Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

Appreciating force and shape — the rise of mechanotransduction in cell biology

Nature Reviews Molecular Cell Biology volume 15, pages 825–833 (2014)Cite this article

Subjects

Abstract

Although the shapes of organisms are encoded in their genome, the developmental processes that lead to the final form of vertebrates involve a constant feedback between dynamic mechanical forces, and cell growth and motility. Mechanobiology has emerged as a discipline dedicated to the study of the effects of mechanical forces and geometry on cell growth and motility — for example, during cell–matrix adhesion development — through the signalling process of mechanotransduction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanotransduction.
Figure 2: Timeline of milestones in the history of mechanotransduction research.
Figure 3: Experimental tools in mechanobiology.

References

  1. Delbruck, M. A physicist's renewed look at biology: twenty years later. Science 168, 1312–1315 (1970).

    CAS  PubMed  Google Scholar 

  2. Lim, C. T., Bershadsky, A. & Sheetz, M. P. Mechanobiology. J. R. Soc. Interface 7, S291–S293 (2010).

    PubMed  PubMed Central  Google Scholar 

  3. Thompson, D. A. W. On Growth and Form (Cambridge University Press, 1917).

    Google Scholar 

  4. Sanford, K. K., Likely, G. D. & Earle, W. R. The development of variations in transplantability and morphology within a clone of mouse fibroblasts transformed to sarcoma-producing cells in vitro. J. Natl Cancer Inst. 15, 215–237 (1954).

    CAS  PubMed  Google Scholar 

  5. Temin, H. M. & Rubin, H. Characteristics of an assay for Rous sarcoma virus and Rous sarcoma cells in tissue culture. Virology 6, 669–688 (1958).

    CAS  PubMed  Google Scholar 

  6. Sheetz, M. P. & Singer, S. J. Biological membranes as bilayer couples. A molecular mechanism of drug-erythrocyte interactions. Proc. Natl Acad. Sci. USA 71, 4457–4461 (1974).

    CAS  PubMed  Google Scholar 

  7. Gauthier, N. C., Fardin, M. A., Roca-Cusachs, P. & Sheetz, M. P. Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading. Proc. Natl Acad. Sci. USA 108, 14467–14472 (2011).

    CAS  PubMed  Google Scholar 

  8. Curtis, A. S. The mechanism of adhesion of cells to glass. A study by interference reflection microscopy. J. Cell Biol. 20, 199–215 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Izzard, C. S. & Lochner, L. R. Cell-to-substrate contacts in living fibroblasts: an interference reflexion study with an evaluation of the technique. J. Cell Sci. 21, 129–159 (1976).

    CAS  PubMed  Google Scholar 

  10. Abercrombie, M., Heaysman, J. E. & Pegrum, S. M. The locomotion of fibroblasts in culture. IV. Electron microscopy of the leading lamella. Exp. Cell Res. 67, 359–367 (1971).

    CAS  PubMed  Google Scholar 

  11. Heath, J. P. & Dunn, G. A. Cell to substratum contacts of chick fibroblasts and their relation to the microfilament system. A correlated interference-reflexion and high-voltage electron-microscope study. J. Cell Sci. 29, 197–212 (1978).

    CAS  PubMed  Google Scholar 

  12. Luduena, M. A. & Wessells, N. K. Cell locomotion, nerve elongation, and microfilaments. Dev. Biol. 30, 427–440 (1973).

    CAS  PubMed  Google Scholar 

  13. Huxley, H. & Hanson, J. Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 173, 973–976 (1954).

    CAS  PubMed  Google Scholar 

  14. Huxley, A. F. & Niedergerke, R. Structural changes in muscle during contraction; interference microscopy of living muscle fibres. Nature 173, 971–973 (1954).

    CAS  PubMed  Google Scholar 

  15. Huxley, H. E. The mechanism of muscular contraction. Science 164, 1356–1365 (1969).

    CAS  PubMed  Google Scholar 

  16. Spudich, J. A. The myosin swinging cross-bridge model. Nature Rev. Mol. Cell Biol. 2, 387–392 (2001).

    CAS  Google Scholar 

  17. Harris, A. K., Wild, P. & Stopak, D. Silicone rubber substrata: a new wrinkle in the study of cell locomotion. Science 208, 177–179 (1980).

    CAS  PubMed  Google Scholar 

  18. Oliver, T., Dembo, M. & Jacobson, K. Traction forces in locomoting cells. Cell. Motil. Cytoskeleton 31, 225–240 (1995).

    CAS  PubMed  Google Scholar 

  19. Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).

    CAS  PubMed  Google Scholar 

  20. Wang, N., Butler, J. P. & Ingber, D. E. Mechanotransduction across the cell surface and through the cytoskeleton. Science 260, 1124–1127 (1993).

    CAS  PubMed  Google Scholar 

  21. Rief, M., Gautel, M., Oesterhelt, F., Fernandez, J. M. & Gaub, H. E. Reversible unfolding of individual titin immunoglobulin domains by AFM. Science 276, 1109–1112 (1997).

    CAS  PubMed  Google Scholar 

  22. Moy, V. T., Florin, E. L. & Gaub, H. E. Intermolecular forces and energies between ligands and receptors. Science 266, 257–259 (1994).

    CAS  PubMed  Google Scholar 

  23. Merkel, R., Nassoy, P., Leung, A., Ritchie, K. & Evans, E. Energy landscapes of receptor-ligand bonds explored with dynamic force spectroscopy. Nature 397, 50–53 (1999).

    CAS  PubMed  Google Scholar 

  24. Choquet, D., Felsenfeld, D. P. & Sheetz, M. P. Extracellular matrix rigidity causes strengthening of integrin-cytoskeleton linkages. Cell 88, 39–48 (1997).

    CAS  PubMed  Google Scholar 

  25. Pelham, R. J. Jr & Wang, Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).

    CAS  PubMed  Google Scholar 

  26. von Wichert, G. et al. RPTP-α acts as a transducer of mechanical force on αv/β3-integrin-cytoskeleton linkages. J. Cell Biol. 161, 143–153 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Galbraith, C. G. & Sheetz, M. P. A micromachined device provides a new bend on fibroblast traction forces. Proc. Natl Acad. Sci. USA 94, 9114–9118 (1997).

    CAS  PubMed  Google Scholar 

  28. Balaban, N. Q. et al. Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nature Cell Biol. 3, 466–472 (2001).

    CAS  PubMed  Google Scholar 

  29. Tan, J. L. et al. Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc. Natl Acad. Sci. USA 100, 1484–1489 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Thoumine, O. & Ott, A. Time scale dependent viscoelastic and contractile regimes in fibroblasts probed by microplate manipulation. J. Cell Sci. 110, 2109–2116 (1997).

    CAS  PubMed  Google Scholar 

  31. Micoulet, A., Spatz, J. P. & Ott, A. Mechanical response analysis and power generation by single-cell stretching. Chemphyschem 6, 663–670 (2005).

    CAS  PubMed  Google Scholar 

  32. Beil, M. et al. Sphingosylphosphorylcholine regulates keratin network architecture and visco-elastic properties of human cancer cells. Nature Cell Biol. 5, 803–811 (2003).

    CAS  PubMed  Google Scholar 

  33. Coussen, F., Choquet, D., Sheetz, M. P. & Erickson, H. P. Trimers of the fibronectin cell adhesion domain localize to actin filament bundles and undergo rearward translocation. J. Cell Sci. 115, 2581–2590 (2002).

    CAS  PubMed  Google Scholar 

  34. Sawada, Y. & Sheetz, M. P. Force transduction by Triton cytoskeletons. J. Cell Biol. 156, 609–615 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Giannone, G., Jiang, G., Sutton, D. H., Critchley, D. R. & Sheetz, M. P. Talin1 is critical for force-dependent reinforcement of initial integrin-cytoskeleton bonds but not tyrosine kinase activation. J. Cell Biol. 163, 409–419 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Galbraith, C. G., Yamada, K. M. & Sheetz, M. P. The relationship between force and focal complex development. J. Cell Biol. 159, 695–705 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Meng, F., Suchyna, T. M. & Sachs, F. A fluorescence energy transfer-based mechanical stress sensor for specific proteins in situ. FEBS J. 275, 3072–3087 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Grashoff, C. et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, Y., Yehl, K., Narui, Y. & Salaita, K. Tension sensing nanoparticles for mechano-imaging at the living/nonliving interface. J. Am. Chem. Soc. 135, 5320–5323 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Stabley, D. R., Jurchenko, C., Marshall, S. S. & Salaita, K. S. Visualizing mechanical tension across membrane receptors with a fluorescent sensor. Nature Methods 9, 64–67 (2012).

    CAS  Google Scholar 

  41. Jurchenko, C., Chang, Y., Narui, Y., Zhang, Y. & Salaita, K. S. Integrin-generated forces lead to streptavidin-biotin unbinding in cellular adhesions. Biophys. J. 106, 1436–1446 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Margadant, F. et al. Mechanotransduction in vivo by repeated talin stretch-relaxation events depends upon vinculin. PLoS Biol. 9, e1001223 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao, R., Boudou, T., Wang, W. G., Chen, C. S. & Reich, D. H. Decoupling cell and matrix mechanics in engineered microtissues using magnetically actuated microcantilevers. Adv. Mater. 25, 1699–1705 (2013).

    CAS  PubMed  Google Scholar 

  44. Rahmouni, S. et al. Hydrogel micropillars with integrin selective peptidomimetic functionalized nanopatterned tops: a new tool for the measurement of cell traction forces transmitted through αvβ3- or α5β1-integrins. Adv. Mater. 25, 5869–5874 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ghassemi, S. et al. Cells test substrate rigidity by local contractions on submicrometer pillars. Proc. Natl Acad. Sci. USA 109, 5328–5333 (2012).

    CAS  PubMed  Google Scholar 

  46. Campellone, K. G. & Welch, M. D. A nucleator arms race: cellular control of actin assembly. Nature Rev. Mol. Cell Biol. 11, 237–251 (2010).

    CAS  Google Scholar 

  47. Iskratsch, T. et al. FHOD1 is needed for directed forces and adhesion maturation during cell spreading and migration. Dev. Cell 27, 545–559 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yu, C. H., Law, J. B., Suryana, M., Low, H. Y. & Sheetz, M. P. Early integrin binding to Arg-Gly-Asp peptide activates actin polymerization and contractile movement that stimulates outward translocation. Proc. Natl Acad. Sci. USA 108, 20585–20590 (2011).

    CAS  PubMed  Google Scholar 

  49. Riveline, D. et al. Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an Mdia1-dependent and ROCK-independent mechanism. J. Cell Biol. 153, 1175–1186 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hotulainen, P. & Lappalainen, P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J. Cell Biol. 173, 383–394 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Schulze, N. et al. FHOD1 regulates stress fiber organization by controlling the dynamics of transverse arcs and dorsal fibers. J. Cell Sci. 127, 1379–1393 (2014).

    CAS  PubMed  Google Scholar 

  52. Hayakawa, K., Sato, N. & Obinata, T. Dynamic reorientation of cultured cells and stress fibers under mechanical stress from periodic stretching. Exp. Cell Res. 268, 104–114 (2001).

    CAS  PubMed  Google Scholar 

  53. Kozlov, M. M. & Bershadsky, A. D. Processive capping by formin suggests a force-driven mechanism of actin polymerization. J. Cell Biol. 167, 1011–1017 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Courtemanche, N., Lee, J. Y., Pollard, T. D. & Greene, E. C. Tension modulates actin filament polymerization mediated by formin and profilin. Proc. Natl Acad. Sci. USA 110, 9752–9757 (2013).

    CAS  PubMed  Google Scholar 

  55. Jegou, A., Carlier, M. F. & Romet-Lemonne, G. Formin mDia1 senses and generates mechanical forces on actin filaments. Nature Commun. 4, 1883 (2013).

    Google Scholar 

  56. Lazarides, E. & Burridge, K. α-actinin: immunofluorescent localization of a muscle structural protein in nonmuscle cells. Cell 6, 289–298 (1975).

    CAS  PubMed  Google Scholar 

  57. Burridge, K. & Connell, L. Talin: a cytoskeletal component concentrated in adhesion plaques and other sites of actin-membrane interaction. Cell. Motil. 3, 405–417 (1983).

    CAS  PubMed  Google Scholar 

  58. Hu, K., Ji, L., Applegate, K. T., Danuser, G. & Waterman-Storer, C. M. Differential transmission of actin motion within focal adhesions. Science 315, 111–115 (2007).

    CAS  PubMed  Google Scholar 

  59. Wang, Y. L. Flux at focal adhesions: slippage clutch, mechanical gauge, or signal depot. Sci. STKE 2007, e10 (2007).

    Google Scholar 

  60. Aratyn-Schaus, Y. & Gardel, M. L. Transient frictional slip between integrin and the ECM in focal adhesions under myosin II tension. Curr. Biol. 20, 1145–1153 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009).

    CAS  PubMed  Google Scholar 

  62. Kiema, T. et al. The molecular basis of filamin binding to integrins and competition with talin. Mol. Cell 21, 337–347 (2006).

    CAS  PubMed  Google Scholar 

  63. Nieves, B. et al. The NPIY motif in the integrin β1 tail dictates the requirement for talin-1 in outside-in signaling. J. Cell Sci. 123, 1216–1226 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Roca-Cusachs, P. et al. Integrin-dependent force transmission to the extracellular matrix by α-actinin triggers adhesion maturation. Proc. Natl Acad. Sci. USA 110, E1361–E1370 (2013).

    CAS  PubMed  Google Scholar 

  65. Roca-Cusachs, P., Iskratsch, T. & Sheetz, M. P. Finding the weakest link: exploring integrin-mediated mechanical molecular pathways. J. Cell Sci. 125, 3025–3038 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Lynch, C. D., Lazar, A. M., Iskratsch, T., Zhang, X. & Sheetz, M. P. Endoplasmic spreading requires coalescence of vimentin intermediate filaments at force-bearing adhesions. Mol. Biol. Cell 24, 21–30 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Ithychanda, S. S. & Qin, J. Evidence for multisite ligand binding and stretching of filamin by integrin and migfilin. Biochemistry 50, 4229–4231 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Rognoni, L., Stigler, J., Pelz, B., Ylanne, J. & Rief, M. Dynamic force sensing of filamin revealed in single-molecule experiments. Proc. Natl Acad. Sci. USA 109, 19679–19684 (2012).

    CAS  PubMed  Google Scholar 

  69. Xu, Y. et al. Filamin A regulates focal adhesion disassembly and suppresses breast cancer cell migration and invasion. J. Exp. Med. 207, 2421–2437 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lochter, A. & Bissell, M. J. Involvement of extracellular matrix constituents in breast cancer. Semin. Cancer Biol. 6, 165–173 (1995).

    CAS  PubMed  Google Scholar 

  71. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    CAS  PubMed  Google Scholar 

  72. Jiang, G., Huang, A. H., Cai, Y., Tanase, M. & Sheetz, M. P. Rigidity sensing at the leading edge through αvβ3 integrins and RPTPα. Biophys. J. 90, 1804–1809 (2006).

    CAS  PubMed  Google Scholar 

  73. Giannone, G. et al. Periodic lamellipodial contractions correlate with rearward actin waves. Cell 116, 431–443 (2004).

    CAS  PubMed  Google Scholar 

  74. Dubin-Thaler, B. J. et al. Quantification of cell edge velocities and traction forces reveals distinct motility modules during cell spreading. PLoS ONE 3, e3735 (2008).

    PubMed  PubMed Central  Google Scholar 

  75. Prager-Khoutorsky, M. et al. Fibroblast polarization is a matrix-rigidity-dependent process controlled by focal adhesion mechanosensing. Nature Cell Biol. 13, 1457–1465 (2011).

    CAS  PubMed  Google Scholar 

  76. Plotnikov, S. V., Pasapera, A. M., Sabass, B. & Waterman, C. M. Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration. Cell 151, 1513–1527 (2012).

    CAS  PubMed  Google Scholar 

  77. Bruinsma, R. Theory of force regulation by nascent adhesion sites. Biophys. J. 89, 87–94 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Schwarz, U. S. et al. Calculation of forces at focal adhesions from elastic substrate data: the effect of localized force and the need for regularization. Biophys. J. 83, 1380–1394 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Shemesh, T., Geiger, B., Bershadsky, A. D. & Kozlov, M. M. Focal adhesions as mechanosensors: a physical mechanism. Proc. Natl Acad. Sci. USA 102, 12383–12388 (2005).

    CAS  PubMed  Google Scholar 

  80. Nicolas, A. & Safran, S. A. Limitation of cell adhesion by the elasticity of the extracellular matrix. Biophys. J. 91, 61–73 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Chan, C. E. & Odde, D. J. Traction dynamics of filopodia on compliant substrates. Science 322, 1687–1691 (2008).

    CAS  PubMed  Google Scholar 

  82. De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nature Rev. Cancer 13, 97–110 (2013).

    CAS  Google Scholar 

  83. Zaidel-Bar, R. & Geiger, B. The switchable integrin adhesome. J. Cell Sci. 123, 1385–1388 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hill, A. V. The heat of shortening and the dynamic constants of muscle. Proc. Biol. Sci. 126, 136–195 (1938).

    Google Scholar 

  85. Trinick, J., Knight, P. & Whiting, A. Purification and properties of native titin. J. Mol. Biol. 180, 331–356 (1984).

    CAS  PubMed  Google Scholar 

  86. Lange, S. et al. The kinase domain of titin controls muscle gene expression and protein turnover. Science 308, 1599–1603 (2005).

    CAS  PubMed  Google Scholar 

  87. Puchner, E. M. et al. Mechanoenzymatics of titin kinase. Proc. Natl Acad. Sci. USA 105, 13385–13390 (2008).

    CAS  PubMed  Google Scholar 

  88. Knoll, R. et al. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111, 943–955 (2002).

    CAS  PubMed  Google Scholar 

  89. Samarel, A. M. Costameres, focal adhesions, and cardiomyocyte mechanotransduction. Am. J. Physiol. Heart Circ. Physiol. 289, H2291–H2301 (2005).

    CAS  PubMed  Google Scholar 

  90. Buckley, M. J. et al. Osteoblasts increase their rate of division and align in response to cyclic, mechanical tension in vitro. Bone Miner. 4, 225–236 (1988).

    CAS  PubMed  Google Scholar 

  91. Neidlinger-Wilke, C., Wilke, H. J. & Claes, L. Cyclic stretching of human osteoblasts affects proliferation and metabolism: a new experimental method and its application. J. Orthop. Res. 12, 70–78 (1994).

    CAS  PubMed  Google Scholar 

  92. Carisey, A. et al. Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner. Curr. Biol. 23, 271–281 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Jungbauer, S., Gao, H., Spatz, J. P. & Kemkemer, R. Two characteristic regimes in frequency-dependent dynamic reorientation of fibroblasts on cyclically stretched substrates. Biophys. J. 95, 3470–3478 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Goldyn, A. M., Rioja, B. A., Spatz, J. P., Ballestrem, C. & Kemkemer, R. Force-induced cell polarisation is linked to RhoA-driven microtubule-independent focal-adhesion sliding. J. Cell Sci. 122, 3644–3651 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, W. F., Nelson, C. M., Tan, J. L. & Chen, C. S. Cadherins, RhoA, and Rac1 are differentially required for stretch-mediated proliferation in endothelial versus smooth muscle cells. Circ. Res. 101, e44–e52 (2007).

    CAS  PubMed  Google Scholar 

  96. Kaunas, R., Nguyen, P., Usami, S. & Chien, S. Cooperative effects of Rho and mechanical stretch on stress fiber organization. Proc. Natl Acad. Sci. USA 102, 15895–15900 (2005).

    CAS  PubMed  Google Scholar 

  97. Brown, A. C., Fiore, V. F., Sulchek, T. A. & Barker, T. H. Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions. J. Pathol. 229, 25–35 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. O'Connor, J. W. & Gomez, E. W. Cell adhesion and shape regulate TGF-β1-induced epithelial-myofibroblast transition via MRTF-A signaling. PLoS ONE 8, e83188 (2013).

    PubMed  PubMed Central  Google Scholar 

  99. Baarlink, C., Wang, H. & Grosse, R. Nuclear actin network assembly by formins regulates the SRF coactivator MAL. Science 340, 864–867 (2013).

    CAS  PubMed  Google Scholar 

  100. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    CAS  PubMed  Google Scholar 

  101. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    CAS  PubMed  Google Scholar 

  102. Nelson, C. M. & Bissell, M. J. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 22, 287–309 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Puklin-Faucher, E. & Sheetz, M. P. The mechanical integrin cycle. J. Cell Sci. 122, 179–186 (2009).

    CAS  PubMed  Google Scholar 

  104. Arias-Salgado, E. G. et al. Src kinase activation by direct interaction with the integrin β cytoplasmic domain. Proc. Natl Acad. Sci. USA 100, 13298–13302 (2003).

    CAS  PubMed  Google Scholar 

  105. Chang, F., Lemmon, C. A., Park, D. & Romer, L. H. FAK potentiates Rac1 activation and localization to matrix adhesion sites: a role for βPIX. Mol. Biol. Cell 18, 253–264 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Miki, H., Yamaguchi, H., Suetsugu, S. & Takenawa, T. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408, 732–735 (2000).

    CAS  PubMed  Google Scholar 

  107. Berrier, A. L., Martinez, R., Bokoch, G. M. & LaFlamme, S. E. The integrin β tail is required and sufficient to regulate adhesion signaling to Rac1. J. Cell Sci. 115, 4285–4291 (2002).

    CAS  PubMed  Google Scholar 

  108. Kostic, A. & Sheetz, M. P. Fibronectin rigidity response through Fyn and p130Cas recruitment to the leading edge. Mol. Biol. Cell 17, 2684–2695 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Giannone, G. & Sheetz, M. P. Substrate rigidity and force define form through tyrosine phosphatase and kinase pathways. Trends Cell Biol. 16, 213–223 (2006).

    CAS  PubMed  Google Scholar 

  110. Cai, Y. et al. Cytoskeletal coherence requires myosin-IIA contractility. J. Cell Sci. 123, 413–423 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kolega, J. Effects of mechanical tension on protrusive activity and microfilament and intermediate filament organization in an epidermal epithelium moving in culture. J. Cell Biol. 102, 1400–1411 (1986).

    CAS  PubMed  Google Scholar 

  112. Singhvi, R. et al. Engineering cell shape and function. Science 264, 696–698 (1994).

    CAS  PubMed  Google Scholar 

  113. Sawada, Y. et al. Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell 127, 1015–1026 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

    CAS  PubMed  Google Scholar 

  115. Schiller, H. B., Friedel, C. C., Boulegue, C. & Fassler, R. Quantitative proteomics of the integrin adhesome show a myosin II-dependent recruitment of LIM domain proteins. EMBO Rep. 12, 259–266 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Knowlton, F. P. & Starling, E. H. The influence of variations in temperature and blood-pressure on the performance of the isolated mammalian heart. J. Physiol. 44, 206–219 (1912).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Markwalder, J. & Starling, E. H. On the constancy of the systolic output under varying conditions. J. Physiol. 48, 348–356 (1914).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Patterson, S. W. & Starling, E. H. On the mechanical factors which determine the output of the ventricles. J. Physiol. 48, 357–379 (1914).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Patterson, S. W., Piper, H. & Starling, E. H. The regulation of the heart beat. J. Physiol. 48, 465–513 (1914).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Olesen, S. P., Clapham, D. E. & Davies, P. F. Haemodynamic shear stress activates a K+ current in vascular endothelial cells. Nature 331, 168–170 (1988).

    CAS  PubMed  Google Scholar 

  121. Hynes, R. O. The emergence of integrins: a personal and historical perspective. Matrix Biol. 23, 333–340 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Franck, C., Hong, S., Maskarinec, S., Tirrell, D. & Ravichandran, G. Three-dimensional full-field measurements of large deformations in soft materials using confocal microscopy and digital volume correlation. Exp. Mechan. 47, 427–438 (2007).

    Google Scholar 

Download references

Acknowledgements

T.I. was supported by a Postdoctoral Fellowship from the American Heart Association. H.W. was supported by a Marie Curie International Outgoing Fellowship within the Seventh European Commission Framework Programme (PIOF-GA-2012-332045). M.P.S. was partially supported by the Mechanobiology Institute, National University of Singapore.

Author information

Author notes

  1. Thomas Iskratsch and Haguy Wolfenson: T.I. and H.W. contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, 10027, New York, USA

    Thomas Iskratsch & Haguy Wolfenson

  2. and the Department of Biological Sciences, Mechanobiology Institute, National University of Singapore, Singapore 117411, Columbia University, New York 10027, USA.,

    Michael P. Sheetz

Authors
  1. Thomas Iskratsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haguy Wolfenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael P. Sheetz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael P. Sheetz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Actomyosin

A basic force-producing or structural unit in cells consisting of myosin motors that bind and pull on actin filaments.

Adhesome

The combined molecular composition of focal adhesions.

Dorsal stress fibres

Long parallel actomyosin bundles that are anchored to focal adhesions at one end.

Finite element analysis

A numerical method of approximation.

Frank–Starling mechanism

Also known as the Frank–Starling law of the heart; states that there is a direct relationship between the force of cardiac contraction and the volume of blood filling the heart. The stretching of muscle fibres through the increasing blood volume increases calcium sensitivity, thus causing the formation of more actin–myosin crossbridges and hence more force.

Isotropic spreading

Spreading of cells during which their entire edge (or large parts of it) extends rapidly.

Ligand valency

The combined effects of the binding of multiple ligands.

Local contraction units

Multiprotein complexes that are similar to muscle sarcomeres and are used by cells to measure substrate rigidity.

Microcontact printing

Also known as micropatterning. A form of surface patterning, usually with fluorescent-labelled extracellular matrix proteins.

Optical trap

Also known as laser tweezers. An appliance that provides force from a highly focused laser beam to hold or move objects such as microspheres.

Sliding filament theory

A model of muscle contraction postulating that thin filament (mostly actin)-containing I-bands slide past the myosin-containing A-bands to generate force.

Swinging crossbridge model

The first model of the myosin power stroke, which suggests that ATP-dependent changes in the actin–myosin crossbridge angle would cause the thin filaments to slide past the myosin (see sliding filament theory).

Transverse arcs

Curved, antiparallel actomyosin bundles that interact with dorsal stress fibres and flow inward towards the cell centre.

Ventral stress fibres

Antiparallel actomyosin bundles anchored to focal adhesions at both ends.

Z-disc

A protein complex that defines the boundaries of the muscle sarcomere. It anchors and links actin filaments and titin from adjacent sarcomeres, provides mechanical stability and is a centre of cardiomyocyte signal transduction, including mechanotransduction.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iskratsch, T., Wolfenson, H. & Sheetz, M. Appreciating force and shape — the rise of mechanotransduction in cell biology. Nat Rev Mol Cell Biol 15, 825–833 (2014). https://doi.org/10.1038/nrm3903

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3903

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing