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J. Biol. Chem., Vol. 283, Issue 26, 18393-18401, June 27, 2008

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The Ectodomain Shedding of E-cadherin by ADAM15 Supports ErbB Receptor Activation^*

Abdo J. Najy, Kathleen C. Day, and Mark L. Day¹

From the Department of Urology and Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan 48109

The zinc-dependent disintegrin metalloproteinases (a disintegrin and metalloproteinases (ADAMs) have been implicated in several disease processes, including human cancer. Previously, we demonstrated that the expression of a catalytically active member of the ADAM family, ADAM15, is associated with the progression of prostate and breast cancer. The accumulation of the soluble ectodomain of E-cadherin in human serum has also been associated with the progression of prostate and breast cancer and is thought to be mediated by metalloproteinase shedding. Utilizing two complementary models, overexpression and stable short hairpin RNA-mediated knockdown of ADAM15 in breast cancer cells, we demonstrated that ADAM15 cleaves E-cadherin in response to growth factor deprivation. We also demonstrated that the extracellular shedding of E-cadherin was abrogated by a metalloproteinase inhibitor and through the introduction of a catalytically inactive mutation in ADAM15. We have made the novel observation that this soluble E-cadherin fragment was found in complex with the HER2 and HER3 receptors in breast cancer cells. These interactions appeared to stabilize HER2 heterodimerization with HER3 and induced receptor activation and signaling through the Erk pathway, supporting both cell migration and proliferation. In this study, we provide evidence that ADAM15 catalyzes the cleavage of E-cadherin to generate a soluble fragment that in turn binds to and stimulates ErbB receptor signaling.

Received for publication, February 19, 2008 , and in revised form, April 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 DK56137 (to M. L. D.). This work was also supported by Department of Defense Grants PC050253 (A. J. N.) and PC030659 (to M. L. D.). 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.

¹ To whom correspondence should be addressed: Dept. of Urology, University of Michigan, 6219 CCGC 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0944. Tel.: 734-647-9968; Fax: 734-647-9271; E-mail: mday{at}umich.edu.

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