It is well established that ras oncogenes play a central role in the pathogenesis of a wide variety of human malignancies. Ras proteins are essential components of receptor-mediated signal transduction pathways regulating cell growth and differentiation. The long-term objective of this research project is to define the mechanisms by which Ras proteins convey signals from cell surface receptors to intracellular effector molecules. This will provide a necessary perspective from which to achieve an understanding of the mode of action of Ras proteins both in normal and transformed cells. The goal of the proposed studies is to determine the mechanisms by which upstream regulators and downstream targets of Ras proteins impart signal diversity and specificity within the Ras pathway. These studies will consist of the following specific aims: 1. To define the pathways by which guanine nucleotide exchange factors control Ras activity. 2. To establish the contribution of putative downstream effectors of Ras to the signaling activities of Ras. 3. To identify cellular components that mediate the effects of Ras on cell morphology. In the course of these studies a number of important questions will be addressed. These include: a) Are different forms of Ras proteins regulated differentially by upstream activators? b) What are the physiological roles of the recently identified putative effectors of Ras? c) How do these effectors contribute to the mitogenic activity of Ras and d) How do Ras protein exert their effects on cell morphology. These studies should provide new insights into the regulation of Ras and its actions in mammalian cells and thus should deepen our understanding of the biochemical pathways that control normal cell proliferation and contribute to oncogenic transformation.
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