PHOSPHOLIPIDN METABOLISM ACTIVATED BY V-SRC

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The objective of this proposal is to understand how phospholipid metabolism, activated by the oncogenic protein-tyrosine kinase (PTK) v- Src, contributes to the complex set of intracellular signals initiated by v-Src that ultimately lead to transformation. The mechanisms by which v-Src and other PTKs generate the complex intracellular signals that frequently lead to cell proliferation is not well understood. To generate the signals necessary to induce a process as cell proliferation is not well understood. To generate the signals necessary to induce a process as complex as cell proliferation, many intracellular signalling molecules ar likely recruited by PTKs. In recent years it has become increasingly apparent that the complexity of the lipid components in membranes far exceeds that required for function as a biological barrier. Phospholipids, which comprise the majority of membrane lipids, can be metabolized to variety of biologically active molecules by many distinct enzymatic activities. In this proposal experiments are described that will follow up on our observation that v-Src-induced increases in diglycerides results not from the more established mechanism of phospholipase C-mediated hydrolysis of phosphoinositides, but rather by a phospholipase D-mediated hydrolysis of phosphatidylcholine (Song et al., 1991). In this proposal, experiments are described that will 1) characterize the mechanism by which v-Src activities phospholipid metabolism and 2) characterize the phospholipid metabolites including diglycerides, monoglycerides, phosphatidic acid and possibly lyso- phosphatidic acid generated in response to v-Src. Malignant transformation involves a progressive loss of control of intracellular signalling mechanisms. The many enzymes involved in the complex signals generated by metabolism of membrane lipids provides many potential targets for interfering with the intracellular signals that may contribute to malignant transformation. The studies proposed here will identify potential targets for interfering with the PTK-initiated intracellular signals that contribute to transformation.