Paper
Salicylate Inhibits Phosphorylation of the Nonreceptor Tyrosine Kinases, Proline-Rich Tyrosine Kinase 2 and c-Src
Published Jan 1, 2001 · Zhongyan Wang, P. Brecher
Hypertension: Journal of the American Heart Association
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Abstract
The anti-inflammatory effects of salicylate are well known, but the intracellular mechanisms underlying those effects remain to be clarified and are not explained solely by an influence on cyclooxygenase activity. In the present study, we have used cardiac fibroblasts stimulated by either angiotensin II (Ang II) or platelet-derived growth factor (PDGF) to demonstrate an inhibitory effect of salicylate on the phosphorylation of the nonreceptor tyrosine kinases, proline-rich tyrosine kinase 2 (PYK2) and c-Src, by immunoprecipitation and immunoblotting methods. This inhibition was dose dependent, with a clear effect observed at concentrations between 5 and 20 mmol/L salicylate. Intracellular Ca2+ chelation and protein kinase C (PKC) inhibition reduced Ang II and PDGF-induced PYK2 and c-Src phosphorylation. Salicylate significantly inhibited the phosphorylation of both of the tyrosine kinases activated by either ionophore A23187 or thapsigargin treatment, which led to an elevation of cytosolic Ca2+. Activation of PKC by phorbol ester phosphorylated both PYK2 and Src, and this effect also was attenuated by salicylate. In contrast, salicylate had no effect on either the transactivation of the epidermal growth factor receptor by Ang II or the phosphorylation of phospholipase C-&ggr; by PDGF. These studies indicate a novel site of action for salicylate on PYK2 and c-Src phosphorylation and suggest that this inhibitory effect on these important signaling intermediates may be through a Ca2+- and PKC-dependent mechanism.
In Vitro StudySalicylate inhibits phosphorylation of nonreceptor tyrosine kinases, PYK2 and c-Src, potentially through a calcium- and PKC-dependent mechanism.
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