The potential importance of the heparin binding of fibroblast growth factors (HBGFs) as regulators of cell growth and migration, angiogenesis, wound repair, neurite extension and mesoderm induction has become more apparent over the last several years. As many as five newly identified and related proteins have been described, three of which are the products of cellular oncogenes. These findings provide additional pressure to evaluate the transforming potential of over-expression of the HBGFs as a family. At least two receptors for the HBGFs have been identified in the last year. The receptor tyrosine kinase activity has been established and specific substrates involved in signal transduction have been identified. The receptor family may indeed be as large as that of the ligand. The long term goals of this research program remain: to provide a rigorous structural basis for the mechanisms of action of the HBGF family of polypeptides with major emphasis on HBGF-I which is referred to more commonly as acidic fibroblast growth factor. At this time relatively little is known regarding the functional domains of any of the HBGFs and even less is known about their mechanisms of action in inducing cellular mitogenesis, chemotaxis, differentiation or transformation. A better understanding of the structural basis for the different functions of these proteins should facilitate the development of agonists and antagonists of specific HBGF activities. Similarly, an understanding of the structural basis for the interaction of the HBGFs with their cell surface receptors could ultimately lead to the design of HBGF analogues with altered affinities for the different receptor molecules. This approach could be useful in targeting HBGFs to specific sites in clinical applications. The current proposal has evolved over the last few years from one that proposed a """"""""shot gun"""""""". approach to structure-function studies based on peptide analogues and limited cleavage of intact protein to one where data from this laboratory and others have been incorporated into a rational approach to site-directed mutagenesis of the ligand.
The specific aims are: 1) to continue the characterization of site-directed mutants of HBGF-I in order to understand the structural basis for the multiple activities of this protein; 2) to extend the structure-function studies to include identification and characterization of the ligand binding domains of the two identified human receptor-protein tyrosine kinases for HBGF- I and HBGF-2; and 3) to determine whether there is an intracellular or post-receptor pathway utilized by HBGF-I to mediate its mitogenic activity.
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