Molecular mechanisms of cellular mechanosensing

Luo, Tian; Mohan, Krithika; Iglesias, Pablo A.; Robinson, Douglas N.

doi:10.1038/nmat3772

Cited by 249 publications

(361 citation statements)

References 54 publications

(70 reference statements)

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“…3 A). Similarly, the actin cross-linking protein filamin can accumulate in response to shear stress in multiple cell types (18,49). However, the mammalian paralog filamin B shows higher mechanosensitive accumulation than filamin A (Fig.…”

Section: Force Sensing By Other Actin-associated Proteinsmentioning

confidence: 97%

“…Inward forces include Laplace pressure, contraction driven by myosin motors, and actin cross-linker dynamics coupled with actin polymer disassembly (18)(19)(20)22). An ideal process for studying these inward forces is cytokinesis, where cells must contract inward along the cleavage furrow to divide one cell into two.…”

Section: Forces Acting On the Cell Cortexmentioning

confidence: 99%

“…At higher forces, these bonds then slip so that they display a catch-slip behavior, depending on the force regime. The catch-slip bond also accounts for the mechanosensitive accumulation (the accumulation of a protein in response to applied stress) of the actin cross-linking protein a-actinin (18,49) and its recruitment to focal adhesions under high tension (50). In mammalian cells, mechanoaccumulation is unique to the a-actinin 4 paralog, and is not observed for a-actinin 1 (49) (Fig.…”

Section: Force Sensing By Other Actin-associated Proteinsmentioning

confidence: 99%

“…In wild-type and filaminnull Dictyostelium, damper g b approaches zero, so the initial deformation is largely elastic and happens in <1 s (Fig. 1 C) (18). However, in some mutants where cytoskeletal regulation is disturbed, such as in the racE-null Dictyostelium, the damper g b becomes significant, and the initial deformation occurs over a few seconds (Fig.…”

mentioning

confidence: 93%

“…1 C) (18). When parameterized with directly measured values, these models help account for cell behavior during retraction from an applied force (18), cytokinesis (19,20), and cell motility (17,21).…”

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confidence: 99%

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Mechanochemical Signaling Directs Cell-Shape Change

Schiffhauer

Robinson

2017

Biophysical Journal

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For specialized cell function, as well as active cell behaviors such as division, migration, and tissue development, cells must undergo dynamic changes in shape. To complete these processes, cells integrate chemical and mechanical signals to direct force production. This mechanochemical integration allows for the rapid production and adaptation of leading-edge machinery in migrating cells, the invasion of one cell into another during cell-cell fusion, and the force-feedback loops that ensure robust cytokinesis. A quantitative understanding of cell mechanics coupled with protein dynamics has allowed us to account for furrow ingression during cytokinesis, a model cell-shape-change process. At the core of cell-shape changes is the ability of the cell's machinery to sense mechanical forces and tune the force-generating machinery as needed. Force-sensitive cytoskeletal proteins, including myosin II motors and actin cross-linkers such as a-actinin and filamin, accumulate in response to internally generated and externally imposed mechanical stresses, endowing the cell with the ability to discern and respond to mechanical cues. The physical theory behind how these proteins display mechanosensitive accumulation has allowed us to predict paralogspecific behaviors of different cross-linking proteins and identify a zone of optimal actin-binding affinity that allows for mechanical stress-induced protein accumulation. These molecular mechanisms coupled with the mechanical feedback systems ensure robust shape changes, but if they go awry, they are poised to promote disease states such as cancer cell metastasis and loss of tissue integrity.The concept ''form begets function begets form'' provides an excellent foundation for understanding the behavior of biological systems. Even specialized cells, the smallest unit of complex living systems, perform all of the necessary functions of an organism by assuming distinct shapes, mechanical properties, and physical behaviors. Different cell types use a common set of cytoskeletal elements to provide precise physical support for their distinct functions. For example, red blood cells and neurons have very different shapes that allow them to perform their specific roles. However, they both utilize alternating patterns of actin and spectrin to form cortices with appropriate viscous and elastic properties, albeit in different structural arrangements. Perturbations to this structural network cause a breakdown in the mechanical properties, or the form, of these cells, which inhibits cell function (1,2).Fascinatingly, the physical properties of cells are both determined and acted upon by the cytoskeletal apparatus. Cells are capable of modifying their own physical properties and driving changes in cell shape in response to internal and external chemical and mechanical stimuli. These modifications occur through the remodeling of the cell cortex, the network of cytoskeletal proteins directly under the plasma membrane. Much progress has been made recently in deciphering how chemical signa...

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Section: Force Sensing By Other Actin-associated Proteinsmentioning

confidence: 97%

Section: Forces Acting On the Cell Cortexmentioning

confidence: 99%

Section: Force Sensing By Other Actin-associated Proteinsmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

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Mechanochemical Signaling Directs Cell-Shape Change

Schiffhauer

Robinson

2017

Biophysical Journal

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Crowding tunes the organization and mechanics of actin bundles formed by crosslinking proteins

Park

Lee

et al. 2020

FEBS Letters

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Fascin and α‐actinin form higher‐ordered actin bundles that mediate numerous cellular processes including cell morphogenesis and movement. While it is understood crosslinked bundle formation occurs in crowded cytoplasm, how crowding affects the bundling activities of the two crosslinking proteins is not known. Here, we demonstrate how solution crowding modulates the organization and mechanical properties of fascin‐ and α‐actinin‐induced bundles, utilizing total internal reflection fluorescence and atomic force microscopy imaging. Molecular dynamics simulations support the inference that crowding reduces binding interaction between actin filaments and fascin or the calponin homology 1 domain of α‐actinin evidenced by interaction energy and hydrogen bonding analysis. Based on our findings, we suggest a mechanism of crosslinked actin bundle assembly and mechanics in crowded intracellular environments.

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Detailed Balance Broken by Catch Bond Kinetics Enables Mechanical‐Adaptation in Active Materials

Tabatabai

Seara

Tibbs

et al. 2020

Adv Funct Materials

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Unlike nearly all engineered materials which contain bonds that weaken under load, biological materials contain “catch” bonds which are reinforced under load. Consequently, materials, such as the cell cytoskeleton, can adapt their mechanical properties in response to their state of internal, non‐equilibrium (active) stress. However, how large‐scale material properties vary with the distance from equilibrium is unknown, as are the relative roles of active stress and binding kinetics in establishing this distance. Through course‐grained molecular dynamics simulations, the effect of breaking of detailed balance by catch bonds on the accumulation and dissipation of energy within a model of the actomyosin cytoskeleton is explored. It is found that the extent to which detailed balance is broken uniquely determines a large‐scale fluid‐solid transition with characteristic time‐reversal symmetries. The transition depends critically on the strength of the catch bond, suggesting that active stress is necessary but insufficient to mount an adaptive mechanical response.

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Molecular mechanisms of cellular mechanosensing

Cited by 249 publications

References 54 publications

Mechanochemical Signaling Directs Cell-Shape Change

Mechanochemical Signaling Directs Cell-Shape Change

Crowding tunes the organization and mechanics of actin bundles formed by crosslinking proteins

Detailed Balance Broken by Catch Bond Kinetics Enables Mechanical‐Adaptation in Active Materials

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