Requirement of regulated activation of Ras for response of MDCK cells to hepatocyte growth factor/scatter factor

Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering, m igration, and branching tubule formation of MDCK cells. To examine the role of the Ras protein in the HGF/SF-induced responses, we constructed MDCK ce ll clones expressing either inducible dominant-negative Ras or constitutive ly activated Ras and analyzed their effects on responses of cells to HGF/SF . Induced expression of dominant-negative Ras prevented cell dissociation r equired for cell scattering, migration, and cystic formation as well as bra nching morphology required for branching tubule formation. Constitutively a ctivated Ras induced cell dissociation, but not a scattered fibroblastic mo rphology even in the presence of HGF/SF. MDCK cells expressing constitutive ly activated Ras migrated at a level similar to that of wild-type MDCK cell s stimulated by HGF/SF. MDCK cells expressing constitutively activated Ras showed disorganized growth in three-dimensional culture and did not form th e branching tubule structures. These results indicate that activation of th e Ras protein is essential for the cell scattering, migration, and branchin g tubule formation of MDCK cells induced by HGF/SF, and a properly regulate d activation is required for some stages of the HGF/SF-induced responses of MDCK cells. (C) 2000 Academic Press.