Abstract
The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Weiss, P. A. in The Molecular Control of Cellular Activity (ed. Allen, J. M.) 1–72 (McGraw-Hill, 1961).
dos Remedios, C. G. et al. Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol. Rev. 83, 433–473 (2003).
Machesky, L. M. et al. Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex. Proc. Natl Acad. Sci. USA 96, 3739–3744 (1999).
Weiner, O. D., Marganski, W. A., Wu, L. F., Altschuler, S. J. & Kirschner, M. W. An actin-based wave generator organizes cell motility. PLoS Biol. 5, e221 (2007).
Bieling, P. et al. Reconstitution of a microtubule plus-end tracking system in vitro. Nature 450, 1100–1105 (2007).
Brangwynne, C. P. et al. Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcement. J. Cell Biol. 173, 733–741 (2006).
Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer 4, 253–265 (2004).
Mitchison, T. & Kirschner, M. Dynamic instability of microtubule growth. Nature 312, 237–242 (1984).
Holy, T. E. & Leibler, S. Dynamic instability of microtubules as an efficient way to search in space. Proc. Natl Acad. Sci. USA 91, 5682–5685 (1994). This paper showed that microtubule dynamics have a central role in spatial organization within cells.
Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).
Parent, C. A. Making all the right moves: chemotaxis in neutrophils and Dictyostelium . Curr. Opin. Cell Biol. 16, 4–13 (2004).
Naumanen, P., Lappalainen, P. & Hotulainen, P. Mechanisms of actin stress fibre assembly. J. Microsc. 231, 446–454 (2008).
Wiche, G. Role of plectin in cytoskeleton organization and dynamics. J. Cell Sci. 111, 2477–2486 (1998).
Flitney, E. W., Kuczmarski, E. R., Adam, S. A. & Goldman, R. D. Insights into the mechanical properties of epithelial cells: the effects of shear stress on the assembly and remodeling of keratin intermediate filaments. FASEB J. 23, 2110–2119 (2009).
Tsai, M. Y. et al. A mitotic lamin B matrix induced by RanGTP required for spindle assembly. Science 311, 1887–1893 (2006).
Nedelec, F. J., Surrey, T., Maggs, A. C. & Leibler, S. Self-organization of microtubules and motors. Nature 389, 305–308 (1997).
Heald, R. et al. Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. Nature 382, 420–425 (1996). The reconstitution of spindles in a cell extract, as reported in this paper, was a remarkable demonstration of the self-assembling properties of the cytoskeleton.
Mullins, R. D., Heuser, J. A. & Pollard, T. D. The interaction of Arp2/3 complex with actin: nucleation, high affinity pointed end capping, and formation of branching networks of filaments. Proc. Natl Acad. Sci. USA 95, 6181–6186 (1998). This paper presented the dendritic nucleation model for the assembly of branched actin networks.
Bailly, M. et al. Relationship between Arp2/3 complex and the barbed ends of actin filaments at the leading edge of carcinoma cells after epidermal growth factor stimulation. J. Cell Biol. 145, 331–345 (1999).
Svitkina, T. M. & Borisy, G. G. Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia. J. Cell Biol. 145, 1009–1026 (1999).
Cooper, J. A. & Sept, D. New insights into mechanism and regulation of actin capping protein. Int. Rev. Cell. Mol. Biol. 267, 183–206 (2008).
Carlier, M. F. et al. Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility. J. Cell Biol. 136, 1307–1322 (1997).
Wachsstock, D. H., Schwarz, W. H. & Pollard, T. D. Cross-linker dynamics determine the mechanical properties of actin gels. Biophys. J. 66, 801–809 (1994).
Hsiung, F., Ramirez-Weber, F. A., Iwaki, D. D. & Kornberg, T. B. Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 437, 560–563 (2005).
Liu, A. P. et al. Membrane-induced bundling of actin filaments. Nature Phys. 4, 789–793 (2008).
Janmey, P. A. & McCulloch, C. A. Cell mechanics: integrating cell responses to mechanical stimuli. Annu. Rev. Biomed. Eng. 9, 1–34 (2007).
Campellone, K. G., Webb, N. J., Znameroski, E. A. & Welch, M. D. WHAMM is an Arp2/3 complex activator that binds microtubules and functions in ER to Golgi transport. Cell 134, 148–161 (2008).
Waterman-Storer, C. M., Worthylake, R. A., Liu, B. P., Burridge, K. & Salmon, E. D. Microtubule growth activates Rac1 to promote lamellipodial protrusion in fibroblasts. Nature Cell Biol. 1, 45–50 (1999).
MacKintosh, F. C., Kas, J. & Janmey, P. A. Elasticity of semiflexible biopolymer networks. Phys. Rev. Lett. 75, 4425–4428 (1995).
Storm, C., Pastore, J. J., MacKintosh, F. C., Lubensky, T. C. & Janmey, P. A. Nonlinear elasticity in biological gels. Nature 435, 191–194 (2005). In this study, the role of entropic elasticity was shown experimentally and modelled for a broad set of cytoskeletal polymers.
Gardel, M. L. et al. Elastic behavior of cross-linked and bundled actin networks. Science 304, 1301–1305 (2004).
Tharmann, R., Claessens, M. M. & Bausch, A. R. Viscoelasticity of isotropically cross-linked actin networks. Phys. Rev. Lett. 98, 088103 (2007).
Koenderink, G. H. et al. An active biopolymer network controlled by molecular motors. Proc. Natl Acad. Sci. USA 106, 15192–15197 (2009).
Chaudhuri, O., Parekh, S. H. & Fletcher, D. A. Reversible stress softening of actin networks. Nature 445, 295–298 (2007). This paper showed that the architecture of actin-filament networks affects the relative importance of entropic and enthalpic elasticity.
Wagner, B., Tharmann, R., Haase, I., Fischer, M. & Bausch, A. R. Cytoskeletal polymer networks: the molecular structure of cross-linkers determines macroscopic properties. Proc. Natl Acad. Sci. USA 103, 13974–13978 (2006).
Herant, M., Heinrich, V. & Dembo, M. Mechanics of neutrophil phagocytosis: behavior of the cortical tension. J. Cell Sci. 118, 1789–1797 (2005).
Charras, G. T., Yarrow, J. C., Horton, M. A., Mahadevan, L. & Mitchison, T. J. Non-equilibration of hydrostatic pressure in blebbing cells. Nature 435, 365–369 (2005).
Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nature Rev. Mol. Cell Biol. 10, 75–82 (2009).
Basu, A., Joanny, J. F., Julicher, F. & Prost, J. Thermal and non-thermal fluctuations in active polar gels. Eur. Phys. J. E 27, 149–160 (2008).
Bursac, P. et al. Cytoskeletal remodelling and slow dynamics in the living cell. Nature Mater. 4, 557–561 (2005).
Keren, K. et al. Mechanism of shape determination in motile cells. Nature 453, 475–480 (2008).
Dogterom, M. & Yurke, B. Measurement of the force–velocity relation for growing microtubules. Science 278, 856–860 (1997).
Footer, M. J., Kerssemakers, J. W., Theriot, J. A. & Dogterom, M. Direct measurement of force generation by actin filament polymerization using an optical trap. Proc. Natl Acad. Sci. USA 104, 2181–2186 (2007).
Parekh, S. H., Chaudhuri, O., Theriot, J. A. & Fletcher, D. A. Loading history determines the velocity of actin-network growth. Nature Cell Biol. 7, 1219–1223 (2005).
Prass, M., Jacobson, K., Mogilner, A. & Radmacher, M. Direct measurement of the lamellipodial protrusive force in a migrating cell. J. Cell Biol. 174, 767–772 (2006).
Janmey, P. A., Winer, J. P., Murray, M. E. & Wen, Q. The hard life of soft cells. Cell. Motil. Cytoskeleton 66, 597–605 (2009).
Discher, D. E., Janmey, P. & Wang, Y. L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).
Chen, C. S. Mechanotransduction — a field pulling together? J. Cell Sci. 121, 3285–3292 (2008).
Thery, M. et al. The extracellular matrix guides the orientation of the cell division axis. Nature Cell Biol. 7, 947–953 (2005).
Krieg, M. et al. Tensile forces govern germ-layer organization in zebrafish. Nature Cell Biol. 10, 429–436 (2008).
Cheng, G., Tse, J., Jain, R. K. & Munn, L. L. Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells. PLoS ONE 4, e4632 (2009).
Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).
Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006). This paper showed that substrate elasticity can control the differentiation of mesenchymal stem cells.
Saha, K. et al. Substrate modulus directs neural stem cell behavior. Biophys. J. 95, 4426–4438 (2008).
Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).
Berdyyeva, T. K., Woodworth, C. D. & Sokolov, I. Human epithelial cells increase their rigidity with ageing in vitro: direct measurements. Phys. Med. Biol. 50, 81–92 (2005).
Burns, J. M., Cuschieri, A. & Campbell, P. A. Optimisation of fixation period on biological cells via time-lapse elasticity mapping. Jpn. J. Appl. Phys. 45, 2341–2344 (2006).
Kato, S. et al. Characterization and phenotypic variation with passage number of cultured human endometrial adenocarcinoma cells. Tissue Cell 40, 95–102 (2008).
Sawada, Y. et al. Force sensing by mechanical extension of the Src family kinase substrate p130Cas . Cell 127, 1015–1026 (2006).
Mammoto, A. et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457, 1103–1108 (2009).
Weiss, P. A. Principles of Development; A Text in Experimental Embryology (H. Holt, 1939).
Sonneborn, T. M. The differentiation of cells. Proc. Natl Acad. Sci. USA 51, 915–929 (1964).
Beisson, J. & Sonneborn, T. M. Cytoplasmic inheritance of organization of cell cortex in Paramecium aurelia . Proc. Natl Acad. Sci. USA 53, 275–282 (1965).
Albrecht-Buehler, G. Phagokinetic tracks of 3T3 cells: parallels between the orientation of track segments and of cellular structures which contain actin or tubulin. Cell 12, 333–339 (1977).
Albrecht-Buehler, G. Daughter 3T3 cells. Are they mirror images of each other? J. Cell Biol. 72, 595–603 (1977).
Delhanty, P., Leung, H. & Locke, M. Paired cytoskeletal patterns in an epithelium of siamese twin cells. Eur. J. Cell Biol. 56, 443–450 (1991).
Anderson, C. T. & Stearns, T. Centriole age underlies asynchronous primary cilium growth in mammalian cells. Curr. Biol. 19, 1498–1502 (2009).
Sato, M., Levesque, M. J. & Nerem, R. M. Micropipette aspiration of cultured bovine aortic endothelial cells exposed to shear stress. Arteriosclerosis 7, 276–286 (1987).
Janmey, P. A. The cytoskeleton and cell signaling: component localization and mechanical coupling. Physiol. Rev. 78, 763–781 (1998).
Locke, M. Is there somatic inheritance of intracellular patterns? J. Cell Sci. 96, 563–567 (1990). This paper summarized early examples of 'cytoskeletal epigenetics'.
Kaksonen, M., Toret, C. P. & Drubin, D. G. A modular design for the clathrin- and actin-mediated endocytosis machinery. Cell 123, 305–320 (2005).
Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009).
Omary, M. B., Coulombe, P. A. & McLean, W. H. Intermediate filament proteins and their associated diseases. N. Engl. J. Med. 351, 2087–2100 (2004).
Fygenson, D. K., Elbaum, M., Shraiman, B. & Libchaber, A. Microtubules and vesicles under controlled tension. Phys. Rev. E 55, 850–859 (1997).
Pontani, L. L. et al. Reconstitution of an actin cortex inside a liposome. Biophys. J. 96, 192–198 (2009).
Liu, A. P. & Fletcher, D. A. Biology under construction: in vitro reconstitution of cellular function. Nature Rev. Mol. Cell Biol. 10, 644–650 (2009).
Jones, L. J., Carballido-Lopez, R. & Errington, J. Control of cell shape in bacteria: helical, actin-like filaments in Bacillus subtilis . Cell 104, 913–922 (2001).
Ausmees, N., Kuhn, J. R. & Jacobs-Wagner, C. The bacterial cytoskeleton: an intermediate filament-like function in cell shape. Cell 115, 705–713 (2003).
Garner, E. C., Campbell, C. S. & Mullins, R. D. Dynamic instability in a DNA-segregating prokaryotic actin homolog. Science 306, 1021–1025 (2004).
Garner, E. C., Campbell, C. S., Weibel, D. B. & Mullins, R. D. Reconstitution of DNA segregation driven by assembly of a prokaryotic actin homolog. Science 315, 1270–1274 (2007).
Derman, A. I. et al. Phylogenetic analysis identifies many uncharacterized actin-like proteins (Alps) in bacteria: regulated polymerization, dynamic instability and treadmilling in Alp7A. Mol. Microbiol. 73, 534–552 (2009).
Rochlin, M. W., Dailey, M. E. & Bridgman, P. C. Polymerizing microtubules activate site-directed F-actin assembly in nerve growth cones. Mol. Biol. Cell 10, 2309–2327 (1999).
Henson, J. H. et al. Two components of actin-based retrograde flow in sea urchin coelomocytes. Mol. Biol. Cell 10, 4075–4090 (1999).
Svitkina, T. M. et al. Mechanism of filopodia initiation by reorganization of a dendritic network. J. Cell Biol. 160, 409–421 (2003).
Stossel, T. P. et al. Filamins as integrators of cell mechanics and signalling. Nature Rev. Mol. Cell Biol. 2, 138–145 (2001).
Svitkina, T. M., Verkhovsky, A. B. & Borisy, G. G. Improved procedures for electron microscopic visualization of the cytoskeleton of cultured cells. J. Struct. Biol. 115, 290–303 (1995).
Chaudhuri, O., Parekh, S. H., Lam, W. A. & Fletcher, D. A. Combined atomic force microscopy and side-view optical imaging for mechanical studies of cells. Nature Methods 6, 383–387 (2009).
Stachowiak, J. C. et al. Unilamellar vesicle formation and encapsulation by microfluidic jetting. Proc. Natl Acad. Sci. USA 105, 4697–4702 (2008).
Acknowledgements
We thank O. Chaudhuri, D. Richmond, V. Risca and other members of the Fletcher laboratory for discussion and assistance with this Review. We also benefited from interactions with the researchers and students in the 2009 Physiology course at the Marine Biological Laboratory, Woods Hole, Massachusetts. Work in our laboratories is supported by R01 grants from the National Institutes of Health (NIH) and by the Cell Propulsion Lab, an NIH Nanomedicine Development Center. We apologize to those colleagues whose work could not be cited because of space constraints.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Additional information
Reprints and permissions information is available at htpp://www.nature.com/reprints.
Correspondence should be addressed to D.A.F. (fletch@berkeley.edu) or R.D.M. (dyche@mullinslab.ucsf.edu).
Rights and permissions
About this article
Cite this article
Fletcher, D., Mullins, R. Cell mechanics and the cytoskeleton. Nature 463, 485–492 (2010). https://doi.org/10.1038/nature08908
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature08908
This article is cited by
-
Spike structure of gold nanobranches induces hepatotoxicity in mouse hepatocyte organoid models
Journal of Nanobiotechnology (2024)
-
Immunofluorescence study of cytoskeleton in endothelial cells induced with malaria sera
Malaria Journal (2024)
-
Pattern recognition in the nucleation kinetics of non-equilibrium self-assembly
Nature (2024)
-
Translational implications of CHRFAM7A, an elusive human-restricted fusion gene
Molecular Psychiatry (2024)
-
Dual-color live imaging unveils stepwise organization of multiple basal body arrays by cytoskeletons
EMBO Reports (2024)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.