THE MOTILITY SIGNAL OF SCATTER FACTOR HEPATOCYTE GROWTH-FACTOR MEDIATED THROUGH THE RECEPTOR TYROSINE KINASE MET REQUIRES INTRACELLULAR ACTION OF RAS

Scatter factor/hepatocyte growth factor (SF/HGF) has various biologica l effects upon different cells, i.e. induces increased motility and pr oliferation as well as invasiveness and morphogenesis. The signals giv en to epithelial cells by SF/HGF are all mediated through the Met rece ptor tyrosine kinase (Weidner, K. M., Sachs, M., and Birchmeier, W. (1 993) J. Cell Biol. 111, 145-154) suggesting that signal diversity is d ue to the interplay of different downstream pathways. It has also been shown that SF/HGF activates the protooncogene product Ras, i.e. stimu lates guanine nucleotide exchange. In order to examine whether Ras is involved in mediating the dissociation and motility signal of SF/HGF t o epithelial cells, we have expressed in Madin-Darby canine kidney cel ls the dominant-negative N17Ras under the control of a modified metall othionein promoter. Induced expression of N17Ras by the addition of Zn 2+ clearly prevented dissociation of the cells by SF/HGF. These data i ndicate that the Ras pathway is indeed essential to mediate the motili ty signal of SF/HGF-Met to the cell-cell adhesion system and the cytos keleton of epithelial cells.