A molecular switch that controls cell spreading and retraction

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 β₃ at Tyr⁷⁵⁹ switches the functional outcome of integrin signaling from cell spreading to retraction. Expression of a calpain cleavage–resistant β₃ 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 β₃ fails to mediate cell spreading, but inhibition of the RhoA signaling pathway corrects this defect. Importantly, the calpain-cleaved β₃ fails to bind c-Src, which is required for integrin-induced cell spreading, and this requirement of β₃-associated c-Src results from its inhibition of RhoA-dependent contractile signals. Thus, calpain cleavage of β₃ at Tyr⁷⁵⁹ relieves c-Src–mediated RhoA inhibition, activating the RhoA pathway that confines cell spreading and causes cell retraction.