Receptor tyrosine kinases (RTKs) are key mediators of signal transmission in response to extracellular cues that regulate cell proliferation and differentiation. A ubiquitous and highly conserved route by which RTKs initiate signals that control cell growth is through the activation of the small genuine nucleotide binding protein Ras. Specific and precise signaling by the RTK-Ras pathway requires that both the intensity and duration of the elicited intracellular signals be tightly regulated, and disruption of this regulation is intimately linked to the loss of growth control displayed by cancer cells. The broad objective of this research project is to define the molecular mechanisms that control signaling dynamics by RTKs. The studies outlined in this application are aimed at determining how the signaling output of the RTK-Ras pathway is balanced through positive and negative modulation. The proposed experiments will focus on two signaling events that are central to the regulation of RTK-Ras pathway: (1) Sos-mediated Ras activation will be used as a prototype for the positive regulation of the pathway. (2) Sprouty-mediated inhibition of RTK-Ras signaling will be used as a prototype for the negative regulation of the pathway. Genetic, biochemical and cell biological approaches will be used to pursue the following specific aims: 1. To define the molecular mechanisms of Ras activation by Sos 2. To establish the significance of inter- and intra-molecular interactions for Sos function. 3. To determine the role of Sprouty in the regulation of RTK-Ras signaling. Collectively, the experiments proposed herein will provide new insights into the molecular mechanisms that determine the levels of activity of the RTK-Ras pathway. As such, these studies will advance our understanding of cellular processes that control cell growth and the nature of their subversion in cancer cells.
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