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.

Common and Diverging Integrin Signals Downstream of Adhesion and Mechanical Stimuli and Their Interplay with Reactive Oxygen Species

“…RhoA/ROCK-dependent inactivation of MLC phosphatase and phospholipase C (PLC)/Ca 2+ /calmodulin-dependent activation of MLC kinase (36). Interestingly, the RhoA activity can be suppressed by β3-associated Src catalyzing an activating phosphorylation of RhoA GAP (37), while the β1 cytoplasmic domain does not bind Src (38). This is consistent with lower RhoA activity after adhesion mediated by αvβ3 compared to α5β1 (39).…”

Rho GTPases in osteoclasts: Orchestrators of podosome arrangement

“…Many proteins critical for podosome organization are regulated by calcium. For example, Pyk2 can be 14 activated by calcium (Sanjay et al, 2001) and calpains are Ca2+-dependent proteases critical for osteoclasts function (Marzia et al, 2006) that may cleave 3 integrin (Flevaris et al, 2007), RhoA (Kulkarni et al, 2002), Pyk2 (Marzia et al, 2006) and WASp (de la Fuente et al, 2007). Change in calcium concentration affects podosome organization of osteoclast (Miyauchi et al, 1990) and knocking out the calcium transporter TRPV5 generates inactive osteoclasts (van der Eedern et al, 2005).…”

The filamins

“…42,86 Consistent with this notion, diminished expression of FLNa increases the invasiveness of human breast cancer cells. 87 Since FLNa silencing also induces activation of calpain, which leads to degradation of focal adhesion proteins, 88,89 suppression of FLNa expression may facilitate focal adhesion turnover, thereby promoting the invasion. Recycling of integrin is also essential for sustained cell migration.…”