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

Oncogene. 1999 Apr 8;18(14):2343-50. doi: 10.1038/sj.onc.1202547.

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 proto-oncogene. 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 noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells / metabolism
  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Carcinoma, Papillary / genetics*
  • Cell Transformation, Neoplastic / genetics
  • Codon / genetics
  • DNA Mutational Analysis
  • DNA, Neoplasm / genetics*
  • Humans
  • Kidney Neoplasms / genetics*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplastic Syndromes, Hereditary / genetics
  • Phosphorylation
  • Point Mutation*
  • Protein Conformation
  • Protein Processing, Post-Translational / genetics
  • Proto-Oncogene Proteins c-met / chemistry
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Proto-Oncogenes*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Transfection

Substances

  • Codon
  • DNA, Neoplasm
  • Neoplasm Proteins
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-met

Associated data

  • PDB/1IRK