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

Oncogene. 1999 Feb 4;18(5):1139-46. doi: 10.1038/sj.onc.1202607.

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 (Met2xGrb2) 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 (Met2xPI3K) or p85 and Grb2 (MetPI3K/Grb2) to evaluate the relative importance of Ras and PI 3-kinase as downstream effectors of Met. Met2xPI3K was competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, MetP13K/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 Met2xGrb2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Transformation, Neoplastic*
  • Consensus Sequence
  • Dogs
  • Enzyme Activation
  • Fibroblasts / cytology
  • GRB2 Adaptor Protein
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasm Metastasis*
  • Nuclear Pore Complex Proteins
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Binding
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Rats
  • Recombinant Proteins / metabolism
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Grb2 protein, rat
  • Nuclear Pore Complex Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • TPR protein, human
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-met