Cross-talk between the proto-oncogenes Met and Ron

Scatter Factors control a complex genetic program known as 'invasive growth '. HGF (Scatter factor 1) and MSP (Scatter Factor 2) bind to tyrosine kinas e receptors encoded by the proto-oncogenes MET and RON. Using the appropria te 'kinase inactive' mutant receptors, we show that ligand-induced activati on of Met results in transphosphorylation of Roll, and Vice ver sn. Transph osphorylation is direct, as it occurs in Met or Ron receptors lacking the d ocking sites for signal transducers. Phosphate groups are transferred to th e tyrosine phosphorylation sites responsible both for kinase up-regulation (Met: Y1234/Y1235 and Ron: Y1238/Y1239) and for generation of signal transd ucer docking sites (Met: Y1349/Y1356 and Ron Y1353/Y1360). The transphospho rylation specifically takes place for the receptor subfamily, as it is not observed between Met or Ron and ErbB1, ErbB2 or TrkA. Cross-linking experim ents show that non-covalent Met-Roll complexes are present on the cell surf ace, before ligand-induced dimerization. Go-expression of a kinase inactive Ron receptor with naturally-occurring oncogenic Met mutants suppresses the transforming phenotype, suggesting a dominant negative role for the ineffi cient kinase partner. These data show that, while specific for their ligand s, scatter factor receptors cross-talk and cooperate in intracellular signa ling.