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.

Integration of actin dynamics and cell adhesion by a three-dimensional, mechanosensitive molecular clutch

Abstract

During cell migration, the forces generated in the actin cytoskeleton are transmitted across transmembrane receptors to the extracellular matrix or other cells through a series of mechanosensitive, regulable protein–protein interactions termed the molecular clutch. In integrin-based focal adhesions, the proteins forming this linkage are organized into a conserved three-dimensional nano-architecture. Here we discuss how the physical interactions between the actin cytoskeleton and focal-adhesion-associated molecules mediate force transmission from the molecular clutch to the extracellular matrix.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The molecular clutch hypothesis.
Figure 2: Nano-scale architecture of the focal adhesion clutch.
Figure 3: Molecular clutches may mediate diverse cell adhesive interactions.

References

  1. Friedl, P. Prespecification and plasticity: shifting mechanisms of cell migration. Curr. Opin. Cell Biol. 16, 14–23 (2004).

    CAS  PubMed  Google Scholar 

  2. Paluch, E. K. & Raz, E. The role and regulation of blebs in cell migration. Curr. Opin. Cell Biol. 25, 582–590 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Stroka, K. M. et al. Water permeation drives tumor cell migration in confined microenvironments. Cell 157, 611–623 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Renkawitz, J. et al. Adaptive force transmission in amoeboid cell migration. Nat. Cell Biol. 11, 1438–1443 (2009).

    CAS  PubMed  Google Scholar 

  5. Petrie, R. J., Koo, H. & Yamada, K. M. Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science 345, 1062–1065 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pollard, T. D. & Cooper, J. A. Actin, a central player in cell shape and movement. Science 326, 1208–1212 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu, Y-J. et al. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells. Cell 160, 659–672 (2015).

    CAS  PubMed  Google Scholar 

  8. Ruprecht, V. et al. Cortical contractility triggers a stochastic switch to fast amoeboid cell motility. Cell 160, 673–685 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Petrie, R. J., Doyle, A. D. & Yamada, K. M. Random versus directionally persistent cell migration. Nat. Rev. Mol. Cell Biol. 10, 538–549 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, Y. L. Exchange of actin subunits at the leading edge of living fibroblasts: possible role of treadmilling. J. Cell Biol. 101, 597–602 (1985).

    CAS  PubMed  Google Scholar 

  11. Theriot, J. A. & Mitchison, T. J. Actin microfilament dynamics in locomoting cells. Nature 352, 126–131 (1991).

    CAS  PubMed  Google Scholar 

  12. Mogilner, A. & Oster, G. Cell motility driven by actin polymerization. Biophys. J. 71, 3030–3045 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lin, C. H. & Forscher, P. Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron 14, 763–771 (1995).

    CAS  PubMed  Google Scholar 

  14. Mitchison, T. & Kirschner, M. Cytoskeletal dynamics and nerve growth. Neuron 1, 761–772 (1988).

    CAS  PubMed  Google Scholar 

  15. Marjoram, R. J., Lessey, E. C. & Burridge, K. Regulation of RhoA activity by adhesion molecules and mechanotransduction. Curr. Mol. Med. 14, 199–208 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rose, D. M., Alon, R. & Ginsberg, M. H. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol. Rev. 218, 126–134 (2007).

    CAS  PubMed  Google Scholar 

  17. Dunn, G. A. & Jones, G. E. Cell motility under the microscope: Vorsprung durch Technik. Nat. Rev. Mol. Cell Biol. 5, 667–672 (2004).

    CAS  PubMed  Google Scholar 

  18. Abercrombie, M. The bases of the locomotory behaviour of fibroblasts. Exp. Cell Res. 8, 188–198 (1961).

    PubMed  Google Scholar 

  19. Abercrombie, M., Heaysman, J. E. M. & Pegrum, S. M. The locomotion of fibroblasts in culture: I. Movements of the leading edge. Exp. Cell Res. 59, 393–398 (1970).

    CAS  PubMed  Google Scholar 

  20. Abercrombie, M., Heaysman, J. E. M. & Pegrum, S. M. The locomotion of fibroblasts in culture: III. Movements of particles on the dorsal surface of the leading lamella. Exp. Cell Res. 62, 389–398 (1970).

    CAS  PubMed  Google Scholar 

  21. Harris, A. & Dunn, G. Centripetal transport of attached particles on both surfaces of moving fibroblasts. Exp. Cell Res. 73, 519–523 (1972).

    CAS  PubMed  Google Scholar 

  22. Harris, A. K. Cell surface movements related to cell locomotion. Ciba Found. Symp. 14, 3–26 (1973).

    CAS  PubMed  Google Scholar 

  23. Abercrombie, M., Heaysman, J. E. M. & 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 

  24. Small, J. V., Isenberg, G. & Celis, J. E. Polarity of actin at the leading edge of cultured cells. Nature 272, 638–639 (1978).

    CAS  PubMed  Google Scholar 

  25. Forscher, P. Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J. Cell Biol. 107, 1505–1516 (1988).

    CAS  PubMed  Google Scholar 

  26. Lee, J., Ishihara, A., Theriot, J. A. & Jacobson, K. Principles of locomotion for simple-shaped cells. Nature 362, 167–171 (1993).

    CAS  PubMed  Google Scholar 

  27. Henson, J. H. et al. Two components of actin-based retrograde flow in sea urchin coelomocytes. Mol. Biol. Cell 10, 4075–4090 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Ponti, A., Machacek, M., Gupton, S. L., Waterman-Storer, C. M. & Danuser, G. Two distinct actin networks drive the protrusion of migrating cells. Science 305, 1782–1786 (2004).

    CAS  PubMed  Google Scholar 

  29. Cramer, L. P. Molecular mechanism of actin-dependent retrograde flow in lamellipodia of motile cells. Front. Biosci. 2, 260–70 (1997).

    Google Scholar 

  30. Cortese, J. D., Schwab, B., Frieden, C. & Elson, E. L. Actin polymerization induces a shape change in actin-containing vesicles. Proc. Natl Acad. Sci. USA 86, 5773–5777 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Alberts, J. B. & Odell, G. M. In silico reconstitution of Listeria propulsion exhibits nano-saltation. PLoS Biol. 2, e412 (2004).

    PubMed  PubMed Central  Google Scholar 

  32. Iwasa, J. H. & Mullins, R. D. Spatial and temporal relationships between actin-filament nucleation, capping, and disassembly. Curr. Biol. 17, 395–406 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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 

  34. Small, J. V. V, Rottner, K., Kaverina, I. & Anderson, K. I. I. Assembling an actin cytoskeleton for cell attachment and movement. Biochim. Biophys. Acta 1404, 271–281 (1998).

    CAS  PubMed  Google Scholar 

  35. Kovac, B., Teo, J. L., Mäkelä, T. P. & Vallenius, T. Assembly of non-contractile dorsal stress fibers requires α-actinin-1 and Rac1 in migrating and spreading cells. J. Cell Sci. 126, 263–73 (2013).

    CAS  PubMed  Google Scholar 

  36. Verkhovsky, A. B., Svitkina, T. M. & Borisy, G. G. Myosin II filament assemblies in the active lamella of fibroblasts: their morphogenesis and role in the formation of actin filament bundles. J. Cell Biol. 131, 989–1002 (1995).

    CAS  PubMed  Google Scholar 

  37. Wilson, C. A. et al. Myosin II contributes to cell-scale actin network treadmilling through network disassembly. Nature 465, 373–377 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Waterman-Storer, C. M. & Salmon, E. D. Actomyosin-based retrograde flow of microtubules in the lamella of migrating epithelial cells influences microtubule dynamic instability and turnover and is associated with microtubule breakage and treadmilling. J. Cell Biol. 139, 417–434 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gardel, M. L. et al. Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed. J. Cell Biol. 183, 999–1005 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Medeiros, N. A., Burnette, D. T. & Forscher, P. Myosin II functions in actin-bundle turnover in neuronal growth cones. Nat. Cell Biol. 8, 215–226 (2006).

    CAS  PubMed  Google Scholar 

  41. Jurado, C., Haserick, J. R. & Lee, J. Slipping or gripping? Fluorescent speckle microscopy in fish keratocytes reveals two different mechanisms for generating a retrograde flow of actin. Mol. Biol. Cell 16, 507–518 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vallotton, P., Danuser, G., Bohnet, S., Meister, J.-J. & Verkhovsky, A. B. Tracking retrograde flow in keratocytes: news from the front. Mol. Biol. Cell 16, 1223–1231 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Del Alamo, J. C. et al. Spatio-temporal analysis of eukaryotic cell motility by improved force cytometry. Proc. Natl Acad. Sci. USA 104, 13343–13348 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hynes, R. O. & Destree, A. T. Relationships between fibronectin (LETS protein) and actin. Cell 15, 875–886 (1978).

    CAS  PubMed  Google Scholar 

  45. Singer, I. I. The fibronexus: a transmembrane association of fibronectin-containing fibers and bundles of 5 nm microfilaments in hamster and human fibroblasts. Cell 16, 675–685 (1979).

    CAS  PubMed  Google Scholar 

  46. Singer, I. I. Association of fibronectin and vinculin with focal contacts and stress fibers in stationary hamster fibroblasts. J. Cell Biol. 92, 398–408 (1982).

    CAS  PubMed  Google Scholar 

  47. Tamkun, J. W. et al. Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin. Cell 46, 271–282 (1986).

    CAS  PubMed  Google Scholar 

  48. Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    CAS  PubMed  Google Scholar 

  49. Takagi, J., Erickson, H. P. & Springer, T. A. C-terminal opening mimics “inside-out” activation of integrin α5β1 . Nat. Struct. Biol. 8, 412–416 (2001).

    CAS  PubMed  Google Scholar 

  50. Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599–611 (2002).

    CAS  PubMed  Google Scholar 

  51. Calderwood, D. A. et al. The talin head domain binds to integrin subunit cytoplasmic tails and regulates integrin activation. J. Biol. Chem. 274, 28071–28074 (1999).

    CAS  PubMed  Google Scholar 

  52. Otey, C. A., Pavalko, F. M. & Burridge, K. An interaction between α-actinin and the β1 integrin subunit in vitro. J. Cell Biol. 111, 721–729 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Harburger, D. S., Bouaouina, M. & Calderwood, D. A. Kindlin-1 and -2 directly bind the C-terminal region of β integrin cytoplasmic tails and exert integrin-specific activation effects. J. Biol. Chem. 284, 11485–11497 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Calderwood, D. A. et al. Integrin β cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc. Natl Acad. Sci. USA 100, 2272–2277 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Legate, K. R. & Fässler, R. Mechanisms that regulate adaptor binding to β-integrin cytoplasmic tails. J. Cell Sci. 122, 187–198 (2009).

    CAS  PubMed  Google Scholar 

  56. Morse, E. M., Brahme, N. N. & Calderwood, D. A. Integrin cytoplasmic tail interactions. Biochemistry 53, 810–820 (2014).

    CAS  PubMed  Google Scholar 

  57. Zaidel-Bar, R., Itzkovitz, S., Ma'ayan, A., Iyengar, R. & Geiger, B. Functional atlas of the integrin adhesome. Nat. Cell Biol. 9, 858–867 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Han, X., Hsiao, C-T. T., Yates Iii, J. R. & Waterman, C. M. Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nat. Cell Biol. 13, 383–393 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. Byron, A., Humphries, J. D., Bass, M. D., Knight, D. & Humphries, M. J. Proteomic analysis of integrin adhesion complexes. Sci. Signal. 4, 2 (2011).

    Google Scholar 

  60. Schiller, H. B., Friedel, C. C., Boulegue, C. & Fässler, 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 

  61. Zaidel-Bar, R., Ballestrem, C., Kam, Z. & Geiger, B. Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J. Cell Sci. 116, 4605–4613 (2003).

    CAS  PubMed  Google Scholar 

  62. Choi, C. K. et al. Actin and α-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner. Nat. Cell Biol. 10, 1039–1050 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lawson, C. et al. FAK promotes recruitment of talin to nascent adhesions to control cell motility. J. Cell Biol. 196, 223–232 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Oakes, P. W., Beckham, Y., Stricker, J. & Gardel, M. L. Tension is required but not sufficient for focal adhesion maturation without a stress fiber template. J. Cell Biol. 196, 363–374 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Shroff, H. et al. Dual-color superresolution imaging of genetically expressed probes within individual adhesion complexes. Proc. Natl Acad. Sci. USA 104, 20308–20313 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Shtengel, G. et al. Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure. Proc. Natl Acad. Sci. USA 106, 3125–3130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kanchanawong, P. et al. Nanoscale architecture of integrin-based cell adhesions. Nature 468, 580–584 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Paszek, M. J. et al. Scanning angle interference microscopy reveals cell dynamics at the nanoscale. Nat. Methods 9, 825–827 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Case, L. B. et al. Molecular mechanism of vinculin activation and nanoscale spatial organization in focal adhesions. Nat. Cell Biol. 17, 880–892 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Critchley, D. R. Biochemical and structural properties of the integrin-associated cytoskeletal protein talin. Annu. Rev. Biophys. 38, 235–254 (2009).

    CAS  PubMed  Google Scholar 

  71. Horwitz, A., Duggan, K., Buck, C., Beckerle, M. C. & Burridge, K. Interaction of plasma membrane fibronectin receptor with talin — a transmembrane linkage. Nature 320, 531–533 (1986).

    CAS  PubMed  Google Scholar 

  72. Goldmann, W. H. et al. Examining F-actin interaction with intact talin and talin head and tail fragment using static and dynamic light scattering. Eur. J. Biochem. 250, 447–450 (1997).

    CAS  PubMed  Google Scholar 

  73. Wolfenson, H. et al. A role for the juxtamembrane cytoplasm in the molecular dynamics of focal adhesions. PLoS One 4, e4304 (2009).

    PubMed  PubMed Central  Google Scholar 

  74. Zamir, E. et al. Molecular diversity of cell-matrix adhesions. J. Cell Sci. 112, 1655–1669 (1999).

    CAS  PubMed  Google Scholar 

  75. Zaidel-Bar, R., Milo, R., Kam, Z. & Geiger, B. A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell-matrix adhesions. J. Cell Sci. 120, 137–148 (2007).

    CAS  PubMed  Google Scholar 

  76. 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 

  77. Shibata, A. C. E. et al. Archipelago architecture of the focal adhesion: membrane molecules freely enter and exit from the focal adhesion zone. Cytoskeleton 69, 380–392 (2012).

    CAS  PubMed  Google Scholar 

  78. Rossier, O. et al. Integrins β1 and β3 exhibit distinct dynamic nanoscale organizations inside focal adhesions. Nat. Cell Biol. 14, 1057–1067 (2012).

    CAS  PubMed  Google Scholar 

  79. Von Wichert, G., Haimovich, B., Feng, G-S. & Sheetz, M. P. Force-dependent integrin-cytoskeleton linkage formation requires downregulation of focal complex dynamics by Shp2. EMBO J. 22, 5023–5035 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lele, T. P., Thodeti, C. K., Pendse, J. & Ingber, D. E. Investigating complexity of protein-protein interactions in focal adhesions. Biochem. Biophys. Res. Commun. 369, 929–934 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lavelin, I. et al. Differential effect of actomyosin relaxation on the dynamic properties of focal adhesion proteins. PLoS One 8, e73549 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Bachir, A. I. et al. Integrin-associated complexes form hierarchically with variable stoichiometry in ascent adhesions. Curr. Biol. 24, 1845–1853 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hoffmann, J.-E., Fermin, Y., Stricker, R. L., Ickstadt, K. & Zamir, E. Symmetric exchange of multi-protein building blocks between stationary focal adhesions and the cytosol. eLife 3, e02257 (2014).

    PubMed  PubMed Central  Google Scholar 

  84. Shemesh, T., Verkhovsky, A. B., Svitkina, T. M., Bershadsky, A. D. & Kozlov, M. M. Role of focal adhesions and mechanical stresses in the formation and progression of the lamellipodium-lamellum interface [corrected]. Biophys. J. 97, 1254–1264 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  86. Alexandrova, A. Y. et al. Comparative dynamics of retrograde actin flow and focal adhesions: formation of nascent adhesions triggers transition from fast to slow flow. PLoS One 3, e3234 (2008).

    PubMed  PubMed Central  Google Scholar 

  87. Gupton, S. L. & Waterman-Storer, C. M. Spatiotemporal feedback between actomyosin and focal-adhesion systems optimizes rapid cell migration. Cell 125, 1361–1374 (2006).

    CAS  PubMed  Google Scholar 

  88. Chrzanowska-Wodnicka, M. & Burridge, K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133, 1403–1415 (1996).

    CAS  PubMed  Google Scholar 

  89. Webb, D. J. et al. FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat. Cell Biol. 6, 154–161 (2004).

    CAS  PubMed  Google Scholar 

  90. Zhu, J. et al. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol. Cell 32, 849–861 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Tanentzapf, G. & Brown, N. H. An interaction between integrin and the talin FERM domain mediates integrin activation but not linkage to the cytoskeleton. Nat. Cell Biol. 8, 601–606 (2006).

    CAS  PubMed  Google Scholar 

  92. O'Toole, T. E. et al. Integrin cytoplasmic domains mediate inside-out signal transduction. J. Cell Biol. 124, 1047–1059 (1994).

    CAS  PubMed  Google Scholar 

  93. Anthis, N. J. et al. The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J. 28, 3623–3632 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Huttenlocher, A., Ginsberg, M. H. & Horwitz, A. F. Modulation of cell migration by integrin-mediated cytoskeletal linkages and ligand-binding affinity. J Cell Biol 134, 1551–1562 (1996).

    CAS  PubMed  Google Scholar 

  95. Chigaev, A., Buranda, T., Dwyer, D. C., Prossnitz, E. R. & Sklar, L. A. FRET detection of cellular α4-integrin conformational activation. Biophys. J. 85, 3951–3962 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kim, M., Carman, C. V & Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301, 1720–1725 (2003).

    CAS  PubMed  Google Scholar 

  97. Wu, C. et al. Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis. Cell 148, 973–987 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Beckham, Y. et al. Arp2/3 inhibition induces amoeboid-like protrusions in MCF10A epithelial cells by reduced cytoskeletal-membrane coupling and focal adhesion assembly. PLoS One 9, e100943 (2014).

    PubMed  PubMed Central  Google Scholar 

  99. DeMali, K. A., Barlow, C. A. & Burridge, K. Recruitment of the Arp2/3 complex to vinculin: coupling membrane protrusion to matrix adhesion. J. Cell Biol. 159, 881–891 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Serrels, B. et al. Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex. Nat. Cell Biol. 9, 1046–1056 (2007).

    CAS  PubMed  Google Scholar 

  101. Laukaitis, C. M., Webb, D. J., Donais, K. & Horwitz, A. F. Differential dynamics of α5 integrin, paxillin, and α-actinin during formation and disassembly of adhesions in migrating cells. J. Cell Biol. 153, 1427–1440 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Vicente-Manzanares, M., Zareno, J., Whitmore, L., Choi, C. K. & Horwitz, A. F. Regulation of protrusion, adhesion dynamics, and polarity by myosins IIA and IIB in migrating cells. J. Cell Biol. 176, 573–580 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Thievessen, I. et al. Vinculin-actin interaction couples actin retrograde flow to focal adhesions, but is dispensable for focal adhesion growth. J. Cell Biol. 202, 163–177 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 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 

  105. 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 

  106. Helfman, D. M. et al. Caldesmon inhibits nonmuscle cell contractility and interferes with the formation of focal adhesions. Mol. Biol. Cell 10, 3097–3112 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 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  PubMed Central  Google Scholar 

  108. 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 

  109. 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 

  110. Gupton, S. L., Eisenmann, K., Alberts, A. S. & Waterman-Storer, C. M. mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration. J. Cell Sci. 120, 3475–3587 (2007).

    CAS  PubMed  Google Scholar 

  111. 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 

  112. 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 

  113. 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 

  114. Morimatsu, M., Mekhdjian, A. H., Adhikari, A. S. & Dunn, A. R. Molecular tension sensors report forces generated by single integrin molecules in living cells. Nano Lett. 13, 3985–3989 (2013).

    CAS  PubMed  Google Scholar 

  115. Wang, X. & Ha, T. Defining single molecular forces required to activate integrin and notch signaling. Science 340, 991–994 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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 

  117. 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 

  118. Kong, F., García, A. J., Mould, A. P., Humphries, M. J. & Zhu, C. Demonstration of catch bonds between an integrin and its ligand. J. Cell Biol. 185, 1275–1284 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Jiang, G., Giannone, G., Critchley, D. R., Fukumoto, E. & Sheetz, M. P. Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature 424, 334–337 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  121. Yao, M. et al. Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Sci. Rep. 4, 4610 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. 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 

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

    PubMed  Google Scholar 

  124. 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 

  125. Sabass, B., Gardel, M. L., Waterman, C. M. & Schwarz, U. S. High resolution traction force microscopy based on experimental and computational advances. Biophys. J. 94, 207–220 (2008).

    CAS  PubMed  Google Scholar 

  126. Brown, C. M. et al. Probing the integrin-actin linkage using high-resolution protein velocity mapping. J. Cell Sci. 119, 5204–5214 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  128. Shemesh, T., Bershadsky, A. D. & Kozlov, M. M. Physical model for self-organization of actin cytoskeleton and adhesion complexes at the cell front. Biophys. J. 102, 1746–1756 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 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 

  130. Zhang, X. et al. Talin depletion reveals independence of initial cell spreading from integrin activation and traction. Nat. Cell Biol. 10, 1062–1068 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Chen, H., Choudhury, D. M. & Craig, S. W. Coincidence of actin filaments and talin is required to activate vinculin. J. Biol. Chem. 281, 40389–40398 (2006).

    CAS  PubMed  Google Scholar 

  132. Dumbauld, D. W. et al. How vinculin regulates force transmission. Proc. Natl Acad. Sci. USA 110, 9788–9793 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Diez, G., Auernheimer, V., Fabry, B. & Goldmann, W. H. Head/tail interaction of vinculin influences cell mechanical behavior. Biochem. Biophys. Res. Commun. 406, 85–88 (2011).

    CAS  PubMed  Google Scholar 

  134. 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, 1361–1370 (2013).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  136. Vasquez, C. G., Tworoger, M. & Martin, A. C. Dynamic myosin phosphorylation regulates contractile pulses and tissue integrity during epithelial morphogenesis. J. Cell Biol. 206, 435–450 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Giannone, G. et al. Lamellipodial actin mechanically links myosin activity with adhesion-site formation. Cell 128, 561–575 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Muller, W. A. Mechanisms of leukocyte transendothelial migration. Annu. Rev. Pathol. 6, 323–344 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Celli, L., Ryckewaert, J.-J., Delachanal, E. & Duperray, A. Evidence of a functional role for interaction between ICAM-1 and nonmuscle α-actinins in leukocyte diapedesis. J. Immunol. 177, 4113–4121 (2006).

    CAS  PubMed  Google Scholar 

  140. Martinelli, R. et al. Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds. J. Cell Biol. 201, 449–465 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Dustin, M. L. Cell adhesion molecules and actin cytoskeleton at immune synapses and kinapses. Curr. Opin. Cell Biol. 19, 529–533 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Hauck, C. R., Agerer, F., Muenzner, P. & Schmitter, T. Cellular adhesion molecules as targets for bacterial infection. Eur. J. Cell Biol. 85, 235–242 (2006).

    CAS  PubMed  Google Scholar 

  143. Hamiaux, C., van Eerde, A., Parsot, C., Broos, J. & Dijkstra, B. W. Structural mimicry for vinculin activation by IpaA, a virulence factor of Shigella flexneri. EMBO Rep. 7, 794–799 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Leckband, D. E. & de Rooij, J. Cadherin adhesion and mechanotransduction. Annu. Rev. Cell Dev. Biol. 30, 291–315 (2014).

    CAS  PubMed  Google Scholar 

  145. Bard, L. et al. A molecular clutch between the actin flow and N-cadherin adhesions drives growth cone migration. J. Neurosci. 28, 5879–5890 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kametani, Y. & Takeichi, M. Basal-to-apical cadherin flow at cell junctions. Nat. Cell Biol. 9, 92–98 (2007).

    CAS  PubMed  Google Scholar 

  147. Locascio, A. & Nieto, M. A. Cell movements during vertebrate development: integrated tissue behaviour versus individual cell migration. Curr. Opin. Genet. Dev. 11, 464–469 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Michelle Baird and Michael Davidson (Florida State University) for assistance with figure design and members of the Waterman Lab for helpful discussions. Funding was provided by the Division of Intramural Research, NHLBI (L.B.C. and C.M.W.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Clare M. Waterman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Case, L., Waterman, C. Integration of actin dynamics and cell adhesion by a three-dimensional, mechanosensitive molecular clutch. Nat Cell Biol 17, 955–963 (2015). https://doi.org/10.1038/ncb3191

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb3191

This article is cited by

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