The ron oncogenic activity induced by the MEN2b-like substitution overcomes the requirement for the multifunctional docking site

Massimo Mattia Santoro, Lorenza Penengo, Sara Orecchia, Michele Cilli, Giovanni Gaudino

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogenic activation of the Ron tyrosine kinase (Macrophage Stimulating Protein receptor) relies on substitutions of two highly conserved residues in the catalytic domain (D1232V and M1254T), which result in ligand-independent activation of the receptor, in vivo tumorigenesis and metastasis. We show here that the Y/F conversion of the Y1317 residue in the kinase domain impairs tumorigenic and metastatic properties of Ron activated by the MEN2B-like mutation (Ron(M1254T)), but not by other two oncogenic substitutions. Furthermore, Ron(M1254T) lacking the multifunctional docking site retains transforming and metastatic activity. These data reveal that the transforming activity of Ron(M1254T) mutant is dependent on Y1317 phosphorylation, suggesting a shift in intramolecular substrate specificity. Consistently, a shift of Ron(M1254T) kinase substrate specificity was observed by in vitro peptide phosphorylation assays and in vivo receptor autophosphorylation. The Y1317 phosphorylation elicits by itself activation of PI-3K/Akt and MAPK signalling pathways. Our data indicate that the accomplishment of the full oncogenic phenotype of Ron(M1254T) requires the phosphorylation both of the canonical C-terminal docking site and of the unique Y1317 residue in the tyrosine kinase domain.

Original languageEnglish
Pages (from-to)5208-5211
Number of pages4
JournalOncogene
Volume19
Issue number45
Publication statusPublished - Oct 26 2000

Keywords

  • Ron
  • Substrate specificity
  • Tumorigenesis
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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