Specific uncoupling of GRB2 from the met receptor - Differential effects on transformation and motility

The biological effects of hepatocyte growth factor/scatter scatter factor are mediated by autophosphorylation of its receptor, the Met tyrosine kinase, on two carboxyl-terminal tyrosines. These phosphotyrosines (Y(1349)VHVNATY(1356)VNV) are multifunctional docking sites for several effecters. Grb2, the adaptor for the Res guanyl-nucleotide exchanger SOS, binds to Tyr(1356) in the <YV(N)under bar V> motif. By site-directed mutagenesis we either abrogated or duplicated the Grb2 consensus, without interfering with the other effecters. Loss of the Link with Grb2 severely impaired transformation. The same mutation, however, had no effect on the ''scattering'' response, indicating that the level of signal which can be reached by Grb2-independent routes is permissive for motility. Duplication of the Grb2 binding site enhanced transformation and left motility unchanged. Thus, two Met-mediated biological responses, motility and growth, can be dissociated on the basis of their differential requirement for a direct link with Ras.