A POINT MUTATION IN THE MET ONCOGENE ABROGATES METASTASIS WITHOUT AFFECTING TRANSFORMATION

The MET oncogene encodes the tyrosine kinase receptor for hepatocyte g rowth factor/scatter factor (NGF, known to stimulate invasive growth o f epithelial cells. MET is overexpressed in a significant percentage o f human cancers and is amplified during the transition between primary tumors and metastasis, To investigate whether this oncogene is direct ly responsible for the acquisition of the metastatic phenotype, we exp loited a single-hit oncogenic version of MET, able to transform and to confer invasive and metastatic properties to nontumorigenic cells, bo th in vitro and in nude mice, We mutagenized the signal transducer doc king site of Met ((YVHVX3YVNV)-V-1349-V-1356), which has the uncommon property of binding and activating multiple src homology region 2 (SH2 )-containing intracellular effecters. Notably, a point mutation (H-135 1 --> N) increased the transforming ability of the oncogene but abolis hed its metastatic potential. This mutation duplicates the Grb2 bindin g site, super-activating the Ras pathway and pl eventing the binding o f the other intracellular transducers. Complementation in trans with a nother nonmetastatic mutant (N-1358 --> H), recruiting all the transdu cers downstream to Met except Grb2, rescued the invasive-metastatic ph enotype. It is concluded that the metastatic potential of the MET onco gene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissoc iate neoplastic transformation from metastasis.