Project 2: Elucidating the mechanisms and consequences of erbB/Met family crosstalk Summary Diane Lidke, Project PI This project focuses on crosstalk between Receptor Tyrosine Kinases (RTKs) that trigger intracellular signaling cascades and control important cellular processes. We will apply state-of-the art microscopy (single molecule, single cell and in vivo) with biochemical assays and mathematical modeling - across five spatial scales - to provide a comprehensive picture of how receptor crosstalk modulates cell response. Our target receptors are members of the erbB and Met RTK families, shown to be important in oncogenesis, metastasis and drug resistance. Our goal is to determine the molecular mechanisms and physiological consequences of crosstalk between erbB and Met, beginning with evaluating how the dynamic and stochastic behavior of protein-protein interactions influences signal propagation. Through experiments in live cells and animals engrafted with human ovarian or colon tumor cells, we will determine how erbB and Met crosstalk controls cell fate, tumor growth and drug responses. This interdisciplinary project brings together a team of cell biologists, biophysicists, cancer biologists, biochemists and mathematical modelers, reflecting the strengths of the NM Center for Spatiotemporal Modeling. The proposed work will provide information on protein interactions, signaling pathway integration and physiological outcome. Since aberrant erbB/Met signaling has been implicated in a number of cancers, we expect that this information will open new avenues for combination therapies that target receptor crosstalk.
This proposal is relevant to public health since signaling though membrane receptor tyrosine kinases (RTKs) is involved in many cancers. In order to further our fundamental understanding of RTK signaling, we will integrate state-of-the art microscopy (single molecule, single cell and in vivo) with biochemical assays and computational modeling to generate a comprehensive picture of how receptor interactions regulate signaling and modulate cell fate. Therefore, the proposal is relevant to the part of NIH's mission that is in pursuit of fostering fundamental creative discoveries, innovative research strategies, and their applications to biomedical problems.
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