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J. Biol. Chem., Vol. 279, Issue 46, 47929-47938, November 12, 2004

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Distinct ADAM Metalloproteinases Regulate G Protein-coupled Receptor-induced Cell Proliferation and Survival^*

Beatrix Schäfer, Beatrice Marg, Andreas Gschwind, and Axel Ullrich¶

From the Department of Molecular Biology, Max-Planck Institute of Biochemistry, Martinsried D-82152, Germany

Cross-talk between G protein-coupled receptor (GPCR) and epidermal growth factor receptor (EGFR) signaling systems is widely established in a variety of normal and transformed cell types. Here, we demonstrate that the EGFR transactivation signal requires metalloproteinase cleavage of epidermal growth factor-like growth factor precursors in fibroblasts, ACHN kidney, and TccSup bladder carcinoma cells. Furthermore, we present evidence that blockade of the metalloproteinase-disintegrin tumor necrosis factor--converting enzyme (TACE/ADAM17) by a dominant negative ADAM17 mutant prevents angiotensin II-stimulated pro-HB-EGF cleavage, EGFR activation, and cell proliferation in ACHN tumor cells. Moreover, we found that in TccSup cancer cells, the lysophosphatidic acid-induced transactivation signal is mediated by ADAM15, demonstrating that distinct combinations of growth factor precursors and ADAMs (a disintegrin and metalloproteinases) regulate GPCR-EGFR cross-talk pathways in cell lines derived from urogenital cancer. Our data show further that activation of ADAMs results in discrete cellular responses; whereas GPCR agonists promote activation of the Ras/MAPK pathway and cell proliferation via the EGFR in fibroblasts and ACHN cells, EGFR transactivation pathways regulate activation of the survival mediator Akt/protein kinase B and the susceptibility of fibroblasts and TccSup bladder carcinoma cells to proapoptotic signals such as serum deprivation, death receptor stimulation, and the chemotherapeutic drug doxorubicin. Thus, ADAM15 and -17 function as effectors of GPCR-mediated signaling and define critical characteristics of cancer cells.

Received for publication, January 7, 2004 , and in revised form, August 11, 2004.

^* 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.

Current address: Genentech Inc., Dept. of Immunology, South San Francisco, CA 94080.

^¶ To whom correspondence should be addressed. Tel.: 89-8578-2513; Fax: 89-8578-2454; E-mail: ullrich{at}biochem.mpg.de.

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