THE MUTATIONALLY ACTIVATED MET RECEPTOR MEDIATES MOTILITY AND METASTASIS

Mutations in Met have been identified in human papillary renal carcino mas. We have shown previously that these mutations deregulate the enzy matic activity of Met and that NIH 3T3 cells expressing mutationally a ctivated Met are transformed in vitro and are tumorigenic in vivo. In the present investigation, we find that mutant Met induces the motilit y of Madin-Darby canine kidney cells in vitro and experimental metasta sis of NIH 3T3 cells in vivo, and that the Ras-Raf-MEK-ERK signaling p athway, which has been implicated previously in cellular motility and metastasis, is constitutively activated by the Met mutants. We also re port that transgenic mice harboring mutationally activated Met develop metastatic mammary carcinoma. These data confirm the tumorigenic acti vity of mutant Met molecules and dem onstrate their ability to induce the metastatic phenotype.