The fibroblast growth factors (FGFs) are a family of 22 related polypeptides that regulate the proliferation, differentiation and migration of a wide variety of cell types. FGF1 and FGF2 are the prototypes of the family initially described as promoting neuronal proliferation, neurite extension and survival, and fibroblast growth, respectively. Many of their native roles are in early development, where they control early aspects of embryonic differentiation. Thus, an understanding of how these growth factors signal, and how this signaling may be regulated or controlled, will have direct applicability to the treatment of cancer and birth defects. One of the intricacies of FGF signaling is that two types of receptors collaborate at the cell surface to generate the signal. One of these types is a family of receptor tyrosine kinases The other type if heparan sulfate proteoglycans. The FGFs are united by a common affinity for haparan sulfate, the highly sulfated glycosaminoglycan chain found on heparan sulfate proteogycans of the cell surface and the extracellular matrix. In addition, the receptors have a heparan sulfate- binding domain, and successful docking of the FGF with the receptor relies on both proteins recognizing a common domain in the heparan sulfate chain. An important feature of heparan sulfate is its variable sulfation patterns. Our hypothesis, for which we now have evidence, is that this sulfation pattern may be cell- or tissue-type specific. Thus, although it is variable, it is not random. This proposal will use FGF and FGF receptor probes to detect structural differences in heparan sulfate during early mouse development. The probes will be used to isolate the specific heparan sulfate sequences to which they bind, and these sequences will then be identified chemically. The long term outcome of this work will be left the derivation of chemical mimetics that can be used as therapeutics in the treatment of cancer and the prevention of birth defects.
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