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J. Biol. Chem., Vol. 280, Issue 28, 26592-26599, July 15, 2005

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G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor^*

From the ^aCardiovascular Research Center and the Departments of ⁱPhysiology and ^cPharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, the ^dDepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the ^eDepartment of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0301, Japan, the ^fMolecular Endocrinology Laboratory, Baker Medical Research Institute, Melbourne 8008, Australia, the ^gCenter for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and the ^hPacific Northwest Research Institute, Seattle, Washington 98122

A G protein-coupled receptor agonist, angiotensin II (AngII), induces epidermal growth factor (EGF) receptor (EGFR) transactivation possibly through metalloprotease-dependent, heparin-binding EGF (HB-EGF) shedding. Here, we have investigated signal transduction of this process by using COS7 cells expressing an AngII receptor, AT₁. In these cells AngII-induced EGFR transactivation was completely inhibited by pretreatment with a selective HB-EGF inhibitor, or with a metalloprotease inhibitor. We also developed a COS7 cell line permanently expressing a HB-EGF construct tagged with alkaline phosphatase, which enabled us to measure HB-EGF shedding quantitatively. In the COS7 cell line AngII stimulated release of HB-EGF. This effect was mimicked by treatment either with a phospholipase C activator, a Ca²⁺ ionophore, a metalloprotease activator, or H₂O₂. Conversely, pretreatment with an intracellular Ca²⁺ antagonist or an antioxidant blocked AngII-induced HB-EGF shedding. Moreover, infection of an adenovirus encoding an inhibitor of G_q markedly reduced EGFR transactivation and HB-EGF shedding through AT₁. In this regard, AngII-stimulated HB-EGF shedding was abolished in an AT₁ mutant that lacks G_q protein coupling. However, in cells expressing AT₁ mutants that retain G_q protein coupling, AngII is still able to induce HB-EGF shedding. Finally, the AngII-induced EGFR transactivation was attenuated in COS7 cells overexpressing a catalytically inactive mutant of ADAM17. From these data we conclude that AngII stimulates a metalloprotease ADAM17-dependent HB-EGF shedding through AT₁/G_q/phospholipase C-mediated elevation of intracellular Ca²⁺ and reactive oxygen species production, representing a key mechanism indispensable for EGFR transactivation.

Received for publication, March 16, 2005 , and in revised form, May 10, 2005.

^* This work was supported in part by National Institutes of Health Grants HL076770 (to S. E.), HL076575 (to G. D. F.), and HL058205 (to T. I.) and American Heart Association Scientist Development Grant 0130053N (to S. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b These authors contributed equally to this work.

^j To whom correspondence should be addressed: Cardiovascular Research Center, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, PA 19140. Tel./Fax: 215-707-8378; E-mail: seguchi{at}temple.edu.

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