The heparin binding growth factors (fibroblast growth factor or FGFs) are a family of polypeptides that regulate a variety of cellular behaviors, including cell proliferation, migration and shape change, and cellular determination and differentiation. The diversity of these responses suggests intricate signalling mechanisms. One of the intricacies that will be studied here is the requirement for two types of FGF binding molecules to collaborate at the cell surface in order for FGF signalling to be carried out. One molecule is a membrane-spanning receptor with a cytoplasmic tyrosine-kinase domain that is activated upon ligand binding. The second molecule is a heparan sulfate proteoglycan that binds FGF via its heparan sulfate chains. This latter class of molecules is typified by syndecan, a transmembrane protein. Several other proteoglycans of this general type have been described. A contrasting form of cell surface proteoglycan is glypican, which is tethered to the membrane by a lipid tail.
The aim of this work will be to understand the biochemistry of how these types of proteoglycans interact with the tyrosine kinase receptors in order to regulate FGF binding and signalling. Potential regulatory mechanisms include (i) the specific structure of the heparan sulfate chains, which are known to exhibit widely differing affinities for the growth factor, affinities that may vary between the two types of proteoglycans and are expected to vary among cell types and (ii) the nature of the proteoglycan anchorage in the membrane, which may be a critical regulator in the formation of an active complex between the proteoglycan, the receptor and the FGF. These regulatory mechanisms will be studied using two well-defined system: (i) a lymphoid cell expressing a single FGF receptors or receptors and proteoglycans expressed as pairs, and (ii) a myoblast cell line that responds quantitatively to FGF. The lymphoid cells will provide valuable information on ow a single type of receptor interacts with a single type of proteoglycan. The myoblast will provide the means for verifying the role of the interaction in FGF signalling. The potent role of the FGFs in cell growth and differentiation makes them obvious candidates for defects that lead to human disease, particularly in cancer, birth defects and neuromuscular degenerative disorders. Specific examples include their induction of mammary carcinomas, role in sarcoma growth or role as a tumor angiogenic factor. A better understanding of how FGF action is regulated in these diseases will provide insights into potential treatments.
Showing the most recent 10 out of 20 publications
