Article

Role of the actin cytoskeleton in tuning cellular responses to external mechanical stress

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Scandinavian Journal of Medicine and Science in Sports (Impact Factor: 3.17). 05/2009; 19(4):490-9. DOI: 10.1111/j.1600-0838.2009.00928.x
Source: PubMed

ABSTRACT Mechanical forces are essential for tissue homeostasis. In adherent cells, cell-matrix adhesions connect the extracellular matrix (ECM) with the cytoskeleton and transmit forces in both directions. Integrin receptors and signaling molecules in cell-matrix adhesions transduce mechanical into chemical signals, thereby regulating many cellular processes. This review focuses on how cellular mechanotransduction is tuned by actin-generated cytoskeletal tension that balances external with internal mechanical forces. We point out that the cytoskeleton rapidly responds to external forces by RhoA-dependent actin assembly and contraction. This in turn induces remodeling of cell-matrix adhesions and changes in cell shape and orientation. As a consequence, a cell constantly modulates its response to new bouts of external mechanical stimulation. Changes in actin dynamics are monitored by MAL/MKL-1/MRTF-A, a co-activator of serum response factor. Recent evidence suggests that MAL is also involved in coupling mechanically induced changes in the actin cytoskeleton to gene expression. Compared with other, more rapid and transient signals evoked at the cell surface, this parallel mechanotransduction pathway is more sustained and provides spatial and temporal specificity to the response. We describe examples of genes that are regulated by mechanical stress in a manner depending on actin dynamics, among them the ECM protein, tenascin-C.

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    • "Translocation to the nucleus occurs following Rho family activation and polymerization of actin cytoskeleton into stress fibers linking actin dynamics to transcription [73] . These related factors are the proteins that respond to stretching or force [80] . MRTF-B is required for vascular development and differentiation of smooth muscle cell [81] . "
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    • "Mechanical forces stimulate cell differentiation and control/maintain tissue function via membrane associated " mechanoreceptor " mechanisms, activation of second messengers and downstream gene regulation in various mammalian systems like musculoskeletal and cardiovascular tissues (Hahn and Schwartz, 2009; Jani and Schock, 2009; Papachroni et al., 2009). Cell adhesion molecules like integrins, membrane associated receptors and strain sensitive channels have been described to transmit mechanical forces to intracellular structures like the actin cytoskeleton and second messengers like calcium flux (Asparuhova et al., 2009; Huveneers and Danen, 2009; Kiselyov and Patterson, 2009; Puklin-Faucher and Sheetz, 2009; Sharif-Naeini et al., 2010). Mechanobiochemical transformation in single cells is elicited by the stimulation of ERK1/2 kinase phosphorylation cascades, activation and nuclear translocation of transcription factors and modulation of gene expression (Khatiwala et al., 2009; Klossner et al., 2009; Liu et al., 2009; Rangaswami et al., 2009; Young et al., 2009). "
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    • "MAL (MKL-1; MRTF-A) is a transcriptional co-activator of serum response factor (SRF) that cycles between the cytoplasm and the nucleus under the control of RhoA-dependent actin dynamics (Asparuhova et al., 2009; Miralles et al., 2003). Mechanical strain stimulates actin reorganization and was shown to promote a shift of MAL from the cytoplasm to the nucleus in serum-starved cells (Maier et al., 2008; Zhao et al., 2007). "
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