We have continued to characterize the biological properties and mechanisms of action of two fibrobast-derived mitogens which we previously had purified and cloned: keratinocyte growth factor (KGF, a member of the fibroblast growth factor [FGF] family) and a variant of hepatocyte growth factor (HGF). The former is specific for epithelial-cell targets. while the latter is a broad-spectrum mitogen with activity on endothelial cells and melanocytes as well as epithelial cells. Molecular cloning of the KGF receptor established that it is a transmembrane tyrosine kinase with alternative extracellular domains comprised of either two or three immunoglobulin-like loops. These forms arise from alternatively-spliced transcripts of the bek gene, which recently had been reported to encode a receptor for other members of the FGF family. Of particular note, the alternative exon encoding the carboxy-terminal half of the immunoglobulin loop closest to the transmembrane domain is crucial in determining the KGF-binding capacity of the receptor molecule. A synthetic peptide corresponding to this region of the receptor specifically antagonized the mitogenic activity of KGF. An HGF receptor has been identified as the c-met proto-oncogene product, another transmembrane tyrosine kinase. An alternative HGF transcript which contains the sequence for the amino-terminal and first two kringle domains encodes a protein that also binds the met protein but functions as a specific, competitive HGF antagonist.
