Defective Posttranslational Processing Activates the Tyrosine Kinase Encoded by the MET Proto-Oncogene (Hepatocyte Growth Factor Receptor)

Anna Mondino, Silvia Giordano, Paolo M. Comoglio

Research output: Contribution to journalArticle

Abstract

The MET proto-oncogene encodes a 190-kDa disulfide-linked heterodimeric receptor (p190αβ) whose tyrosine kinase activity is triggered by the hepatocyte growth factor. The mature receptor is made of two subunits: an α chain of 50 kDa and a β chain of 145 kDa, arising from proteolytic cleavage of a single-chain precursor of 170 kDa (pr170). In a colon carcinoma cell line (LoVo), the precursor is not cleaved and the Met protein is exposed at the cell surface as a single-chain polypeptide of 190 kDa (p190NC). The expression of the uncleaved Met protein is due to defective posttranslational processing, since in this cell line (i) the proteolytic cleavage site Lys-303-Arg-Lys-Lys-Arg-Ser-308 is present in the precursor, (ii) p190NC is sensitive to mild trypsin digestion of the cell surface, generating α and β chains of the correct size, and (iii) the 205-kDa insulin receptor precursor is not cleaved as well. p190NC is a functional tyrosine kinase in vitro and is activated in vivo, as shown by constitutive autophosphorylation on tyrosine. The MET gene is neither amplified nor rearranged in LoVo cells. Overlapping cDNA clones selected from a library derived from LoVo mRNA were sequenced. No mutations were present in the MET-coding region. These data indicate that the tyrosine kinase encoded by the MET proto-oncogene can be activated as a consequence of a posttranslational defect.

Original languageEnglish
Pages (from-to)6084-6092
Number of pages9
JournalMolecular and Cellular Biology
Volume11
Issue number12
Publication statusPublished - Dec 1991

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

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