Protein kinase C (PKC) is a family of closely related isoenzymes that have assumed a critical role in signal transduction and cell regulation. Studies from the Applicant's laboratory have concentrated on developing approaches and insight on the regulation of PKC by lipid second messengers. These studies have resulted in defining the mechanism of regulation of PKC by diacylglycerol and cis-unsaturated fatty acids in vitro and in cells. The multiplicity of PKC isoenzymes and the complexity of their regulation have posed a very vexing question on the selective regulation and function of individual isoenzymes. The Applicant's laboratory has recently taken a novel approach aimed at examining isoenzyme selective functions at a biochemical and molecular level in an attempt to generate novel insight and provide specific handles for determination of isoenzyme-specific functions. These studies have concentrated primarily on PKC betaI and betaII which derive by alternate splicing of the same gene and which display very limited sequence differences (they are identical except for the last 50-52 carboxy amino acids). These studies disclose that PKC betaI partner for the c-ABL protooncogene whereas PKC betaII is an actin binding protein. Therefore, the Specific Aims are: 1) Define the binding/interaction between PKC betaII and actin at a biochemical and molecular level and determine its physiologic significance; and 2) Define the biochemical and molecular basis of the binding/interaction of PKC betaI with c-ABL and its physiologic significance. These studies are beginning to define a novel isoenzyme-specific domain in PKC; thus suggesting that individual isoenzymes are involved in distinct signal transduction mechanisms. Knowledge gained from these studies should prove to be of great usefulness in propelling the understanding of PKC isoenzyme regulation and function to a biochemical and molecular level, and they should provide useful tools for exploring the physiologic function of individual enzymes.
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