Activating mutations for the Met tyrosine kinase receptor in human cancer

Abstract

Recently, mutations in the Met tyrosine kinase receptor have been identified in both hereditary and sporadic forms of papillary renal carcinoma. 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 tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wild-type Met. Moreover, NIH 3T3 cells expressing mutant Met molecules form foci in vitro and are tumorigenic in nude mice. Enzymatic and biological differences were evident among the various mutants examined, and the somatic mutations were generally more active than those of germ-line origin. A strong correlation between 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 originally identified in human papillary renal carcinoma are oncogenic and thus are likely to play a determinant role in this disease, and these results raise the possibility that activating Met mutations also may contribute to other human malignancies.

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

“…Substitution of these residues is responsible for the oncogenic conversion of Kit and Ret receptors (Kitayama et al, 1995;Santoro et al, 1995), and causes subversion of substrate speci®city (Songyang and Cantley, 1995;Santoro et al, 1995, Piao andBernstein, 1996). Recently these activating mutations have been found also in Met, in sporadic and hereditary papillary renal carcinomas Je ers et al, 1997).…”

Missense Mutation of the MET Gene Detected in Human Glioma

“…The missense mutation in exon 17 (Case 3) is one of the most commonly mutated regions of the tyrosine kinase domain of MET. Mutation studies on known mutations identified in papillary renal carcinoma exhibited increased levels of tyrosine phosphorylation and enhanced kinase activity in response to exogenous ligands when compared with wild-type MET (29). Moreover, NIH 3T3 cells expressing mutant MET molecules formed foci in vitro and were tumorigenic in nude mice.…”

Activating mutations in the Met receptor overcome the requirement for autophosphorylation of tyrosines crucial for wild type signaling

“…We previously demonstrated that mutationally activated Met mediates the transformation and tumorigenicity of NIH3T3 cells (Je ers et al, 1997a). However, for the present investigation we were concerned that the endogenous production of both Met and HGF/SF by these cells could interfere with our proposed experiments.…”

“…Finally, Met can be oncogenically activated via a number of speci®c point mutations introduced into its kinase domain. Mutations originally identi®ed in human papillary renal carcinomas were found to generate Met molecules possessing constitutive kinase activity and transforming ability (Je ers et al, 1997a;Schmidt et al, 1997).…”

“…[Throughout this study, mutationally activated Met will refer to a molecule possessing two independent point mutations altering leucine (L) at residue 1213 to valine (V) and methionine (M) at residue 1268 to threonine (T) (Je ers et al, 1997a)]. Following transfection into NIH3T3 cells and Western blotting with anti-Met antibody, each construct expressed a doublet which was not present in mock-transfected cells ( Figure 1a).…”