Protein tyrosine kinase activity is required for oxidant-induced extracellular signal-regulated protein kinase activation and c-fos and c-jun expression

Cell Signal. 1997 Feb;9(2):181-7. doi: 10.1016/s0898-6568(96)00139-8.


Hydrogen peroxide stimulated tyrosine phosphorylation of several proteins in growth-arrested vascular smooth muscle cells (VSMC). One of these proteins was identified as fibroblast growth factor receptor type I (FGFR1). In addition, induced tyrosine phosphorylation of FGFR1 by hydrogen peroxide resulted in complex formation with Grb2. Hydrogen peroxide also caused a time-dependent activation of extracellular signal-regulated protein kinases (ERKs; p42&p44) group of mitogen-activated protein kinases (MAPKs) in VSMC. The time courses of the hydrogen peroxide-stimulated FGFR1 tyrosine phosphorylation and ERKs activation were followed by induced expression of c-fos and c-jun. Genistein, a potent inhibitor of protein tyrosine kinases, significantly blunted the hydrogen peroxide-induced FGFR1 tyrosine phosphorylation, ERKs activation and c-fos and c-jun expression. PD98059, a specific inhibitor of MEK1, attenuated the hydrogen peroxide-induced ERKs activation and c-fos and c-jun expression. Together, these results suggest that oxidants such as hydrogen peroxide stimulate tyrosine phosphorylation of receptor tyrosine kinases and these, in turn, mediate the down-stream signalling events including the recruitment of Grb2 by the receptor, activation of ERKs and induction of c-fos and c-jun expression.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cells, Cultured
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • GRB2 Adaptor Protein
  • Genistein
  • Hydrogen Peroxide / pharmacology*
  • Isoflavones / pharmacology
  • MAP Kinase Kinase 1
  • Male
  • Mitogen-Activated Protein Kinase Kinases*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / enzymology
  • Muscle, Smooth, Vascular / metabolism
  • Oxidants / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / analysis
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-fos / biosynthesis*
  • Proto-Oncogene Proteins c-jun / biosynthesis*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases*
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction / physiology


  • Adaptor Proteins, Signal Transducing
  • Enzyme Inhibitors
  • Flavonoids
  • GRB2 Adaptor Protein
  • Grb2 protein, rat
  • Isoflavones
  • Oxidants
  • Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, Fibroblast Growth Factor
  • Hydrogen Peroxide
  • Genistein
  • Fgfr1 protein, rat
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one