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J Biol Chem, Vol. 273, Issue 31, 19525-19531, July 31, 1998

Cleavage of the Cytoplasmic Domain of the Integrin ₃ Subunit during Endothelial Cell Apoptosis

Jere Meredith Jr., Zhaomei Mu^¶, Takaomi Saido, and Xiaoping Du^¶

From the ^¶ Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612, the  Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, and the  Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama 351-0198, Japan

In this study, we report that the cytoplasmic domain of the integrin ₃ subunit is a target for limited proteolysis during apoptosis of human umbilical vein endothelial cells. Calpain inhibitors inhibited the cleavage of the ₃ cytoplasmic domain, indicating that calpain is required. Calpain-mediated proteolysis of fodrin was also detected, indicating that calpain is activated during endothelial cell apoptosis. A phosphatase inhibitor, sodium orthovanadate, inhibited endothelial cell apoptosis and cleavage ₃, suggesting that protein dephosphorylation preceded integrin cleavage in the apoptosis signaling pathway. ₃ cleavage was observed in cells that were viable, suggesting that it is an early event and not the consequence of post-death proteolysis. The extent of ₃ cleavage correlated with a loss in the capacity of cells to reattach to matrix proteins. Loss of reattachment capacity during apoptosis was significantly retarded by a calpain inhibitor. As the ₃ cytoplasmic domain is required for integrin signaling and interaction with the cytoskeleton, our results suggest that cleavage in the ₃ cytoplasmic domain by calpain or a calpain-like protease negatively regulates integrin-mediated adhesion, signaling, and cytoskeleton association.

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