ACTIVATING MUTATIONS FOR THE MET TYROSINE KINASE RECEPTOR IN HUMAN CANCER

Recently, mutations in the Met tyrosine kinase receptor have been iden tified in both hereditary and sporadic forms of papillary renal carcin oma. We have introduced the corresponding mutations into the met cDNA and examined the effect of each mutation in biochemical and biological assays. We find that the Met mutants exhibit increased levels of tyro sine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wild-type Met. Moreover, NIH 3T3 cells ex pressing mutant Met molecules form foci in vitro and are tumorigenic i n nude mice. Enzymatic and biological differences were evident among t he various mutants examined, and the somatic mutations were generally more active than those of germ-line origin. A strong correlation betwe en the enzymatic and biological activity of the mutants was observed, indicating that tumorigenesis by Met is quantitatively related to its level of activation. These results demonstrate that the Met mutants or iginally identified in human papillary renal carcinoma are oncogenic a nd thus are likely to play a determinant role in this disease, and the se results raise the possibility that activating Met mutations also ma y contribute to other human malignancies.