Regulation of Ras and Rho small G proteins by SHP-2.

Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through the tyrosine kinase-type HGF/SF receptor, c-Met. We have previously shown that SHP-2, a protein tyrosine phosphatase, positively regulates the HGF/SF-induced cell scattering through modulating the activity of Rho to form stress fibres and focal adhesions. To further investigate the role of SHP-2 in HGF/SF-induced cell scattering, we have now examined the effect of a dominant active mutant of SHP-2 (SHP-2-DA). Expression of SHP-2-DA markedly increased the formation of lamellipodia with ruffles, while it decreased the accumulation of E-cadherin and beta-catenin at cell-cell adhesion sites in MDCK cells. In addition, expression of SHP-2-DA markedly enhanced cell scattering of MDCK cells in response to HGF/SF. Expression of SHP-2-DA induced the activation of MAP kinase without HGF/SF stimulation, whereas an inhibitor of MEK partly reversed the SHP-2-DA-induced morphological phenotypes. Furthermore, expression of either a dominant-active mutant of Rho or Vav2 also reversed the SHP-2-DA-induced morphological phenotypes. These results indicate that SHP-2 plays a crucial role in the HGF/SF-induced cell scattering through the regulation of two distinct small G proteins, Ras and Rho.