Abstract
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
Substances
-
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