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The Ron oncogenic activity induced by the MEN2B-like substitution overcomes the requirement for the multifunctional

M M Santoro1, L Penengo, S Orecchia

  • 1Dibit-HSR, via Olgettina 58, I-20138, Milano, Italy.

Oncogene
|November 7, 2000
PubMed

Insights

Oncogenic Ron receptor activation requires specific mutations. Y1317 phosphorylation in the kinase domain is crucial for the RonM1254T mutant

Area of Science:

  • Molecular oncology
  • Cell signaling
  • Receptor tyrosine kinases

Background:

  • Oncogenic activation of the Ron tyrosine kinase (Macrophage Stimulating Protein receptor) is driven by specific mutations in its catalytic domain.
  • These mutations lead to ligand-independent receptor activation, promoting tumorigenesis and metastasis.

Purpose of the Study:

  • To investigate the role of the Y1317 residue in the kinase domain of the Ron receptor in oncogenic activation.
  • To determine the impact of Y1317 phosphorylation on the transforming and metastatic properties of oncogenic Ron mutants.

Main Methods:

  • Site-directed mutagenesis (Y1317F conversion) was used to assess the functional significance of Y1317.
  • Tumorigenesis and metastasis assays were performed in vivo.
  • In vitro peptide phosphorylation assays and in vivo auto-phosphorylation studies were conducted to analyze kinase substrate specificity.
  • Activation of downstream signaling pathways (PI-3K/Akt and MAPK) was evaluated.

Main Results:

  • The Y/F conversion at Y1317 impaired tumorigenic and metastatic properties of the RonM1254T mutant, but not other oncogenic substitutions.
  • RonM1254T lacking its docking site retained transforming and metastatic activity, indicating Y1317 phosphorylation is critical.
  • Y1317 phosphorylation was shown to be dependent on the RonM1254T mutation, suggesting a shift in substrate specificity.
  • Phosphorylation of Y1317 independently activated PI-3K/Akt and MAPK signaling pathways.

Conclusions:

  • The oncogenic phenotype of the RonM1254T mutant is critically dependent on the phosphorylation of Y1317 within the tyrosine kinase domain.
  • Full oncogenic potential requires phosphorylation of both the canonical C-terminal docking site and the unique Y1317 residue.
  • These findings highlight Y1317 as a potential therapeutic target in cancers driven by oncogenic Ron signaling.

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