Comprehensive Physiology Wiley Online Library

Mechanotransduction

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Abstract

Physical forces are central players in development and morphogenesis, provide an ever‐present backdrop influencing physiological functions, and contribute to a variety of pathologies. Mechanotransduction encompasses the rich variety of ways in which cells and tissues convert cues from their physical environment into biochemical signals. These cues include tensile, compressive and shear stresses, and the stiffness or elastic modulus of the tissues in which cells reside. This article focuses on the proximal events that lead directly from a change in physical state to a change in cell‐signaling state. A large body of evidence demonstrates a prominent role for the extracellular matrix, the intracellular cytoskeleton, and the cell matrix adhesions that link these networks in transduction of the mechanical environment. Recent work emphasizes the important role of physical unfolding or conformational changes in proteins induced by mechanical loading, with examples identified both within the focal adhesion complex at the cell‐matrix interface and in extracellular matrix proteins themselves. Beyond these adhesion and matrix‐based mechanisms, classical and new mechanisms of mechanotransduction reside in stretch‐activated ion channels, the coupling of physical forces to interstitial autocrine and paracrine signaling, force‐induced activation of extracellular proteins, and physical effects directly transmitted to the cell's nucleus. Rapid progress is leading to detailed delineation of molecular mechanisms by which the physical environment shapes cellular signaling events, opening up avenues for exploring how mechanotransduction pathways are integrated into physiological and pathophysiological cellular and tissue processes. © 2011 American Physiological Society. Compr Physiol 1:1057‐1073, 2011.

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Figure 1. Figure 1.

Integrin signaling can be controlled by a molecular switch that toggles between relaxed and tensioned states through conformational changes and integrin α5β1 interactions with a synergy (syn) site in fibronectin. The conformational switch can be triggered by internally driven tension, or externally applied forces, resulting in enhanced integrin‐dependent signaling. Release of tension can revert integrin conformation to the adherent but relaxed state. Adapted with permission from .

Figure 2. Figure 2.

Forced unfolding of talin activates vinculin binding. (A) A portion of the talin rod domain spanning residues 482 to 889, with five cryptic vinculin‐binding sites (H4, 6, 9, 11, 12). (B) Forced unfolding of talin rod domain, showing helix 12 unfolding to expose its vinculin‐binding site. A portion of the vinculin head that binds to talin rod is shown in yellow. (C) X‐ray structure of the interaction of the vinculin head (yellow) with helix 12 of talin rod (red). Adapted with permission from .

Figure 3. Figure 3.

Pathways of force transmission from extracellular matrix to nucleus. Cell adhesions (integrin, dystroglycan) link the extracellular matrix to the actin cytoskeleton. The cytoskeleton is connected to the internal nuclear envelope through the LINC complex (linker of nucleoskeleton and cytoskeleton), composed of Nesprin and SUN proteins. Nuclear lamins connect to SUN proteins, which also bind to the nuclear pore complex. Lamins form stable nuclear structures that can bind DNA, or chromatin, such that mechanical forces could be coupled directly from extracellular matrix to nuclear contents. Adapted with permission from .

Figure 4. Figure 4.

Model for tethered gating of mechanosensitive channels. Here the mechanosensitive transmembrane channel is tethered to both cytoskeletal and extracellular anchors, though either could suffice. External or internal force would mediate channel opening through relative motion of the channel and anchor, applying tension to the channel protein through the tether. Adapted with permission from .

Figure 5. Figure 5.

Model of mechanoregulated TGF‐β activation. In the context of high forces, either internally generated or externally applied, αv integrin bound to RGD sequence on latency‐associated peptide of latent TGF‐β complex exposes active TGF‐β through allosteric changes. In cells resident on soft matrices, or in the absence of external forces, tension applied through av integrin to LAP is insufficient to expose TGF‐β activity. Adapted with permission from .

Figure 6. Figure 6.

Visualizing intercellular deformations under sustained compressive stress. (A) Normal human bronchial epithelial cells imaged with two‐photon microscopy, using fluorescent dextran to label the intercellular space. Comparison of raw and segmented images from matched optical sections at 0, 60, and 600 s after onset of continuous transcellular compressive stress (30 cmH2O). (B) Composite image showing the comparative intercellular geometry at 0, 60, and 600 s after onset of continuous pressure gradient. Note that the cells form a three‐dimensional structure, hence out of plane motions during loading affect the degree to which the optical sections are superimposed. (C) The intercellular volume changes slowly during application of continuous compressive stress (10 and 50 cmH2O), and gradually reverses after stress is removed (vertical dashed line at 600 s). Time‐matched control shows the small variability in volume measurements in the absence of loading. Adapted from .



Figure 1.

Integrin signaling can be controlled by a molecular switch that toggles between relaxed and tensioned states through conformational changes and integrin α5β1 interactions with a synergy (syn) site in fibronectin. The conformational switch can be triggered by internally driven tension, or externally applied forces, resulting in enhanced integrin‐dependent signaling. Release of tension can revert integrin conformation to the adherent but relaxed state. Adapted with permission from .



Figure 2.

Forced unfolding of talin activates vinculin binding. (A) A portion of the talin rod domain spanning residues 482 to 889, with five cryptic vinculin‐binding sites (H4, 6, 9, 11, 12). (B) Forced unfolding of talin rod domain, showing helix 12 unfolding to expose its vinculin‐binding site. A portion of the vinculin head that binds to talin rod is shown in yellow. (C) X‐ray structure of the interaction of the vinculin head (yellow) with helix 12 of talin rod (red). Adapted with permission from .



Figure 3.

Pathways of force transmission from extracellular matrix to nucleus. Cell adhesions (integrin, dystroglycan) link the extracellular matrix to the actin cytoskeleton. The cytoskeleton is connected to the internal nuclear envelope through the LINC complex (linker of nucleoskeleton and cytoskeleton), composed of Nesprin and SUN proteins. Nuclear lamins connect to SUN proteins, which also bind to the nuclear pore complex. Lamins form stable nuclear structures that can bind DNA, or chromatin, such that mechanical forces could be coupled directly from extracellular matrix to nuclear contents. Adapted with permission from .



Figure 4.

Model for tethered gating of mechanosensitive channels. Here the mechanosensitive transmembrane channel is tethered to both cytoskeletal and extracellular anchors, though either could suffice. External or internal force would mediate channel opening through relative motion of the channel and anchor, applying tension to the channel protein through the tether. Adapted with permission from .



Figure 5.

Model of mechanoregulated TGF‐β activation. In the context of high forces, either internally generated or externally applied, αv integrin bound to RGD sequence on latency‐associated peptide of latent TGF‐β complex exposes active TGF‐β through allosteric changes. In cells resident on soft matrices, or in the absence of external forces, tension applied through av integrin to LAP is insufficient to expose TGF‐β activity. Adapted with permission from .



Figure 6.

Visualizing intercellular deformations under sustained compressive stress. (A) Normal human bronchial epithelial cells imaged with two‐photon microscopy, using fluorescent dextran to label the intercellular space. Comparison of raw and segmented images from matched optical sections at 0, 60, and 600 s after onset of continuous transcellular compressive stress (30 cmH2O). (B) Composite image showing the comparative intercellular geometry at 0, 60, and 600 s after onset of continuous pressure gradient. Note that the cells form a three‐dimensional structure, hence out of plane motions during loading affect the degree to which the optical sections are superimposed. (C) The intercellular volume changes slowly during application of continuous compressive stress (10 and 50 cmH2O), and gradually reverses after stress is removed (vertical dashed line at 600 s). Time‐matched control shows the small variability in volume measurements in the absence of loading. Adapted from .

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Daniel J. Tschumperlin. Mechanotransduction. Compr Physiol 2011, 1: 1057-1073. doi: 10.1002/cphy.c100016