HGF-SF stimulates the proliferation of normal human melanocytes in the presence of synergistic factors, one of which is bFGF, and promotes motility and expression of high levels of tyrosinase activity and melanin content. Melanocytes from a recurrent blue nevus were also stimulated by HGF-SF, whereas cells from advanced primary and metastatic lesions either did not respond, were only slightly stimulated or, in one case, were inhibited. Signal transduction was mediated by tyrosyl-phosphorylation of met and several other proteins, including MAP kinase/ERK2. Met expression and phosphorylation in response to HGF-SF was normal in human melanoma cells, and HGF-SF-transduced mouse melanocytes were not tumorigenic. Taken together, the results show that met is not constitutively active in human melanomas and that its activation by an autocrine loop is not sufficient to confer the tumorigenic phenotype. They raise the possibility that exogenous HGF-SF may play a role at early stages of malignant conversion by acting synergistically with bFGF and by promoting the dispersion of factor-dependent cells to ectopic sites.