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J. Biol. Chem., Vol. 283, Issue 26, 18269-18282, June 27, 2008

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Caspase Cleavage of HER-2 Releases a Bad-like Cell Death Effector^*

From the Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Human epidermal growth factor receptor-2 (HER-2/ErbB2/neu), a receptor tyrosine kinase that is amplified/overexpressed in poor prognosis breast carcinomas, confers resistance to apoptosis by activating cell survival pathways. Here we demonstrate that the cytoplasmic tail of HER-2 is cleaved by caspases at Asp¹⁰¹⁶/Asp¹⁰¹⁹ to release a 47-kDa product, which is subsequently proteolyzed by caspases at Asp¹¹²⁵ into an unstable 22-kDa fragment that is degraded by the proteasome and a predicted 25-kDa product. Both the 47- and 25-kDa products translocate to mitochondria, release cytochrome c by a Bcl-x_L-suppressible mechanism, and induce caspase-dependent apoptosis. The 47- and 25-kDa HER-2 cleavage products share a functional BH3-like domain, which is required for cytochrome c release in cells and isolated mitochondria and for apoptosis induction. Caspase-cleaved HER-2 binds Bcl-x_L and acts synergistically with truncated Bid to induce apoptosis, mimicking the actions of the BH3-only protein Bad. Moreover, the HER-2 cleavage products cooperate with Noxa to induce apoptosis in cells expressing both Bcl-x_L and Mcl-1, confirming their Bad-like function. Collectively, our results indicate that caspases activate a previously unrecognized proapoptotic function of HER-2 by releasing a Bad-like cell death effector.

Received for publication, March 18, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01CA097198 (to V. L. C.). This work was also supported by Department of Defense Breast Cancer Research Program Grants DAMD25-02-1-0526 (to V. L. C.) and DMAD25-00-1-0386 (to A. M. S.), a grant from the Breast Cancer Research Foundation (to V. L. C.), and a Katten Muchin Rosenman Travel Scholarship (to A. M. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Lurie 4-113, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Chicago, IL 60611. Tel.: 312-503-0644; Fax: 312-908-9032; E-mail: v-cryns{at}northwestern.edu.

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