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Integrin-dependent force transmission to the extracellular matrix by ?-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 ?-actinin triggers adhesion maturation by linking integrins to actin in nascent adhesions. We show that depletion of the focal adhesion protein ?-actinin enhances force generation in initial adhesions on fibronectin, but impairs mechanotransduction in a subsequent step, preventing adhesion maturation. Expression of an ?-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 ?-actinin for integrin binding. Indeed, we show in an in vitro assay that talin and ?-actinin compete for binding to ?3 integrins, but cooperate in binding to ?1 integrins. Consistently, we find opposite effects of ?-actinin depletion and expression of mutants on substrates that bind ?3 integrins (fibronectin and vitronectin) versus substrates that only bind ?1 integrins (collagen). We thus suggest that nascent adhesions composed of ?3 integrins are initially linked to the actin cytoskeleton by talin, and then ?-actinin competes with talin to bind ?3 integrins. Force transmitted through ?-actinin then triggers adhesion maturation. Once adhesions have matured, ?-actinin recruitment correlates with force generation, suggesting that ?-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 ?-actinin that is different from its well-studied function as an actin cross-linker.

SUBMITTER: Roca-Cusachs P

PROVIDER: S-EPMC3625291 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Integrin-dependent force transmission to the extracellular matrix by α-actinin triggers adhesion maturation.

Roca-Cusachs Pere P del Rio Armando A Puklin-Faucher Eileen E Gauthier Nils C NC Biais Nicolas N Sheetz Michael P MP

Proceedings of the National Academy of Sciences of the United States of America 20130320 15

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. Express ...[more]

PMID: 23515331

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Project description:The ability of cells to impart forces and deformations on their surroundings underlies cell migration and extracellular matrix (ECM) remodeling and is thus an essential aspect of complex, metazoan life. Previous work has resulted in a refined understanding, commonly termed the molecular clutch model, of how cells adhering to flat surfaces such as a microscope coverslip transmit cytoskeletally generated forces to their surroundings. Comparatively less is known about how cells adhere to and exert forces in soft, three-dimensional (3D), and structurally heterogeneous ECM environments such as occur in vivo. We used time-lapse 3D imaging and quantitative image analysis to determine how the actin cytoskeleton is mechanically coupled to the surrounding matrix for primary dermal fibroblasts embedded in a 3D fibrin matrix. Under these circumstances, the cytoskeletal architecture is dominated by contractile actin bundles attached at their ends to large, stable, integrin-based adhesions. Time-lapse imaging reveals that α-actinin-1 puncta within actomyosin bundles move more quickly than the paxillin-rich adhesion plaques, which in turn move more quickly than the local matrix, an observation reminiscent of the molecular clutch model. However, closer examination did not reveal a continuous rearward flow of the actin cytoskeleton over slower moving adhesions. Instead, we found that a subset of stress fibers continuously elongated at their attachment points to integrin adhesions, providing stable, yet structurally dynamic coupling to the ECM. Analytical modeling and numerical simulation provide a plausible physical explanation for this result and support a picture in which cells respond to the effective stiffness of local matrix attachment points. The resulting dynamic equilibrium can explain how cells maintain stable, contractile connections to discrete points within ECM during cell migration, and provides a plausible means by which fibroblasts contract provisional matrices during wound healing.

Dataset Information

Integrin-dependent force transmission to the extracellular matrix by ?-actinin triggers adhesion maturation.

Publications

Integrin-dependent force transmission to the extracellular matrix by α-actinin triggers adhesion maturation.

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