Salicylate inhibits phosphorylation of the nonreceptor tyrosine kinases, proline-rich tyrosine kinase 2 and c-Src

被引:21
作者
Wang, ZY
Brecher, P
机构
[1] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA
关键词
NSAIDs; kinase; signal transduction; fibroblasts;
D O I
10.1161/01.HYP.37.1.148
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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-gamma 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.
引用
收藏
页码:148 / 153
页数:6
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