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Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase

D D Schlaepfer1, S K Hanks, T Hunter

  • 1Molecular Biology and Virology Laboratory, Salk Institute, San Diego, California 92186.

Nature
|December 22, 1994
PubMed

Insights

Fibronectin binding to integrins activates focal adhesion kinase (FAK) signaling. This promotes cell adhesion and activates the Ras/MAPK pathway via GRB2 and c-Src interactions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase (PTK) that localizes with integrin receptors at cell adhesion sites.
  • Integrin engagement with extracellular matrix proteins like fibronectin triggers FAK tyrosine phosphorylation.

Purpose of the Study:

  • To investigate the role of FAK, GRB2, and c-Src in integrin-mediated signaling pathways.
  • To elucidate the mechanism linking integrin engagement to mitogen-activated protein kinase (MAPK) activation.

Main Methods:

  • Studied NIH3T3 fibroblasts adhering to fibronectin.
  • Utilized co-immunoprecipitation to assess protein-protein interactions in vivo.
  • Performed in vitro binding assays with mutated FAK proteins.

Main Results:

  • Fibronectin-induced cell adhesion promoted the association of GRB2 and c-Src with FAK.
  • This association was mediated by the SH2 domain of GRB2 binding to tyrosine-phosphorylated FAK.
  • Mutation of FAK tyrosine 925 blocked GRB2 binding, indicating its critical role.
  • MAPK activation was observed in response to fibronectin stimulation.

Conclusions:

  • Integrin engagement with fibronectin initiates a signaling complex involving FAK, c-Src, and GRB2.
  • FAK phosphorylation at Tyr 925 creates a binding site for GRB2, linking integrin signaling to the Ras/MAPK pathway.

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