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.
Highlights
The correct regulation of cell function in vivo requires the integration of numerous biological and mechanical signals arising from the surrounding cells and the extracellular matrix (ECM).The nanostructure and the composition of the ECM is strictly controlled in a tissue-specific fashion during development and in adulthood in order to favor cell and organ function (Smith et al, 2017)
Molecular process transforming a physical stimulus in a biological response Individual or protein complexes that produce or enable a chemical signal in response to a mechanical stimulus Is the result of substrate mechanical oscillations at cell-ECM interface, that induces internal cellular and molecular rearrangements, in order to recover to an equilibrium state Pulling force transmitted axially by means of an object A basal equilibrium stress state in which cells counteract external force application by moving toward a previous force setpoint that had been established before external force application Resistance of an elastic body to deflection or deformation by an applied force Bundles of F-actin and myosin II held together by cross-linking proteins ensuring the cytoskeletal contractility
Since the main annotation for Yes-associated protein (YAP)/TAZ transcription targets lies within the proliferation category, the activity of Hippo effectors in the nucleus has been historically associated with cell growth and tumor spreading (Zanconato et al, 2015), while our group and others lately proved that the mechanotransduction role of YAP is to be ascribed to its ability to directly promote the transcription of genes involved in cell-matrix interaction, ECM composition (Nardone et al, 2017) and cytoskeleton integrity (Morikawa et al, 2015)
Summary
The correct regulation of cell function in vivo requires the integration of numerous biological and mechanical signals arising from the surrounding cells and the extracellular matrix (ECM). The nanostructure and the composition of the ECM is strictly controlled in a tissue-specific fashion during development and in adulthood in order to favor cell and organ function (Smith et al, 2017). Changes in ECM composition and mechanics are encountered during the progression of all degenerative diseases as the result of aging or as a compensatory attempt of the tissue to preserve its function (Kim et al, 2000; Parker et al, 2014; Klaas et al, 2016). Changes in ECM compliance are considered of prognostic value for solid tumors (Calvo et al, 2013; Hayashi and Iwata, 2015; Reid et al, 2017)
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