Calcium-dependent Epidermal Growth Factor Receptor Transactivation Mediates the Angiotensin II-induced Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells*
- Satoru Eguchi‡§,
- Kotaro Numaguchi‡,
- Hiroaki Iwasaki§,
- Takeshi Matsumoto‡,
- Tadashi Yamakawa‡,
- Hirotoshi Utsunomiya‡,
- Evangeline D. Motley¶,
- Hisaaki Kawakatsu‖,
- Koji M. Owada‖,
- Yukio Hirata§,
- Fumiaki Marumo§ and
- Tadashi Inagami‡**
- From the ‡Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the§2nd Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo 113, Japan, the ¶Department of Anatomy and Physiology, Meharry Medical College, Nashville, Tennessee 37208, and the ‖Institute of Molecular and Cellular Biology for Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto 607, Japan
Abstract
We have recently reported that angiotensin II (Ang II)-induced mitogen-activated protein kinase (MAPK) activation is mainly mediated by Ca2+-dependent activation of a protein tyrosine kinase through Gq-coupled Ang II type 1 receptor in cultured rat vascular smooth muscle cells (VSMC). In the present study, we found Ang II rapidly induced the tyrosine phosphorylation of the epidermal growth factor (EGF) receptor and its association with Shc and Grb2. These reactions were inhibited by the EGF receptor kinase inhibitor, AG1478. The Ang II-induced phosphorylation of the EGF receptor was mimicked by a Ca2+ionophore and completely inhibited by an intracellular Ca2+chelator. Thus, AG1478 abolished the MAPK activation induced by Ang II, a Ca2+ ionophore as well as EGF but not by a phorbol ester or platelet-derived growth factor-BB in the VSMC. Moreover, Ang II induced association of EGF receptor with catalytically active c-Src. This reaction was not affected by AG1478. These data indicate that Ang II induces Ca2+-dependent transactivation of the EGF receptor which serves as a scaffold for pre-activated c-Src and for downstream adaptors, leading to MAPK activation in VSMC.
Footnotes
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↵* This work was supported in part by National Institutes of Health Grants HL-58205, HL-35323, HL-03320, and DK-20593.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵** To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-322-4347; Fax: 615-322-3201.
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↵1 The abbreviations used are: Sos, son-of-sevenless; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; Ang II, angiotensin II; AT1, angiotensin II type 1 receptor; VSMC, vascular smooth muscle cells; GPCR, G protein-coupled receptor; PLC, phospholipase C; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; DMEM, Dulbecco’s modified Eagle’s medium; GST, glutathioneS-transferase; mAb, monoclonal antibody; pAb, polyclonal antibody.
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↵2 S. Eguchi, unpublished data.
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↵3 S. Eguchi, unpublished data.
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- Received March 12, 1997.
- Revision received January 13, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
