Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 15, Pages E1361-E1370Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220723110
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Funding
- National Institutes of Health [EB001480]
- National Institutes of Health Roadmap for Medical Research [PN2 EY016586]
- Spanish Ministry of Economy and Competitiveness [BFU2011-23111]
- Career Integration Grant within the 7th European Community Framework Programme [PCIG 10-GA-2011-303848]
- Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme [PIOF-GA-2008-219401]
- National Institutes of Health award
- Ramon y Cajal award
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Focal adhesions are mechanosensitive elements that enable mechanical communication between cells and the extracellular matrix. Here, we demonstrate a major mechanosensitive pathway in which a-actinin triggers adhesion maturation by linking integrins to actin in nascent adhesions. We show that depletion of the focal adhesion protein a-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 beta(3) integrins, but cooperate in binding to beta(1) integrins. Consistently, we find opposite effects of alpha-actinin depletion and expression of mutants on substrates that bind beta(3) integrins (fibronectin and vitronectin) versus substrates that only bind beta(1) integrins (collagen). We thus suggest that nascent adhesions composed of beta(3) integrins are initially linked to the actin cytoskeleton by talin, and then alpha-actinin competes with talin to bind beta(3) 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.
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