Activation of Extracellular Signal–Regulated Kinases (ERK1/2) by Angiotensin II Is Dependent on c-Src in Vascular Smooth Muscle Cells

From the Department of Medicine (M.I., T.I., B.C.B.), Division of Cardiology, University of Washington, Seattle, and the Department of Medicine/Cancer Biology (S.M.T.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Correspondence to Bradford C. Berk, MD, PhD, University of Washington, Division of Cardiology, Box 357710, Seattle, WA 98195. E-mail bcberk{at}u.washington.edu

Abstract—Among the angiotensin II (Ang II)–mediated signal events likely to be important in vascular smooth muscle cells (VSMCs) is activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2). The upstream mediators by which Ang II activates ERK1/2 remain poorly defined. Recently, we showed that Ang II activated c-Src, a nonreceptor kinase, which is a candidate to mediate Ang II signal events. To determine whether c-Src is required for ERK1/2 activation by Ang II, we studied the effects of Src family–selective tyrosine kinase inhibitors on ERK1/2 activation and also studied Ang II–mediated signal events in Src-deficient and Src-overexpressing VSMCs. The tyrosine kinase inhibitors, genistein and CP-188,556, blocked Ang II–mediated ERK1/2 activation in rat VSMCs (rVSMCs). We derived Src-deficient VSMCs from the aortas of c-Src knockout mice (Src^-/- mVSMCs). Basal ERK1/2 activity was lower, and activation of ERK1/2 by Ang II was significantly decreased in Src^-/- mVSMCs compared with wild-type mVSMCs, whereas ERK1/2 protein expression and ERK1/2 activation by phorbol 12-myristate 13-acetate were similar. To examine the role of c-Src further, we overexpressed wild-type or dominant-negative c-Src in rVSMCs using retroviral vectors. ERK1/2 activation by Ang II was significantly increased in rVSMCs that overexpressed c-Src, whereas ERK1/2 activation by Ang II was significantly inhibited in rVSMCs that overexpressed dominant-negative c-Src compared with control rVSMCs. These findings demonstrate that c-Src activation is required for Ang II stimulation of ERK1/2 in VSMCs and suggest an important role for c-Src in Ang II–mediated signal transduction.

Key Words: tyrosine kinase • signal transduction • mitogen-activated protein kinase

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