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Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses.

Gab1 is a substrate of the receptor tyrosine kinase c-Met and involved in c-Met-specific branching morphogenesis. It associates directly with c-Met via the c-Met-binding domain, which is not related to known phosphotyrosine-binding domains. In addition, Gab1 is engaged in a constitutive complex with the adaptor protein Grb2. We have now mapped the c-Met and Grb2 interaction sites using reverse yeast two-hybrid technology. The c-Met-binding site is localized to a 13-amino acid region unique to Gab1. Insertion of this site into the Gab1-related protein p97/Gab2 was sufficient to confer c-Met-binding activity. Association with Grb2 was mapped to two sites: a classical SH3-binding site (PXXP) and a novel Grb2 SH3 consensus-binding motif (PX(V/I)(D/N)RXXKP). To detect phosphorylation-dependent interactions of Gab1 with downstream substrates, we developed a modified yeast two-hybrid assay and identified PI(3)K, Shc, Shp2, and CRKL as interaction partners of Gab1. In a trk-met-Gab1-specific branching morphogenesis assay, association of Gab1 with Shp2, but not PI(3)K, CRKL, or Shc was essential to induce a biological response in MDCK cells. Overexpression of a Gab1 mutant deficient in Shp2 interaction could also block HGF/SF-induced activation of the MAPK pathway, suggesting that Shp2 is critical for c-Met/Gab1-specific signaling.

Pubmed ID: 10871282

Authors

  • Schaeper U
  • Gehring NH
  • Fuchs KP
  • Sachs M
  • Kempkes B
  • Birchmeier W

Journal

The Journal of cell biology

Publication Data

June 26, 2000

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Cells, Cultured
  • GRB2 Adaptor Protein
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System
  • Molecular Sequence Data
  • Morphogenesis
  • Nuclear Proteins
  • Phosphoproteins
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Proteins
  • Proto-Oncogene Proteins c-met
  • Protozoan Proteins
  • Shc Signaling Adaptor Proteins
  • Two-Hybrid System Techniques