Angiotensin II Type 1 Receptor–Induced Extracellular Signal–Regulated Protein Kinase Activation Is Mediated by Ca²⁺/Calmodulin-Dependent Transactivation of Epidermal Growth Factor Receptor

From the Department of Medicine II (S.M., Y.M., H. Masaki, K.M., Y. Tsutsumi, Y.M., Y.S., Y. Tanaka, T.I., M.I., H. Matsubara), Kansai Medical University, Osaka, Japan; the Pharmacological Laboratory (Y.N.), Taiho Pharmaceutical Co, Ltd, Tokushima, Japan; and the Department of Genetics (N.G., M.S.), Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Correspondence to Hiroaki Matsubara, MD, Division of Endocrine Hypertension and Metabolism, Department of Medicine II, Kansai Medical University, Fumizonocho 10–15, Moriguchi, Osaka 570, Japan. E-mail matsubah{at}takii.kmu.ac.jp

Abstract—The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor stimulation, and recent evidence suggests that G protein–coupled receptors transactivate growth factor receptors to transmit mitogenic effects. In the present study, we report the involvement of epidermal growth factor receptor (EGF-R) in Ang II–induced extracellular signal–regulated kinase (ERK) activation, c-fos gene expression, and DNA synthesis in cardiac fibroblasts. Ang II induced a rapid tyrosine phosphorylation of EGF-R in association with phosphorylation of Shc protein and ERK activation. Specific inhibition of EGF-R function by either a dominant-negative EGF-R mutant or selective tyrphostin AG1478 completely abolished Ang II–induced ERK activation. Induction of c-fos gene expression and DNA synthesis were also abolished by the inhibition of EGF-R function. Calmodulin or tyrosine kinase inhibitors, but not protein kinase C (PKC) inhibitors or downregulation of PKC, completely abolished transactivation of EGF-R by Ang II or the Ca²⁺ ionophore A23187. Epidermal growth factor (EGF) activity in concentrated supernatant from Ang II–treated cells was not detected, and saturation of culture media with anti-EGF antibody did not affect the Ang II–induced transactivation of EGF-R. Conditioned media in which cells were incubated with Ang II could not induce phosphorylation of EGF-R on recipient cells. Platelet-derived growth factor-ß receptor was not phosphorylated on Ang II stimulation, and Ang II–induced c-jun gene expression was not affected by tyrphostin AG1478. Our results demonstrated that in cardiac fibroblasts Ang II–induced ERK activation and its mitogenic signals are dominantly mediated by EGF-R transactivated in a Ca²⁺/calmodulin-dependent manner and suggested that the effects of Ang II on cardiac fibroblasts should be interpreted in association with the signaling pathways regulating cellular proliferation and/or differentiation by growth factors.

Key Words: angiotensin II receptor • angiotensin II • Ca²⁺ • G protein–coupled receptor • epidermal growth factor receptor

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