The fibroblast growth factors (FGFs) comprise a family of at least 18 structurally related polypeptides that play important roles in embryonic development, angiogenesis and wound healing. FGFs exert these diverse effects by binding to and activating a distinct subclass of receptor tyrosine kinases. The mammalian FGF receptor (FGFR) family is composed of four genes (FGFR1-FGFR4). Each FGFR binds a unique repertoire of FGF ligands. The specificity of this binding is determined by differences in primary structure in the extracellular domain as well as alternative splicing. Dimerization is essential for FGFR activation, however, FGFs alone are unable to induce receptor dimerization and activation, requiring heparin-like molecules to facilitate this process. The investigator proposes four specific aims to investigate the molecular mechanisms by which FGFs and heparin sulfate-containing proteoglycans induce receptor dimerization and activation, the structural requirements that impart ligand binding specificity, and the contribution of each subdomain of the extracellular domain to regulation of ligand binding. In addition, the effects of FGFR mutations found in human skeletal disorders on ligand binding will be examined.
These aims will be accomplished by x-ray crystallographic studies combined with biochemical experiments employing cultured cells expressing mutant FGFRs. In addition, the association thermodynamics of FGFs, heparin and the ligand-binding domains of FGFRs will be characterized by isothermal titration calorimetry and BIAcore analysis. These studies will increase our knowledge of FGFR signal transduction and provide a basis for understanding the effects of FGFR mutations that result in human skeletal disorders. Since FGFs are involved in angiogenesis and tumorigenesis, it is anticipated that the results of these structural and functional analyses will facilitate the rational design of novel FGF antagonists for the treatment of cancer as well as enhance our understanding of other heparin-binding growth factors
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