Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

Alberto Bardelli, Maria Lisa Basile, Enrica Audero, Silvia Giordano, Stefan Wennström, Sylvie Ménard, Paolo M. Comoglio, Carola Ponzetto

Research output: Contribution to journalArticlepeer-review

Abstract

The Met tyrosine kinase - the HGF receptor - induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met(2xGrb2)) is permissive for motility, increases transformation, but - surprisingly - is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met(2xP13K) or p85 and Grb2 (Met(P13K/Grb2)) to evaluate the relative importance of Pas and PI 3-kinase as downstream effectors of Met. Met(2xP13K) competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, Met(P13K/Grb2) induced motility, transformation, invasion and metastasis as efficiently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met(2xGrb2) mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.

Original languageEnglish
Pages (from-to)1139-1146
Number of pages8
JournalOncogene
Volume18
Issue number5
DOIs
Publication statusPublished - Feb 4 1999

Keywords

  • Grb2
  • Met signaling
  • Met-mediated metastasis
  • PI 3-kinase
  • Ras

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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