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Review
. 2018 Jul 5;9:824.
doi: 10.3389/fphys.2018.00824. eCollection 2018.

Cellular Mechanotransduction: From Tension to Function

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Free PMC article
Review

Cellular Mechanotransduction: From Tension to Function

Fabiana Martino et al. Front Physiol. .
Free PMC article

Abstract

Living cells are constantly exposed to mechanical stimuli arising from the surrounding extracellular matrix (ECM) or from neighboring cells. The intracellular molecular processes through which such physical cues are transformed into a biological response are collectively dubbed as mechanotransduction and are of fundamental importance to help the cell timely adapt to the continuous dynamic modifications of the microenvironment. Local changes in ECM composition and mechanics are driven by a feed forward interplay between the cell and the matrix itself, with the first depositing ECM proteins that in turn will impact on the surrounding cells. As such, these changes occur regularly during tissue development and are a hallmark of the pathologies of aging. Only lately, though, the importance of mechanical cues in controlling cell function (e.g., proliferation, differentiation, migration) has been acknowledged. Here we provide a critical review of the recent insights into the molecular basis of cellular mechanotransduction, by analyzing how mechanical stimuli get transformed into a given biological response through the activation of a peculiar genetic program. Specifically, by recapitulating the processes involved in the interpretation of ECM remodeling by Focal Adhesions at cell-matrix interphase, we revise the role of cytoskeleton tension as the second messenger of the mechanotransduction process and the action of mechano-responsive shuttling proteins converging on stage and cell-specific transcription factors. Finally, we give few paradigmatic examples highlighting the emerging role of malfunctions in cell mechanosensing apparatus in the onset and progression of pathologies.

Keywords: focal adhesion; mechanobiology; mechanosensor; mechanotransduction; nucleoskeleton.

Figures

FIGURE 1
FIGURE 1
Schematic representation of key mechanosensing players involved in cell-ECM interaction at the focal adhesion (FA) site. Extracellular changes in stiffness, tension or other mechanical stimuli are perceived by integrin clusters whose morphological changes or distribution recruit FAK. Talin rod, vinculin, paxillin, and adaptor protein p130Cas dock to each other and transfer the mechanical cues from integrins to the actin component of the cytoskeleton. In close proximity with the FA inner core, VASP, Zyxin and actinins complex directly regulate actin assembly and dynamics. Adapted from Nardone et al. (2017). ACTN, actinin; FAK, focal adhesion kinase; IT, integrin; PAX, paxillin; TLN, talin; VASP, vasodilator-stimulated phosphoprotein; VCL, vinculin; ZYX, zyxin.
FIGURE 2
FIGURE 2
Principal activities of RhoA in controlling mechanical signal propagation. RhoA regulates actin polymerization, contractile force generation and F-actin stabilization by regulating: (1) actin nucleation/elongation through mDia activation, (2) by promoting MLC phosphorylation directly or (3) through MLC phosphatase inhibition and (4) by inhibiting the actin severing activity of cofilin. LIMK, LIM kinase; mDia, Diaphanous-related formin-1; MLC, myosin light chain; ROCK, Rho-associated protein kinase; SF, stress fiber.
FIGURE 3
FIGURE 3
YAP/TAZ at the crossroad of cellular mechanotransduction. Schematic representation of YAP/TAZ factors as the downstream effectors of a number of distinct mechanosensing and biological pathways in the cell and acting to control cytoskeleton dynamics, cell mechanics and in a feed-forward loop to stabilize ECM structure.
FIGURE 4
FIGURE 4
LINC complex at the center of nuclear-cytoskeletal coupling. On the cytoplasmic side, different nesprin isoforms connect the nucleus to the cytoskeleton. Nesprin-1/2 directly bind actin, nesprin-3 is connected to intermediate filaments (IFs) by plectin and nesprin-4 binds microtubules (MTs) through kinesin-1 or other microtubule motor proteins. In the perinuclear space (PS), nesprins bind SUN proteins which span the inner nuclear membrane (INM) and interact with the nuclear lamina through lamin A. The inner nuclear membrane protein emerin anchors SUN protein to lamin A and interacts directly with chromatin. NPC, nuclear pore complex.
FIGURE 5
FIGURE 5
Schematic representation of cellular mechanotransduction layers. Extracellular physical stimuli are perceived by FAs at the cell-ECM interface; the signals are propagate by the cytoskeleton and transferred to the nucleus where mechanosensitive genes are activated by mechanoactuators (MA). MA can be shuttling mechanotransducers or mechanosensitive transcription factors. Adapted from Nardone et al. (2017). ACTN, actinin; CFL, cofilin; FAK, focal adhesion kinase; INM, inner nuclear membrane; IT, integrin; LIMK, LIM kinase; mDia, Diaphanous-related formin-1; MyoII, myosin II; NPC, nuclear pore complex; ONM, outer nuclear membrane; PAX, paxillin; PS, perinuclear space; ROCK, Rho-associated protein kinase; TLN, talin; VASP, vasodilator-stimulated phosphoprotein; ZYX, zyxin.
FIGURE 6
FIGURE 6
Activation of mechanosensitive genes driven by shuttling mechanotransducers or mechanoresponsive transcription factors. Mechanotransducers (MTR) shuttling from the cytoplasm in response to mechanical stimuli interact and activate given transcription factors (TF, left). Only few mechanosensitive transcription factors have been so far identified that are induced to shuttle from the cytoplasm and activate a given genetic program (right).

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