Molecular Biomechanics: The Molecular Basis of How Forces Regulate Cellular Function

Bao, Gang; Kamm, Roger D.; Thomas, Wendy E.; Hwang, Wonmuk; Fletcher, Daniel A.; Grodzinsky, Alan J.; Zhu, Cheng; Mofrad, Mohammad R. K.

doi:10.1007/s12195-010-0109-z

Cited by 41 publications

(30 citation statements)

References 94 publications

(93 reference statements)

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“…These changes may allow the signaling molecules to bind the force-sensing molecules to elicit the biochemical signals involved in the cellular responses to the matrix rigidity (45). Shp2…”

Section: Discussionmentioning

confidence: 99%

Shp2 plays a crucial role in cell structural orientation and force polarity in response to matrix rigidity

Lee¹,

Lee²,

Chou³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Cells can sense and respond to physical properties of their surrounding extracellular matrix. We have demonstrated here that tyrosine phosphatase Shp2 plays an essential role in the response of mouse embryonic fibroblasts to matrix rigidity. On rigid surfaces, large focal adhesions (FAs) and anisotropically oriented stress fibers are formed, whereas cells plated on compliant substrates form numerous small FAs and radially oriented stress fibers. As a result, traction force is increased and organized to promote cell spreading and elongation on rigid substrates. Shp2-deficient cells do not exhibit the stiffnessdependent increase in FA size and polarized stress fibers nor the intracellular tension and cell shape change. These results indicate the involvement of Shp2 in regulating the FAs and the cytoskeleton for force maintenance and organization. The defect of FA maturation in Shp2-deficient cells was rescued by expressing Y722F Rhoassociated protein kinase II (ROCKII), suggesting that ROCKII is the molecular target of Shp2 in FAs for the FA maturation. Thus, Shp2 serves as a key mediator in FAs for the regulation of structural organization and force orientation of mouse embyonic fibroblasts in determining their mechanical polarity in response to matrix rigidity.he interactions between adherent cells and the extracellular matrix (ECM) are essential for many cellular processes, including proliferation, differentiation, and migration (1-3). It is known that cells can sense the extracellular mechanical cues and respond to these cues by modulating cellular biochemical activities and intracellular force, a process called mechanotransduction (4-7). The altered intracellular cytoskeletal forces modulate cell shape and control complex cell behaviors that are critical for tissue development and homeostasis (8-10). Focal adhesions (FAs) link the cell to the ECM at sites of integrin binding and play dual roles in force transmission and signal transduction (11,12). When a nascent adhesion is formed, the activated integrin links to cytoskeleton via a talin-mediated connection and requires actin-related protein-2/3 (ARP2/3) complex-mediated actin polymerization that is independent of myosin II activity (13,14). Thereafter, some adhesions disassemble, whereas other adhesions mature through myosin-mediated contractility that promotes the recruitment of additional cytoskeletal and signaling proteins to the FAs for adhesion strengthening and signal transmission (15)(16)(17)(18)(19). Therefore, the FAs are mechanosensitive, and the regulation of FA dynamics plays an important role in mechanotransduction (11,12,20).Abnormal cell and tissue responses to mechanical stress have been shown to contribute to the etiology and clinical presentation of many diseases or developmental disorders (21). Tyrosine phosphatase Shp2, encoded by the PTPN11 gene, is a ubiquitously expressed, nonreceptor protein tyrosine phosphatase (PTP) (22). Germline mutations in PTPN11 cause Noonan syndrome (gain of function) and Leopard syndrome (catalytically defec...

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“…These changes may allow the signaling molecules to bind the force-sensing molecules to elicit the biochemical signals involved in the cellular responses to the matrix rigidity (45). Shp2…”

Section: Discussionmentioning

confidence: 99%

Shp2 plays a crucial role in cell structural orientation and force polarity in response to matrix rigidity

Lee¹,

Lee²,

Chou³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Over the past decade, there has been an incredible focus on cell mechanosensing: the ability of cells to sense and respond to the mechanical properties of their surroundings 1–9 . Studies have demonstrated that cell mechanosensing can have profound effects on cell fate, cell survival and cell migration.…”

Section: Introductionmentioning

confidence: 99%

Fibronectin fibrillogenesis facilitates mechano-dependent cell spreading, force generation, and nuclear size in human embryonic fibroblasts

Scott

Mair

Narang

et al. 2015

Integrative Biology

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Cells respond to mechanical cues from the substrate to which they are attached. These mechanical cues drive cell migration, proliferation, differentiation, and survival. Previous studies have highlighted three specific mechanisms through which substrate stiffness directly alters cell function: increasing stiffness drives 1) larger contractile forces; 2) increased cell spreading and size; and 3) altered nuclear deformation. While studies have shown that substrate mechanics are an important cue, the role of the extracellular matrix (ECM) has largely been ignored. The ECM is a crucial component of the mechanosensing system for two reasons: 1) many ECM fibrils are assembled by application of cell-generated forces, and 2) ECM proteins have unique mechanical properties that will undoubtedly alter the local stiffness sensed by a cell. We specifically focused on the role of the ECM protein fibronectin (FN), which plays a critical role in de novo tissue production. In this study, we first measured the effects of substrate stiffness on human embryonic fibroblasts by plating cells onto microfabricated pillar arrays (MPAs) of varying stiffness. Cells responded to increasing substrate stiffness by generating larger forces, spreading to larger sizes, and altering nuclear geometry. These cells also assembled FN fibrils across all stiffnesses, with optimal assembly occurring at approximately 6 kPa. We then inhibited FN assembly, which resulted in dramatic reductions in contractile force generation, cell spreading, and nuclear geometry across all stiffnesses. These findings suggest that FN fibrils play a critical role in facilitating cellular responses to substrate stiffness.

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“…At the focal adhesion, actin filaments of the cellular cytoskeleton are linked to the extra-cellular membrane (ECM) of the substrate [5]. Once linked, both mechanical forces [11] originating from within the cell – such as myosin induced contraction of the actin filaments [12] during cell migration – can act on the ECM and the substrate, and, mechanical forces originating from outside the cell – such as flow induced cyclic stress in the case of endothelial cells [13] – can be transduced to the cellular machinery [14].…”

Section: Introductionmentioning

confidence: 99%

The Interaction of Vinculin with Actin

Golji

Mofrad

2013

PLoS Comput Biol

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Vinculin can interact with F-actin both in recruitment of actin filaments to the growing focal adhesions and also in capping of actin filaments to regulate actin dynamics. Using molecular dynamics, both interactions are simulated using different vinculin conformations. Vinculin is simulated either with only its vinculin tail domain (Vt), with all residues in its closed conformation, with all residues in an open I conformation, and with all residues in an open II conformation. The open I conformation results from movement of domain 1 away from Vt; the open II conformation results from complete dissociation of Vt from the vinculin head domains. Simulation of vinculin binding along the actin filament showed that Vt alone can bind along the actin filaments, that vinculin in its closed conformation cannot bind along the actin filaments, and that vinculin in its open I conformation can bind along the actin filaments. The simulations confirm that movement of domain 1 away from Vt in formation of vinculin 1 is sufficient for allowing Vt to bind along the actin filament. Simulation of Vt capping actin filaments probe six possible bound structures and suggest that vinculin would cap actin filaments by interacting with both S1 and S3 of the barbed-end, using the surface of Vt normally occluded by D4 and nearby vinculin head domain residues. Simulation of D4 separation from Vt after D1 separation formed the open II conformation. Binding of open II vinculin to the barbed-end suggests this conformation allows for vinculin capping. Three binding sites on F-actin are suggested as regions that could link to vinculin. Vinculin is suggested to function as a variable switch at the focal adhesions. The conformation of vinculin and the precise F-actin binding conformation is dependent on the level of mechanical load on the focal adhesion.

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Molecular Biomechanics: The Molecular Basis of How Forces Regulate Cellular Function

Cited by 41 publications

References 94 publications

Shp2 plays a crucial role in cell structural orientation and force polarity in response to matrix rigidity

Shp2 plays a crucial role in cell structural orientation and force polarity in response to matrix rigidity

Fibronectin fibrillogenesis facilitates mechano-dependent cell spreading, force generation, and nuclear size in human embryonic fibroblasts

The Interaction of Vinculin with Actin

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