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Activating mutations for the met tyrosine kinase receptor in human cancer
M Jeffers1, L Schmidt, N Nakaigawa
1Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
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.
Insights
Mutations in the Met tyrosine kinase receptor drive papillary renal carcinoma. These Met mutants show increased activity and promote tumor formation, highlighting their oncogenic role in kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Papillary renal carcinoma (PRC) is linked to mutations in the Met tyrosine kinase receptor.
- Both hereditary and sporadic forms of PRC involve these Met mutations.
Purpose of the Study:
- To investigate the biochemical and biological effects of specific Met mutations found in PRC.
- To determine the oncogenic potential of these Met mutants.
Main Methods:
- Introduced known PRC-associated mutations into met cDNA.
- Performed biochemical assays to measure tyrosine phosphorylation and kinase activity.
- Assessed NIH 3T3 cell transformation (focus formation) and tumorigenicity in nude mice.
Main Results:
- Met mutants displayed elevated tyrosine phosphorylation and enhanced kinase activity compared to wild-type Met.
- Cells expressing mutant Met formed foci in vitro and were tumorigenic in vivo.
- Somatic mutations generally showed higher activity than germ-line mutations.
- A strong correlation was observed between enzymatic activity and biological oncogenic potential.
Conclusions:
- Met mutants identified in human PRC are oncogenic, playing a key role in PRC development.
- The level of Met activation quantitatively correlates with tumorigenesis.
- Activating Met mutations may also contribute to other human cancers.