Protein kinase C (PKC) is a superfamily of protein kinases composed of three major subfamilies: the cPKCs activated by diacylglcerol (DAG) and calcium, the nPKCs activated by DAG, and the aPKC, of unknown activators. This family of isoenzymes has assumed a critical role in signal transduction and cell regulation. Indeed, PKC serves as the prototype of transducers of lipid signals although the bulk of attention has been focused on phosphatidylinositol-derived DAG and calcium as the key regulators of the cPKCs. Our laboratory has had a longstanding interest in the regulation of PKC by lipid second messengers, and the investigator has reasoned that identification of regulation of specific isoenzymes by specific lipids implies the existence of specific lipid-mediated signaling pathways that lead to PKC activation. The preliminary studies show that 1) the nPKCs may be activated by DAG generated from the action of the phospholipase D (PLD) and sphingomyelin synthase (SMS) pathways; 2) the cPKCs are targets for specific inactivation/inhibition by ceramide; and 3) the aPKCs are specifically activated by D-erythro-sphingosine (but not its un-natural isomers). These results have led the investigator to hypothesize that: PKC isoenzymes receive inputs from multiple lipids, generated by different mechanisms. Therefore, PKC isoenzymes serve as molecular transducers of a vast array of lipid metabolic pathways in cell regulation. This hypothesis will be investigated by pursuing the following specific aims: 1) To define the roles of phospholipase D (PLD) and sphingomyelin synthase (SMS) on cellular regulation of PKC isoenzymes; 2) to determine the mechanism and role of ceramide in inactivating PKC; and 3) To determine the role and mechanism of activation of PKC lambda by sphingosine. These studies are beginning to define novel signaling pathways that regulate distinct sub-families of PKC, with important implications for the understanding of tumor promotion, apoptosis and the other critical events regulated by PKC.
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