Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor

Cell. 1993 May 7;73(3):611-20. doi: 10.1016/0092-8674(93)90146-h.


Antisera against murine Son of sevenless (Sos) recognize a protein of M(r) 155,000 in rat-1 fibroblasts with specific guanine nucleotide exchange activity toward p21c-Ha-ras. Epidermal growth factor (EGF) receptor coimmunoprecipitates with Sos from EGF-stimulated, but not quiescent, cells. The SH2 and SH3 domain-containing "adapter" protein Grb2 is also found in Sos immunoprecipitates in an EGF-inducible manner. In vitro reconstitution shows that Grb2 is required for the binding of activated EGF receptor to Sos. A phosphopeptide corresponding to tyrosine 1068 of the EGF receptor blocks both the assembly of the complex and EGF stimulation of nucleotide exchange on p21ras in a permeabilized cell system. These results suggest that EGF-induced activation of nucleotide exchange on p21ras proceeds through the recruitment of cytosolic Sos to a complex with EGF receptor and Grb2 at the plasma membrane.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Antibodies
  • Carcinoma, Squamous Cell
  • Cell Line
  • Cell Membrane / metabolism
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / drug effects
  • ErbB Receptors / isolation & purification
  • ErbB Receptors / metabolism*
  • Fibroblasts / metabolism
  • GRB2 Adaptor Protein
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Immune Sera
  • Immunoblotting
  • Kinetics
  • Membrane Proteins / immunology
  • Membrane Proteins / isolation & purification
  • Membrane Proteins / metabolism*
  • Proteins / genetics
  • Proteins / isolation & purification
  • Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Son of Sevenless Proteins
  • Tumor Cells, Cultured


  • Adaptor Proteins, Signal Transducing
  • Antibodies
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, rat
  • Immune Sera
  • Membrane Proteins
  • Proteins
  • Recombinant Fusion Proteins
  • Son of Sevenless Proteins
  • Epidermal Growth Factor
  • Glutathione Transferase
  • ErbB Receptors
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)