Protein tyrosine kinase activity is required for oxidant-induced extracellular signal-regulated protein kinase activation and c-fos and c-jun expression.
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.
Rao
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Division of Cardiology, University of Texas Medical Branch, Galveston 77555-1064, USA.
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D019833:Genistein; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D005419:Flavonoids; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D007529:Isoflavones; D016877:Oxidants; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D017468:Receptors, Fibroblast Growth Factor; D006861:Hydrogen Peroxide; D019833:Genistein; C496350:Fgfr1 protein, rat; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one