The fibroblast growth factors (FGFs) are a family of ten related polypeptides that regulate the proliferation and differentiation of a wide variety of cell types. FGF-1 and FGF-2 are the prototypes of the family initially described in brain extracts where they are known to promote neuronal proliferation, neurite extension and survival. Many of the remaining family members have been discovered as oncogenes, typically promoting abnormal growth in tumors. However, they have natural roles in early development, where they control early aspects of embryonic differentiation. In cultured cells, the FGFs regulate a variety of behaviors, including cell proliferation, migration and shape changes, as well as cellular determination and differentiation. Thus, an understanding of how their signaling is regulated will provide important insights into defects in human development and cancer. One of the intricacies of FGF signaling is that two types of receptors at the cell surface collaborate to generate the signal. One of these is a family of FGF-specific receptor tyrosine kinases. The other type is heparan sulfate proteoglycans. The FGFs are unified by a common affinity for heparan sulfate, a highly sulfated chain found on proteoglycans at cell surfaces and in the matrix surrounding cells. In addition, the receptors themselves bind to heparan sulfate. The sulfation pattern within the heparan sulfate chain is variable and appears to vary in a cell type-specific and proteoglycan type-specific manner. Emerging evidence suggests that the FGFs and their receptors recognize specific sulfation patterns within heparan sulfates; thus, heparan sulfate appears to regulate the assembly of the signaling complex. Thus, we propose to examine this mechanism of regulation by cell and tissue-specific heparan sulfates. Heparan sulfates expressed on a several cell types or within specific tissues during development will be examined for their ability to regulate the signaling of specific FGF receptor tyrosine kinases and FGFs. In addition, we will examine the hypothesis that endogenous proteoglycans such as syndecan-1 assemble into pre- formed complexes with
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