Novel mutations of the MET proto-oncogene in papillary renal carcinomas

Laura Schmidt, Kerstin Junker, Noboru Nakaigawa, Tracy Kinjerski, Gregor Weirich, Maria Miller, Irina Lubensky, Hartmut Ph Neumann, Hiltrud Brauch, Johann Decker, Cathy Vocke, James A. Brown, Robert Brian Jenkins, Stephane Richard, Ulf Bergerheim, Bernard Gerrard, Michael Dean, W. Marston Linehan, Berton Zbar

Research output: Contribution to journalArticle

396 Scopus citations

Abstract

Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET protooncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that non-inherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.

Original languageEnglish (US)
Pages (from-to)2343-2350
Number of pages8
JournalOncogene
Volume18
Issue number14
StatePublished - Apr 8 1999

    Fingerprint

Keywords

  • MET protooncogene mutations
  • Papillary renal carcinoma
  • Receptor tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Schmidt, L., Junker, K., Nakaigawa, N., Kinjerski, T., Weirich, G., Miller, M., Lubensky, I., Neumann, H. P., Brauch, H., Decker, J., Vocke, C., Brown, J. A., Jenkins, R. B., Richard, S., Bergerheim, U., Gerrard, B., Dean, M., Linehan, W. M., & Zbar, B. (1999). Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene, 18(14), 2343-2350.