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

L Buday1, J Downward

  • 1Signal Transduction Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, England.

Cell
|May 7, 1993
PubMed

Insights

Epidermal growth factor (EGF) signaling activates the Son of sevenless (Sos) protein, a key regulator of Ras signaling. This activation involves the recruitment of Sos to the EGF receptor via the Grb2 adapter protein.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • Son of sevenless (Sos) is a guanine nucleotide exchange factor for p21ras.
  • Epidermal growth factor (EGF) receptor signaling is crucial for cell growth and differentiation.
  • Grb2 is an adapter protein containing SH2 and SH3 domains involved in signal transduction.

Purpose of the Study:

  • To elucidate the mechanism by which EGF stimulates nucleotide exchange activity of Sos on p21ras.
  • To investigate the role of Grb2 and EGF receptor in Sos activation.

Main Methods:

  • Coimmunoprecipitation assays to detect protein-protein interactions.
  • In vitro reconstitution experiments to assess protein complex assembly.
  • Permeabilized cell system assays to measure nucleotide exchange activity.

Main Results:

  • Sos coimmunoprecipitates with EGF receptor in EGF-stimulated cells.
  • Grb2 is essential for the interaction between activated EGF receptor and Sos.
  • A phosphopeptide at tyrosine 1068 of EGF receptor inhibits complex formation and downstream signaling.

Conclusions:

  • EGF-induced activation of p21ras nucleotide exchange involves the recruitment of Sos to a plasma membrane complex.
  • This complex includes the EGF receptor and the Grb2 adapter protein.
  • The interaction is mediated by specific phosphorylation events on the EGF receptor.

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