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.
|Dunstan, C R; Boyce, R; Boyce, B F et al. (1999) Systemic administration of acidic fibroblast growth factor (FGF-1) prevents bone loss and increases new bone formation in ovariectomized rats. J Bone Miner Res 14:953-9|
|Wong, P; Hampton, B; Szylobryt, E et al. (1995) Analysis of putative heparin-binding domains of fibroblast growth factor-1. Using site-directed mutagenesis and peptide analogues. J Biol Chem 270:25805-11|
|Isakov, N; Wange, R L; Burgess, W H et al. (1995) ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. J Exp Med 181:375-80|
|Basilion, J P; Rouault, T A; Massinople, C M et al. (1994) The iron-responsive element-binding protein: localization of the RNA-binding site to the aconitase active-site cleft. Proc Natl Acad Sci U S A 91:574-8|
|Burgess, W H; Friesel, R; Winkles, J A (1994) Structure-function studies of FGF-1: dissociation and partial reconstitution of certain of its biological activities. Mol Reprod Dev 39:56-60;discussion 60-1|
|Zhan, X; Hu, X; Hampton, B et al. (1993) Murine cortactin is phosphorylated in response to fibroblast growth factor-1 on tyrosine residues late in the G1 phase of the BALB/c 3T3 cell cycle. J Biol Chem 268:24427-31|
|Egerton, M; Ashe, O R; Chen, D et al. (1992) VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation. EMBO J 11:3533-40|
|Hampton, B S; Marshak, D R; Burgess, W H (1992) Structural and functional characterization of full-length heparin-binding growth associated molecule. Mol Biol Cell 3:85-93|
|Burgess, W H; Shaheen, A M; Hampton, B et al. (1991) Structure-function studies of heparin-binding (acidic fibroblast) growth factor-1 using site-directed mutagenesis. J Cell Biochem 45:131-8|
|Burgess, W H (1991) Structure-function studies of acidic fibroblast growth factor. Ann N Y Acad Sci 638:89-97|
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