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Evidence for ERK1/2 activation by thrombin that is independent of EGFR transactivation

Unité Mixte de Recherche 7131, Centre Nationale de la Recherche Scientifique, Hôpital Broussais, 75014 Paris, France

Submitted 16 December 2002 ; accepted in final form 25 April 2003

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 the epidermal growth factor receptor (EGFR). Here, using specific antibodies and inhibitors, we investigated the thrombin-induced phosphorylation of Src family kinases, nonreceptor proline-rich tyrosine kinase (Pyk2), EGFR, and ERK1/2. Our results show that Src and Pyk2 are involved upstream of the EGFR transactivation that is required for ERK1/2 phosphorylation. The investigation of the role of intracellular calcium concentration ([Ca²⁺]_i) and calcium mobilization with the Ca²⁺ chelator BAPTA and thapsigargin, respectively, indicated that thrombin- and thapsigargin-induced phosphorylation of the EGFR but not ERK1/2 is dependent on an increase in [Ca²⁺]_i. Moreover, only after BAPTA-AM pretreatment was thrombin-induced activation of ERK1/2 partially preserved from the effects of EGFR and PKC inhibition but not Src family kinase inhibition. These results suggest that BAPTA, by preventing [Ca²⁺]_i elevation, unmasks a new pathway of Src family kinase-dependent thrombin-stimulated ERK1/2 phosphorylation that is independent of EGFR and PKC activation.

calcium; thrombin signaling; vascular smooth muscle cells; 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; extracellular signal-regulated kinase 1/2; epidermal growth factor receptor

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