First Author | Roca-Cusachs P | Year | 2013 |
Journal | Proc Natl Acad Sci U S A | Volume | 110 |
Issue | 15 | Pages | E1361-70 |
PubMed ID | 23515331 | Mgi Jnum | J:195528 |
Mgi Id | MGI:5484721 | Doi | 10.1073/pnas.1220723110 |
Citation | Roca-Cusachs P, et al. (2013) Integrin-dependent force transmission to the extracellular matrix by alpha-actinin triggers adhesion maturation. Proc Natl Acad Sci U S A 110(15):E1361-70 |
abstractText | Focal adhesions are mechanosensitive elements that enable mechanical communication between cells and the extracellular matrix. Here, we demonstrate a major mechanosensitive pathway in which alpha-actinin triggers adhesion maturation by linking integrins to actin in nascent adhesions. We show that depletion of the focal adhesion protein alpha-actinin enhances force generation in initial adhesions on fibronectin, but impairs mechanotransduction in a subsequent step, preventing adhesion maturation. Expression of an alpha-actinin fragment containing the integrin binding domain, however, dramatically reduces force generation in depleted cells. This behavior can be explained by a competition between talin (which mediates initial adhesion and force generation) and alpha-actinin for integrin binding. Indeed, we show in an in vitro assay that talin and alpha-actinin compete for binding to beta3 integrins, but cooperate in binding to beta1 integrins. Consistently, we find opposite effects of alpha-actinin depletion and expression of mutants on substrates that bind beta3 integrins (fibronectin and vitronectin) versus substrates that only bind beta1 integrins (collagen). We thus suggest that nascent adhesions composed of beta3 integrins are initially linked to the actin cytoskeleton by talin, and then alpha-actinin competes with talin to bind beta3 integrins. Force transmitted through alpha-actinin then triggers adhesion maturation. Once adhesions have matured, alpha-actinin recruitment correlates with force generation, suggesting that alpha-actinin is the main link transmitting force between integrins and the cytoskeleton in mature adhesions. Such a multistep process enables cells to adjust forces on matrices, unveiling a role of alpha-actinin that is different from its well-studied function as an actin cross-linker. |