M. Jeffers et al., ACTIVATING MUTATIONS FOR THE MET TYROSINE KINASE RECEPTOR IN HUMAN CANCER, Proceedings of the National Academy of Sciences of the United Statesof America, 94(21), 1997, pp. 11445-11450
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.