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1 Dynamique circulatoire et Atherosclerose, Centre Nationale de la Recherche Scientifique, UMR 7131, Paris, France
* To whom correspondence should be addressed. E-mail: pierre.marche{at}brs.ap-hop-paris.fr.
Thrombin is involved in abnormal proliferation of vascular smooth muscle cells (VSMCs) associated with pathogenic vascular remodeling. Thrombin stimulation results in extracellular signal-regulated kinase (ERK 1/2) activation through transactivation of epidermal growth factor receptor (EGFR). Here, using specific antibodies and inhibitors, we investigated thrombin-induced hosphorylation of Src family kinases, nonreceptor proline-rich tyrosine kinase (Pyk2), EGFR and ERK 1/2. Our results show that Src and Pyk2 are involved upstream of EGFR transactivation that is required for ERK 1/2 phosphorylation. The investigation of the role of intracellular calcium concentration ([Ca2+] i ) and calcium mobilization with Ca2+ chelator BAPTA and thapsigargin, respectively, indicates that thrombin- and thapsigargin-induced phosphorylation of EGFR but not ERK 1/2 is dependent on increase in [Ca2+] i . Moreover, only after BAPTA-AM pretreatment, thrombin-induced activation of ERK 1/2 is partially preserved from effects of EGFR and PKC inhibition but not Src family kinase inhibition. These results suggest that BAPTA, by preventing [Ca2+] i elevation, unmask a new pathway of Src family kinase-dependent thrombin-stimulated ERK 1/2 phosphorylation that is independent of EGFR and PKC activation.
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