Ras proteins act as molecular switches to control the intracellular transduction of extracellular signals. Active mammalian ras protein can be bound by the 120 kilodalton GTPase activating protein (p120GAP)which downregulates the signaling competent form of ras by increasing the hydrolytic activity of ras. p120GAP has been further implicated as an effector of ras signal transduction. The ras pathway is important in the transduction of signals for the growth and differentiation of normal and transformed cells in culture. It is unclear which of the many decisions made during mammalian development which are influenced by extracellular signals are controlled by ras activity. The role of p120GAP toward ras dependent signaling during development is unknown, but it is clear that p120GAP expression is essential for the correct early embryogenesis of mice. The long term objective of this proposal is to determine the role of p120GAP during the various stages of mammalian development. Lines of mice will be created in which expression of the p120GAP protein can be disrupted in a controlled fashion by specifically inducing the proteolytic degradation of p120GAP using recently developed synthetic drug molecules. p120GAP expression will be removed at different points of embryogenesis, during post-natal development, in adults, and in cultured cell lines derived from targeted mice. The phenotypic effects of this conditional p120GAP disruption will be analyzed and the contribution of p120GAP toward tumorigenesis mediated by ras will be determined.
