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J. Cell Biol. 179 (3): 553-565

Copyright © 2007 by the Rockefeller University Press.

Article

A molecular switch that controls cell spreading and retraction

Panagiotis Flevaris, Aleksandra Stojanovic, Haixia Gong, Athar Chishti, Emily Welch, , and Xiaoping Du

Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612

Correspondence to Xiaoping Du: xdu{at}uic.edu

Abstract: Integrin-dependent cell spreading and retraction are required for cell adhesion, migration, and proliferation, and thus are important in thrombosis, wound repair, immunity, and cancer development. It remains unknown how integrin outside-in signaling induces and controls these two opposite processes. This study reveals that calpain cleavage of integrin ß3 at Tyr759 switches the functional outcome of integrin signaling from cell spreading to retraction. Expression of a calpain cleavage–resistant ß3 mutant in Chinese hamster ovary cells causes defective clot retraction and RhoA-mediated retraction signaling but enhances cell spreading. Conversely, a calpain-cleaved form of ß3 fails to mediate cell spreading, but inhibition of the RhoA signaling pathway corrects this defect. Importantly, the calpain-cleaved ß3 fails to bind c-Src, which is required for integrin-induced cell spreading, and this requirement of ß3-associated c-Src results from its inhibition of RhoA-dependent contractile signals. Thus, calpain cleavage of ß3 at Tyr759 relieves c-Src–mediated RhoA inhibition, activating the RhoA pathway that confines cell spreading and causes cell retraction.

Abbreviations used in this paper: RBD, Rho binding domain; ROCK, Rho-dependent kinase; SFK, Src family kinase; WT, wild type.

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