We have continued to characterize the biological properties and mechanisms of action of two fibroblast-derived mitogens which we previously had purified and cloned: keratinocyte growth factor (KGF, a member of the fibroblast growth factor [FGF] family) and hepatocyte growth factor/scatter factor (HGF/SF). The former is specific for epithelial-cell targets, while the latter is a broad-spectrum mitogen and motility factor with activity on endothelial cells and melanocytes as well as epithelial cells. In addition, we have partially purified a putative ligand for the EGF receptor-related erbB-3 tyrosine kinase previously identified in our laboratory. KGF appears to be an important, stromally derived mediator of androgen action in sex hormone-sensitive tissues. Androgen induces KGF expression in fibroblasts from human adult prostate, and KGF stimulates prostatic epithelial cells to proliferate. KGF is also required for the androgen-dependent development of the mouse seminal vesicle. In another context, we documented that interleukin-1 is a major stimulus of KGF expression, which is consistent with the hypothesis that endogenous KGF participates in the postinflammatory healing process. Exogenously administered KGF has a significant and potentially positive impact on wound healing in a pig skin model. The processing of HGF/SF from a single chain polypeptide to a disulfide- linked heterodimer was shown to be required for both its mitogenic and motogenic activities. Detailed studies of HGF/SF action on melanocytes and melanoma cells demonstrated that HGF/SF stimulates tyrosine phosphorylation of the Met kinase as well as several other proteins. The creation of an artificial autocrine loop resulted in factor-independent growth but not transformation of this cell type.
