The members of the fibroblast growth factor (FGF) family appear to have important roles in development and differentiation, angiogenesis and wound healing, and the growth of some tumors. Both secreted and non-secreted members of the fan-lily exist. The FGFs exert their effects through interaction with cell-surface receptors. Little is known about the chemical and biological properties of these receptors. We propose to identify FGF receptors from molecules cloned by our collaborators based on similarity to known FGF receptors. We shall characterize their affinities for and interactions with 3 different members of the FGF family: basic FGF, acidic FGF, and K-FGF. We also shall characterize the ligand binding region of one of the FGF receptors after chemical modification and site-directed mutation of the protein. We will investigate the expression of FGF receptors in glycosylation deficient mutants to determine the effect of glycosylation on the ligand-binding properties of the receptor and on receptor stability. We will explore regulation of receptor expression in cells induced to differentiate in culture. Finally we will investigate whether interaction with the extracellular matrix can modify the interaction of FGFs with their receptors. Since one of the non-secreted members, basic FGF, interacts strongly with the extracellular matrix, we propose that the secreted forms do also, and this may affect their biological properties. We shall investigate the interaction of one of these secreted forms, K-FGF, with extracellular matrix molecules. These studies will lead to a better understanding of factors influencing the biological activity of members of the FGF family: interactions with extracellular matrix; the number of receptor species and their affinities; the structural basis of FGF - FGF receptor interactions; and the regulation of receptor activity.
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