Hydrogen peroxide induces complex formation of SHC-Grb2-SOS with receptor tyrosine kinase and activates Ras and extracellular signal-regulated protein kinases group of mitogen-activated protein kinases

Oncogene. 1996 Aug 15;13(4):713-9.


Protein tyrosine phosphorylation events play determinant roles in cellular processes such as proliferation and differentiation. We have recently reported that hydrogen peroxide, an active oxygen species and a cellular oxidant, stimulates growth response events in vascular smooth muscle cells (VSMC). To understand the mechanisms by which oxidant stress modulates these growth response events, we have studied the effect of hydrogen peroxide on protein tyrosine phosphorylation events in VSMC. Our findings show that hydrogen peroxide stimulates tyrosine phosphorylation of several proteins including epidermal growth factor receptor (EGFR) in VSMC. Hydrogen peroxide-induced tyrosine phosphorylation of EGFR was found to be time dependent; with a threefold increase at 5 min and a 20-fold increase at 30 min of treatment as compared to control levels. Hydrogen peroxide treatment of VSMC also resulted in a time-dependent increase in tyrosine phosphorylation of SHC proteins. In addition, hydrogen peroxide-induced tyrosine-phosphorylated EGFR formed a complex with SHC-Grb2-SOS. These events were followed by activation of Ras and extracellular signal-regulated protein kinases (ERKs) group of mitogen-activated protein kinases (MAPKs). Together these findings demonstrate for the first time that hydrogen peroxide, a cellular oxidant, possess the ability to activate EGFR-mediated signaling events in VSMC. These EGFR-mediated signaling events may be important in oxidant stress-induced cellular responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Cells, Cultured
  • Enzyme Activation
  • GRB2 Adaptor Protein
  • Hydrogen Peroxide / pharmacology*
  • Male
  • Membrane Proteins / metabolism*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Oxidative Stress
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Proteins / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Son of Sevenless Proteins
  • ras Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Grb2 protein, rat
  • Membrane Proteins
  • Proteins
  • Son of Sevenless Proteins
  • Hydrogen Peroxide
  • Protein Kinases
  • Receptor Protein-Tyrosine Kinases
  • ras Proteins