Growth factors are important mediators of intercellular communication. These molecules are generally released by one cell type and influence proliferation of other cell types. Interest in growth factors has been heightened by evidence of their involvement in neoplasia. For instance, the v-sis transforming gene of simian sarcoma virus encodes a protein that is homologous to the .beta. chain of platelet-derived growth factor. In addition, a number of oncogenes are homologues of genes encoding growth factor receptors. Thus, increased understanding of growth factors and their receptor-mediated signal transduction pathways provides insights into mechanisms of both normal and malignant cell growth.
The fibroblast growth factor (FGF) family affects growth of a wide variety of cells including connective tissue cells and includes acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFBF), and the related products of the hst and int-2 oncogenes. Keratinocyte growth factor (KGF) is also a member of this family but is unique in that its activity is restricted to cells of epithelial origin. Biochemical characterization of the KGF receptor (KGFR) suggests that it possesses a high affinity site for KGF and aFGF binding, to which bFGF also binds with much lower affinity. Bottaro et al., J. Biol. Chem. 265, 12767-70 (1990). Isolation of the KGFR cDNA has revealed that it is structurally identical to FGF receptor-2 (FGFR-2), except for a stretch of 49 amino acids. In contrast to the KGFR, FGFR-2 binds aFGF and bFGF with high affinity, but exhibits no detectable binding of KGF.
The prior art, however, fails to identify particular regions in KGFR which bind KGF. Without this knowledge, identification of highly specific antagonists of this interaction is difficult. It is widely recognized that the vast majority of human malignancies are derived from epithelial tissues. Thus, identification of compounds which modulate the effect of KGF is important in the treatment of carcinomas as well as other conditions in which ligand-dependent proliferation, mediated by KGFR, contributes to the pathological disorder. The present invention addresses these and other needs.