Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering

Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering th rough the tyrosine kinase-type HGF/SF receptor c-Met. We have previously sh own that Rho small G protein (Rho) is involved in the HGF/SF-induced scatte ring of Madin-Darby canine kidney (MDCK) cells by regulating at least the a ssembly and disassembly of stress fibers and focal adhesions, but it remain s unknown how c-Met regulates Rho activity. We have found here a novel sign aling pathway of c-Met consisting of SHP-2-Rho that regulates the assembly and disassembly of stress fibers and focal adhesions in MDCK cells. SHP-2 i s a protein-tyrosine phosphatase that contains src homology-2 domains. Expr ession of a dominant negative mutant of SHP-2 (SHP-2-C/S) markedly increase d the formation of stress fibers and focal adhesions in MDCK cells and inhi bited their scattering. C3, a Clostridium botulinum ADP-ribosyltransferase, and Y-27632, a specific inhibitor for ROCK, reversed the stimulatory effec t of SHP-2-C/S on stress fiber formation and the inhibitory effect on cell scattering. Vav2 is a GDP/GTP exchange protein for Rho. Expression of a dom inant negative mutant of Vav2 blocked the stimulatory effect of SHP-2-C/S o n stress fiber formation. Conversely, expression of mutants of Vav2 that in creased stress fiber formation inhibited HGF/SF-induced cell scattering. Th ese results indicate that SHP-2 physiologically modulates the activity of R ho to form stress fibers and focal adhesions and thereby regulates HGF/SF-i nduced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway.