title: Integrin-dependent force transmission to the extracellular matrix by α-actinin triggers adhesion maturation.
abstract: Focal adhesions are mechanosensitive elements that enable mechanical communication between cells and the extracellular matrix. Here, we demonstrate a major mechanosensitive pathway in which α-actinin triggers adhesion maturation by linking integrins to actin in nascent adhesions. We show that depletion of the focal adhesion protein α-actinin enhances force generation in initial adhesions on fibronectin, but impairs mechanotransduction in a subsequent step, preventing adhesion maturation. Expression of an α-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 α-actinin for integrin binding. Indeed, we show in an in vitro assay that talin and α-actinin compete for binding to β3 integrins, but cooperate in binding to β1 integrins. Consistently, we find opposite effects of α-actinin depletion and expression of mutants on substrates that bind β3 integrins (fibronectin and vitronectin) versus substrates that only bind β1 integrins (collagen). We thus suggest that nascent adhesions composed of β3 integrins are initially linked to the actin cytoskeleton by talin, and then α-actinin competes with talin to bind β3 integrins. Force transmitted through α-actinin then triggers adhesion maturation. Once adhesions have matured, α-actinin recruitment correlates with force generation, suggesting that α-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 α-actinin that is different from its well-studied function as an actin cross-linker.
authors.affiliation: Institute for Bioengineering of Catalonia, 08028 Barcelona, Spain. rocacusachs@ub.edu
authors.forename: Pere
authors.initials: P
authors.lastname: Roca-Cusachs
authors.forename: Armando
authors.initials: A
authors.lastname: del Rio
authors.forename: Eileen
authors.initials: E
authors.lastname: Puklin-Faucher
authors.forename: Nils C
authors.initials: NC
authors.lastname: Gauthier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Biais
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sheetz
mesh_terms: D000185:Actinin / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism*; D051379:Mice; D052898:Optical Tweezers; D013314:Stress, Mechanical; D016608:Talin / Q000378:metabolism
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D039661:Integrin beta3; D016608:Talin; D000185:Actinin