physiological processes such as neurotransmission. The regulation of PKC isozymes is complex not only due to the existence of isozyme-selective regulatory mechanisms but also due to the fact that multiple regulatory mechanisms may contribute to the governance of the function of a given isozyme. Most PKC isozymes require trans-phosphorylation by phosphoinositide-dependent kinase-1 (PDK1) to become catalytically competent and stimulation by lipid cofactors (in some cases in conjunction with Ca2+) to be activated. At least two PKC isozymes, d and q, can be proteolytically converted in cells to lipid-independent activated forms that participate in cell signaling. In addition, evidence is now emerging that oxidative stimuli may induce PKC activation in cells under certain conditions via tyrosine phosphorylation of the isozymes, and that under other conditions the oxidants may inactivate PKC isozymes by oxidative modification of Cys residues in the catalytic domain. Isozyme-selective binding proteins that direct the localization of PKC isozymes offer yet another level of regulatory control over PKC signaling.