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J. Biol. Chem., Vol. 282, Issue 8, 5560-5569, February 23, 2007

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Caspase Proteolysis of the Integrin 4 Subunit Disrupts Hemidesmosome Assembly, Promotes Apoptosis, and Inhibits Cell Migration^*

Michael E. Werner^¶||, Feng Chen^¶||, Jose V. Moyano^¶||, Fruma Yehiely^¶||, Jonathan C. R. Jones^¶||, and Vincent L. Cryns^¶||1

From the Cell Death Regulation Laboratory, Departments of Medicine and ^¶Cell and Molecular Biology, and ^||Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Caspases are a conserved family of cell death proteases that cleave intracellular substrates at Asp residues to modify their function and promote apoptosis. In this report we identify the integrin 4 subunit as a novel caspase substrate using an expression cloning strategy. Together with its 6 partner, 64 integrin anchors epithelial cells to the basement membrane at specialized adhesive structures known as hemidesmosomes and plays a critical role in diverse epithelial cell functions including cell survival and migration. We show that integrin 4 is cleaved by caspase-3 and -7 at a conserved Asp residue (Asp¹¹⁰⁹) in vitro and in epithelial cells undergoing apoptosis, resulting in the removal of most of its cytoplasmic tail. Caspase cleavage of integrin 4 produces two products, 1) a carboxyl-terminal product that is unstable and rapidly degraded by the proteasome and 2) an amino-terminal cleavage product (amino acids 1–1109) that is unable to assemble into mature hemidesmosomes. We also demonstrate that caspase cleavage of integrin 4 sensitizes epithelial cells to apoptosis and inhibits cell migration. Taken together, we have identified a previously unrecognized proteolytic truncation of integrin 4 generated by caspases that disrupts key structural and functional properties of epithelial cells and promotes apoptosis.

Received for publication, April 17, 2006 , and in revised form, December 4, 2006.

^* This work was supported in part by National Institutes of Health Grants R01CA097198 (to V. L. C.), P50CA89018 (Specialized Programs of Research Excellence (SPORE) in Breast Cancer (to V. L. C.)), R01AR054184 (to J. C. R. J.), and T32DK07169 (to M. E. W.), by Dept. of Defense Breast Cancer Research Program DAMD17-03-1-0426 (to V. L. C.), and by the Avon Foundation Breast Cancer Research and Care Program (to V. L. C.). 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: Departs. of Medicine and Cell and Molecular Biology, 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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