Fibroblast growth factors (FGFs) comprise a large family of growth factors that play important roles in the control of embryonic development, morphogenesis, wound healing, and tumor angiogenesis. FGFs mediate their diverse cellular responses by acting in concert with heparin sulfate proteoglycans to activate a family of receptor tyrosine kinases (RTK) designated FGF-receptors 1 to 4 (FGFR1-FGFR4). We have identified a family of docking proteins designated FGFR-substrate 2 (FRS2) that function as major mediators of signaling via FGFRs. The current application seeks to obtain a detailed view on cellular signaling through FGFRs. Our main goal is to determine the biological role and mechanism of action of FRS2 in FGFR signaling in vitro and in vivo.
The specific aims of this proposal are to: 1. Identify the FRS2-dependent independent signaling pathways downstream of FGFR1 and FGFR2. 2. Identify the role of Shc in mediating FGF-signaling pathways. 3. Determine the mechanism and biological significance underlying the interaction between FRS2 and MAPK. 4. Determine the role of FRS2 in mediating heterologous control of FGFl-signaling and 5. Develop genetically modified mice to explore the biological role of FRS2 in vivo. The primary means to accomplish these aims are biochemical analysis of cultured cells expressing wild type or mutant proteins, X-ray crystallographic studies of components of FGFR signaling, in vivo studies of genetically modified mice and analysis of FGF-signaling in cells isolated from knock-in and knock-out mice. The information obtained from these studies will enhance our knowledge on intracellular signaling pathways downstream of FGFR and other RTKs. It would also provide a framework for understanding the role of FGFR-signaling in normal biological responses and in diseases caused by dysfunctions in FGFRs such as Crouzon, Apert, Jackson-Weiss syndromes and other skeletal disorders, as well as tumor angiogenesis, and cancer.
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