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  • Review Article
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Local force and geometry sensing regulate cell functions

Nature Reviews Molecular Cell Biology volume 7, pages 265–275 (2006)Cite this article

Key Points

  • The shapes of eukaryotic cells and, ultimately, the organisms that they form are defined by cycles of mechanosensing, mechanotransduction and mechanoresponse. Recent studies have shed light into the molecular mechanisms of local mechanosensing and how transduction into biochemical signals could result in whole-cell responses to substrate rigidity.

  • Cellular mechanical phenomena can be described by sequential events: first, mechanosensing that involves a local molecular change in response to changes in force or in geometry (architecture of recognition sites); second, mechanotransduction that involves the conversion of force- or geometry-induced changes into biochemical signals; and third, mechanoresponses, which are changes in cellular function that involve integrated signal responses by motile systems in the short term, and by changes in the molecular composition of the cell in the long term.

  • Force sensing involves the detection of local changes in protein conformation, including protein unfolding. Known mechanisms that are affected by force include opening ion channels, unfolding matrix proteins, cytoplasmic protein unfolding, alterations of enzyme kinetics and catch-bond formation.

  • Geometry sensing involves the detection of the proper spacing of protein sites in clusters, as well as sensing changes in membrane curvature, or in the overall size of protein complexes.

  • Mechanotransduction involves the activation of several signalling pathways, including, but not limited to, the small G proteins, trimeric G proteins, tyrosine phosphorylation, inositol lipid metabolism and calcium level.

  • In tissue engineering, artificial environments have to be designed such that cells will go through different phases with time; however, modifications of the environment by cells pose an important, and complex, problem. The dynamic interplay between cells and their biological matrices over many cycles of mechanosensing, transduction, integrated cell response and matrix remodelling make it difficult to understand how cells know whether to grow, differentiate or undergo apoptosis.

Abstract

The shapes of eukaryotic cells and ultimately the organisms that they form are defined by cycles of mechanosensing, mechanotransduction and mechanoresponse. Local sensing of force or geometry is transduced into biochemical signals that result in cell responses even for complex mechanical parameters such as substrate rigidity and cell-level form. These responses regulate cell growth, differentiation, shape changes and cell death. Recent tissue scaffolds that have been engineered at the micro- and nanoscale level now enable better dissection of the mechanosensing, transduction and response mechanisms.

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Figure 1: Cellular mechanics involves three steps: mechanosensing, mechanotransduction and mechanoresponse.
Figure 2: Mechanisms of force sensing.
Figure 3: Mechanisms of form sensing.
Figure 4: Mechanisms of rigidity sensing.
Figure 5: Cellular processes of mechanosensing and responses.

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Acknowledgements

The members of our laboratories and the members of the Nanomedicine Center for Mechanical Biology (an NIH funded centre) helped to shape many of the ideas in this review. Also, we would like to apologize to all the researchers whose pioneering research we could not cite owing to space limitations.

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Authors and Affiliations

  1. Department of Materials, Laboratory for Biologically Oriented Materials, Swiss Federal Institute of Technology (ETH), Zurich, Wolfgang-Pauli-Strasse 10, ETH Hönggerberg, HCI F443, Zürich, CH-8093, Switzerland

    Viola Vogel

  2. Department of Biological Sciences, P.O. Box 2408, Columbia University, Sherman Fairchild Center, Room 713, 1212 Amsterdam Avenue, New York, 10027, New York, USA

    Michael Sheetz

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Glossary

Mechanotransduction

Conformation-dependent biochemical reactions (read-out) that activate intracellular signals (amplification); for example, G-protein activation, Tyr-kinase activation, lipase activation, kinase cascades or Ca2+ release.

Rigidity

The compliance (amount of displacement per unit of applied force) of the matrix substrate.

Mechanoresponse

Spatio-temporal signal integration will modify cell motility and contractility. Long-term cellular responses to signals will modify protein expression and the motility systems, and regulate overall cellular behaviour.

Mechanosensing

Force-induced conformational changes or geometry-dependent molecular clustering that can cause changes in biochemical reactions.

Membrane curvature

The radius of curvature along the two principal axes in the membrane (mathematically explained as the sum of 1/r for the two axes).

Mechanosensitive channels

Ion channels that open on the application of matrix forces to cells.

Slip bond

Protein–ligand bonds that decrease in lifetime with increasing force for all rates of force application.

Catch bond

Protein–ligand bonds that increase in lifetime with increasing force at high rates of force application.

BAR domain

(Bin, amphiphysin, Rvs domain). A domain that is found in a large family of proteins. It forms a banana-like dimer, and binds to and tabulates lipid membranes.

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Vogel, V., Sheetz, M. Local force and geometry sensing regulate cell functions. Nat Rev Mol Cell Biol 7, 265–275 (2006). https://doi.org/10.1038/nrm1890

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