Positive and Negative Regulation of RTK-RAS Signaling

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Receptor tyrosine kinases (RTK) are essential mediators of signal transmission in response to extracellular cues that regulate fundamental processes such as cell proliferation, differentiation and survival. A central route by which RTK-initiated signals are transduced involves the activation of the small guanine nucleotide binding protein Ras. Activated Ras in turn induces a broad spectrum of cellular responses through the stimulation of multiple effector pathways. There is now ample genetic and biochemical evidence indicating that changes in the duration and intensity of intracellular signals elicited by the RTK-Ras pathway can lead to profound alterations in the biological outcome. Moreover, deregulated RTK-Ras signaling has been causally linked to a number of human malignancies and developmental disorders. The broad objective of this project is to define regulatory principles that govern the quantitative output of RTK-Ras signaling. The proposed studies will focus on the interaction between Ras and its guanine nucleotide exchange factor Sos as this interaction constitutes the rate limiting step in signal propagation from RTK to Ras. Our own work carried out for over a decade, as well as studies by other groups have indicated that Sos function is controlled through a complex network of inter- and intra-molecular interactions. Experiments described in this application are designed to further our understanding of the identity and functional significance of these interactions. We will undertake a multipronged strategy consisting of state-of-the-art biochemical and cell biological approaches to achieve four specific goals: (1) To establish the spatio-temporal dynamics of Sos-mediated Ras activation (2) To define how Sos-mediated Ras activation is terminated (3) To determine the role of Sos in Ras-driven tumors (4) To develop inhibitors of Ras-Sos interactions The information gathered from these studies should therefore furnish new insights into the regulatory paradigms that account for appropriate cellular adaptation in response to RTK-Ras signaling as well as the adverse consequences of deregulated RTK-Ras signaling.