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.

  • Review Article
  • Published:

Interplay between mechanics and signalling in regulating cell fate

Nature Reviews Molecular Cell Biology volume 23, pages 465–480 (2022)Cite this article

Subjects

Abstract

Mechanical signalling affects multiple biological processes during development and in adult organisms, including cell fate transitions, cell migration, morphogenesis and immune responses. Here, we review recent insights into the mechanisms and functions of two main routes of mechanical signalling: outside-in mechanical signalling, such as mechanosensing of substrate properties or shear stresses; and mechanical signalling regulated by the physical properties of the cell surface itself. We discuss examples of how these two classes of mechanical signalling regulate stem cell function, as well as developmental processes in vivo. We also discuss how cell surface mechanics affects intracellular signalling and, in turn, how intracellular signalling controls cell surface mechanics, generating feedback into the regulation of mechanosensing. The cooperation between mechanosensing, intracellular signalling and cell surface mechanics has a profound impact on biological processes. We discuss here our understanding of how these three elements interact to regulate stem cell fate and development.

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

Fig. 1: Forces inside and outside the cell regulate cell function.
Fig. 2: Examples of cell fate regulation by mechanical signalling.
Fig. 3: Mechanical signalling gated through cell adhesions.
Fig. 4: Mechanical signalling gated through the plasma membrane.
Fig. 5: Interrelationship and feedback between mechanosensors and cell surface mechanics.

Similar content being viewed by others

References

  1. Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 10, 75–82 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Guilak, F. et al. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5, 17–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Solis, A. G. et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature 573, 69–74 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Razzell, W., Wood, W. & Martin, P. Recapitulation of morphogenetic cell shape changes enables wound re-epithelialisation. Development 141, 1814–1820 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yui, S. et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 35–49.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Segel, M. et al. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature 573, 130–134 (2019). This study shows that ageing correlates with increased substrate stiffness in CNS progenitor cells and that age-related loss of function can be reversed by depleting PIEZO1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Anlaş, A. A. & Nelson, C. M. Tissue mechanics regulates form, function, and dysfunction. Curr. Opin. Cell Biol. 54, 98–105 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Le, H. Q. et al. Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nat. Cell Biol. 18, 864–875 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Przybyla, L., Lakins, J. N. & Weaver, V. M. Tissue mechanics orchestrate Wnt-dependent human embryonic stem cell differentiation. Cell Stem Cell 19, 462–475 (2016). This work shows that culturing human PSCs on mechanically different substrates influences differentiation by affecting signalling at cell junctions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Totaro, A. et al. YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate. Nat. Commun. 8, 1–13 (2017).

    Article  CAS  Google Scholar 

  11. Connelly, J. T. et al. Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nat. Cell Biol. 12, 711–718 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6, 483–495 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Clark, A. G., Wartlick, O., Salbreux, G. & Paluch, E. K. Stresses at the cell surface during animal cell morphogenesis. Curr. Biol. 24, R484–R494 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Heisenberg, C.-P. & Bellaïche, Y. Forces in tissue morphogenesis and patterning. Cell 153, 948–962 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Yanagida, A. et al. Cell surface fluctuations regulate early embryonic lineage sorting. Cell 185, 777–793.e20 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hannezo, E. & Heisenberg, C.-P. Mechanochemical feedback loops in development and disease. Cell 178, 12–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Gudipaty, S. A. et al. Mechanical stretch triggers rapid epithelial cell division through Piezo1. Nature 543, 118–121 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Panciera, T., Azzolin, L., Cordenonsi, M. & Piccolo, S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. 18, 758–770 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kechagia, J. Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 20, 457–473 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Yu, F.-X., Zhao, B. & Guan, K.-L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811–828 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McGinn, J. et al. A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium. Nat. Cell Biol. 23, 511–525 (2021). This work shows that build-up of mechanical strains in the developing oesophagus leads to a switch from tissue expansion to homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Vining, K. H. & Mooney, D. J. Mechanical forces direct stem cell behaviour in development and regeneration. Nat. Rev. Mol. Cell Biol. 18, 728–742 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, J. et al. The strength of mechanical forces determines the differentiation of alveolar epithelial cells. Dev. Cell 44, 297–312.e5 (2018). This work shows that the movement of amniotic fluid caused by fetal breathing regulates differentiation of alveolar epithelial cells.

    Article  CAS  PubMed  Google Scholar 

  24. Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aragona, M. et al. Mechanisms of stretch-mediated skin expansion at single-cell resolution. Nature 584, 268–273 (2020). This work shows that stretching in skin epidermis leads to an increase in proliferation and downstream differentiation in stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Miroshnikova, Y. A. et al. Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat. Cell Biol. 20, 69–80 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Kim, H. Y., Jackson, T. R., Stuckenholz, C. & Davidson, L. A. Tissue mechanics drives regeneration of a mucociliated epidermis on the surface of Xenopus embryonic aggregates. Nat. Commun. 11, 665 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Zhao, W., Li, X., Liu, X., Zhang, N. & Wen, X. Effects of substrate stiffness on adipogenic and osteogenic differentiation of human mesenchymal stem cells. Mater. Sci. Eng. C. Mater. Biol. Appl. 40, 316–323 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Kilian, K. A., Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 9, 518–526 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Loebel, C., Mauck, R. L. & Burdick, J. A. Local nascent protein deposition and remodelling guide mesenchymal stromal cell mechanosensing and fate in three-dimensional hydrogels. Nat. Mater. 18, 883–891 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Wen, J. H. et al. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat. Mater. 13, 979–987 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nat. Mater. 11, 642–649 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Labouesse, C. et al. StemBond hydrogels control the mechanical microenvironment for pluripotent stem cells. Nat. Commun. 12, 6132 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taylor-Weiner, H., Ravi, N. & Engler, A. J. Traction forces mediated by integrin signaling are necessary for definitive endoderm specification. J. Cell Sci. 128, 1961–1968 (2015). This study shows that high traction forces and high contractility promote definitive endoderm specification in mouse PSCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nath, S. C. et al. Fluid shear stress promotes embryonic stem cell pluripotency via interplay between β-catenin and vinculin in bioreactor culture. Stem Cells 39, 1166–1177 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Yourek, G., McCormick, S. M., Mao, J. J. & Reilly, G. C. Shear stress induces osteogenic differentiation of human mesenchymal stem cells. Regen. Med. 5, 713–724 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, L., Yuan, W. & Wang, J. Mechanisms for osteogenic differentiation of human mesenchymal stem cells induced by fluid shear stress. Biomech. Model. Mechanobiol. 9, 659–670 (2010).

    Article  PubMed  Google Scholar 

  43. Nguyen, J., Lin, Y.-Y. & Gerecht, S. The next generation of endothelial differentiation: tissue-specific ECs. Cell Stem Cell 28, 1188–1204 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Luo, J. et al. Efficient differentiation of human induced pluripotent stem cells into endothelial cells under xenogeneic-free conditions for vascular tissue engineering. Acta Biomater. 119, 184–196 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. dela Paz, N. G., Melchior, B. & Frangos, J. A. Shear stress induces Gαq/11 activation independently of G protein-coupled receptor activation in endothelial cells. Am. J. Physiol. Cell Physiol. 312, C428–C437 (2017).

    Article  Google Scholar 

  46. Doze, V. A. & Perez, D. M. GPCRs in stem cell function. Prog. Mol. Biol. Transl. Sci. 115, 175–216 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Erdogmus, S. et al. Helix 8 is the essential structural motif of mechanosensitive GPCRs. Nat. Commun. 10, 5784 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Storch, U., Schnitzler, M. M. Y. & Gudermann, T. G protein-mediated stretch reception. Am. J. Physiol. Heart Circ. Physiol. 302, H1241–H1249 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Yang, X. et al. Mechanical stretch inhibits adipogenesis and stimulates osteogenesis of adipose stem cells. Cell Prolif. 45, 158–166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang, X. et al. Cyclic tensile stretch modulates osteogenic differentiation of adipose-derived stem cells via the BMP-2 pathway. Arch. Med. Sci. 6, 152–159 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Verstreken, C. M., Labouesse, C., Agley, C. C. & Chalut, K. J. Embryonic stem cells become mechanoresponsive upon exit from ground state of pluripotency. Roy. Soc. Open Biol. 9, 180203 (2019).

    Article  CAS  Google Scholar 

  52. Delarue, M. et al. mTORC1 controls phase separation and the biophysical properties of the cytoplasm by tuning crowding. Cell 174, 338–349 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). This study shows that YAP/TAZ mediates substrate stiffness mechanosensing during MSC differentiation.

    Article  CAS  PubMed  Google Scholar 

  54. Oliver-De La Cruz, J. et al. Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading. Biomaterials 205, 64–80 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Gopal, S., Arokiasamy, S., Pataki, C., Whiteford, J. R. & Couchman, J. R. Syndecan receptors: pericellular regulators in development and inflammatory disease. Open. Biol. 11, 200377 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Huang, D. L., Bax, N. A., Buckley, C. D., Weis, W. I. & Dunn, A. R. Vinculin forms a directionally asymmetric catch bond with F-actin. Science 357, 703–706 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Elosegui-Artola, A., Trepat, X. & Roca-Cusachs, P. Control of mechanotransduction by molecular clutch dynamics. Trends Cell Biol. 28, 356–367 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Yu, C. et al. Integrin-β3 clusters recruit clathrin-mediated endocytic machinery in the absence of traction force. Nat. Commun. 6, 8672 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schiller, H. B. et al. β1- and αv-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments. Nat. Cell Biol. 15, 625–636 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Kanatsu-Shinohara, M. et al. Homing of mouse spermatogonial stem cells to germline niche depends on β1-integrin. Cell Stem Cell 3, 533–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Brizzi, M. F., Tarone, G. & Defilippi, P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 24, 645–651 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Wong, V. W. et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat. Med. 18, 148–152 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Seong, J. et al. Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins. Proc. Natl Acad. Sci. USA 110, 19372–19377 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhou, J., Bronowska, A., Le Coq, J., Lietha, D. & Gräter, F. Allosteric regulation of focal adhesion kinase by PIP2 and ATP. Biophys. J. 108, 698–705 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Goñi, G. M. et al. Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc. Natl Acad. Sci. USA 111, E3177–E3186 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Lietha, D. et al. Structural basis for the autoinhibition of focal adhesion kinase. Cell 129, 1177–1187 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bauer, M. S. et al. Structural and mechanistic insights into mechanoactivation of focal adhesion kinase. Proc. Natl Acad. Sci. USA 116, 6766–6774 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang, X. et al. Focal adhesion kinase promotes phospholipase C-γ1 activity. Proc. Natl Acad. Sci. USA 96, 9021–9026 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schlaepfer, D. D., Hauck, C. R. & Sieg, D. J. Signaling through focal adhesion kinase. Prog. Biophys. Mol. Biol. 71, 435–478 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Thomas, J. W. et al. SH2- and SH3-mediated interactions between focal adhesion kinase and Src. J. Biol. Chem. 273, 577–583 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Calalb, M. B., Polte, T. R. & Hanks, S. K. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol. Cell. Biol. 15, 954–963 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brown, M. C., Cary, L. A., Jamieson, J. S., Cooper, J. A. & Turner, C. E. Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Mol. Biol. Cell 16, 4316–4328 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. López-Colomé, A. M., Lee-Rivera, I., Benavides-Hidalgo, R. & López, E. Paxillin: a crossroad in pathological cell migration. J. Hematol. Oncol. 10, 50 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Westhoff, M. A., Serrels, B., Fincham, V. J., Frame, M. C. & Carragher, N. O. SRC-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol. Cell Biol. 24, 8113–8133 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Deramaudt, T. B. et al. FAK phosphorylation at Tyr-925 regulates cross-talk between focal adhesion turnover and cell protrusion. Mol. Biol. Cell 22, 964–975 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang, Y., Cao, H., Chen, J. & McNiven, M. A. A direct interaction between the large GTPase dynamin-2 and FAK regulates focal adhesion dynamics in response to active Src. Mol. Biol. Cell 22, 1529–1538 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. D., A. A. & A., R. K. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr. Med. Chem. 19, 3748–3762 (2012).

    Article  Google Scholar 

  79. Mitra, S. K., Hanson, D. A. & Schlaepfer, D. D. Focal adhesion kinase: in command and control of cell motility. Nat. Rev. Mol. Cell Biol. 6, 56–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Renshaw, M. W., Price, L. S. & Schwartz, M. A. Focal adhesion kinase mediates the integrin signaling requirement for growth factor activation of MAP kinase. J. Cell Biol. 147, 611–618 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Howe, A. K., Aplin, A. E. & Juliano, R. L. Anchorage-dependent ERK signaling — mechanisms and consequences. Curr. Opin. Genet. Dev. 12, 30–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Zhang, L., Wang, Y., Zhou, N., Feng, Y. & Yang, X. Cyclic tensile stress promotes osteogenic differentiation of adipose stem cells via ERK and p38 pathways. Stem Cell Res. 37, 101433 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Kunath, T. et al. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134, 2895–2902 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Reinhart-King, C. A., Dembo, M. & Hammer, D. A. Cell–cell mechanical communication through compliant substrates. Biophys. J. 95, 6044–6051 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Aberle, H., Schwartz, H. & Kemler, R. Cadherin–catenin complex: protein interactions and their implications for cadherin function. J. Cell Biochem. 61, 514–523 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Ladoux, B., Nelson, W. J., Yan, J. & Mège, R. M. The mechanotransduction machinery at work at adherens junctions. Integr. Biol. 7, 1109–1119 (2015).

    Article  CAS  Google Scholar 

  87. Yao, M. et al. Force-dependent conformational switch of α-catenin controls vinculin binding. Nat. Commun. 5, 4525 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Kim, T.-J. et al. Dynamic visualization of α-catenin reveals rapid, reversible conformation switching between tension states. Curr. Biol. 25, 218–224 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Buckley, C. D. et al. The minimal cadherin–catenin complex binds to actin filaments under force. Science 346, 1254211 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Muncie, J. M. et al. Mechanical tension promotes formation of gastrulation-like nodes and patterns mesoderm specification in human embryonic stem cells. Dev. Cell 55, 679–694.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Heuberger, J. & Birchmeier, W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb. Perspect. Biol. 2, a002915 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Fernández-Sánchez, M. E. et al. Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature 523, 92–95 (2015).

    Article  PubMed  CAS  Google Scholar 

  93. Hinz, B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 47, 54–65 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Lloyd-Lewis, B., Mourikis, P. & Fre, S. Notch signalling: sensor and instructor of the microenvironment to coordinate cell fate and organ morphogenesis. Curr. Opin. Cell Biol. 61, 16–23 (2019).

    Article  CAS  PubMed  Google Scholar 

  95. Steinhart, Z. & Angers, S. Wnt signaling in development and tissue homeostasis. Development 145, dev146589 (2018).

    Article  PubMed  CAS  Google Scholar 

  96. Gu, Q. et al. Wnt5a/FZD4 mediates the mechanical stretch-induced osteogenic differentiation of bone mesenchymal stem cells. CPB 48, 215–226 (2018).

    CAS  Google Scholar 

  97. Sukharev, S. & Corey, D. P. Mechanosensitive channels: multiplicity of families and gating paradigms. Sci. Signal. 2004, re4 (2004).

    Google Scholar 

  98. Shi, Z., Graber, Z. T., Baumgart, T., Stone, H. A. & Cohen, A. E. Cell membranes resist flow. Cell 175, 1769–1779.e13 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ridone, P., Vassalli, M. & Martinac, B. Piezo1 mechanosensitive channels: what are they and why are they important. Biophys. Rev. 11, 795–805 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Katta, S., Krieg, M. & Goodman, M. B. Feeling force: physical and physiological principles enabling sensory mechanotransduction. Annu. Rev. Cell Dev. Biol. 31, 347–371 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. He, L., Ahmad, M. & Perrimon, N. Mechanosensitive channels and their functions in stem cell differentiation. Exp. Cell Res. 374, 259–265 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Honoré, E., Martins, J. R., Penton, D., Patel, A. & Demolombe, S. The piezo mechanosensitive ion channels: may the force be with you! Rev. Physiol. Biochem. Pharmacol. 169, 25–41 (2015).

    Article  PubMed  CAS  Google Scholar 

  103. Cox, C. D. et al. Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension. Nat. Commun. 7, 1–13 (2016).

    Article  Google Scholar 

  104. Lewis, A. H. & Grandl, J. Mechanical sensitivity of Piezo1 ion channels can be tuned by cellular membrane tension. eLife 4, e12088 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Koser, D. E. et al. Mechanosensing is critical for axon growth in the developing brain. Nat. Neurosci. 19, 1592–1598 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dai, J. & Sheetz, M. P. Regulation of endocytosis, exocytosis, and shape by membrane tension. Cold Spring Harb. Symp. Quant. Biol. 60, 567–571 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Dai, J., Ting-Beall, H. P. & Sheetz, M. P. The secretion-coupled endocytosis correlates with membrane tension changes in RBL 2H3 cells. J. Gen. Physiol. 110, 1–10 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sheetz, M. P. Cell control by membrane–cytoskeleton adhesion. Nat. Rev. Mol. Cell Biol. 2, 392–396 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Joseph, J. G. & Liu, A. P. Mechanical regulation of endocytosis: new insights and recent advances. Adv. Biosyst. 4, 1900278 (2020).

    Article  Google Scholar 

  110. Kaksonen, M. & Roux, A. Mechanisms of clathrin-mediated endocytosis. Nat. Rev. Mol. Cell Biol. 19, 313–326 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Bucher, D. et al. Clathrin-adaptor ratio and membrane tension regulate the flat-to-curved transition of the clathrin coat during endocytosis. Nat. Commun. 9, 1109 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Willy, N. M. et al. Membrane mechanics govern spatiotemporal heterogeneity of endocytic clathrin coat dynamics. Mol. Biol. Cell 28, 3480–3488 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Boulant, S., Kural, C., Zeeh, J.-C., Ubelmann, F. & Kirchhausen, T. Actin dynamics counteract membrane tension during clathrin-mediated endocytosis. Nat. Cell Biol. 13, 1124–1131 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hemalatha, A. & Mayor, S. Recent advances in clathrin-independent endocytosis. F1000Res 8, 138 (2019).

    Article  CAS  Google Scholar 

  115. Mayor, S., Parton, R. G. & Donaldson, J. G. Clathrin-independent pathways of endocytosis. Cold Spring Harb. Perspect. Biol. 6, a016758 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Howes, M. T. et al. Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells. J. Cell Biol. 190, 675–691 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Thottacherry, J. J. et al. Mechanochemical feedback control of dynamin independent endocytosis modulates membrane tension in adherent cells. Nat. Commun. 9, 4217 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Kowalczyk, A. P. & Nanes, B. A. Adherens junction turnover: regulating adhesion through cadherin endocytosis, degradation, and recycling. Subcell. Biochem. 60, 197–222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jha, A., van Zanten, T. S., Philippe, J.-M., Mayor, S. & Lecuit, T. Quantitative control of GPCR organization and signaling by endocytosis in epithelial morphogenesis. Curr. Biol. 28, 1570–1584.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kerridge, S. et al. Modular activation of Rho1 by GPCR signalling imparts polarized myosin II activation during morphogenesis. Nat. Cell Biol. 18, 261–270 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Pouille, P.-A., Ahmadi, P., Brunet, A.-C. & Farge, E. Mechanical signals trigger myosin II redistribution and mesoderm invagination in Drosophila embryos. Sci. Signal. 2, ra16 (2009).

    Article  PubMed  CAS  Google Scholar 

  122. Rauch, C., Brunet, A.-C., Deleule, J. & Farge, E. C2C12 myoblast/osteoblast transdifferentiation steps enhanced by epigenetic inhibition of BMP2 endocytosis. Am. J. Physiol. Cell Physiol. 283, C235–C243 (2002).

    Article  CAS  Google Scholar 

  123. Sorkin, A. & von Zastrow, M. Endocytosis and signalling: intertwining molecular networks. Nat. Rev. Mol. Cell Biol. 10, 609–622 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Belly, H. D. et al. Membrane tension gates ERK-mediated regulation of pluripotent cell fate. Cell Stem Cell 28, 273–284 (2021). This work shows that membrane tension gates early differentiation in mouse PSCs by modulating endocytosis-mediated ERK activation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Palamidessi, A. et al. Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma. Nat. Mater. 18, 1252–1263 (2019).

    Article  CAS  PubMed  Google Scholar 

  126. Parton, R. G., McMahon, K.-A. & Wu, Y. Caveolae: formation, dynamics, and function. Curr. Opin. Cell Biol. 65, 8–16 (2020).

    Article  CAS  PubMed  Google Scholar 

  127. Singh, V. Membrane tension buffering by caveolae: a role in cancer? Cancer Metastasis Rev. 39, 505–517 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Sinha, B. et al. Cells respond to mechanical stress by rapid disassembly of caveolae. Cell 144, 402–413 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Golani, G. Membrane curvature and tension control the formation and collapse of caveolar superstructures. Dev. Cell 48, 523–538.e4 (2011).

    Article  CAS  Google Scholar 

  130. Parton, R. G., Kozlov, M. M. & Ariotti, N. Caveolae and lipid sorting: shaping the cellular response to stress. J. Cell Biol. 219, e201905071 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Garcia, J. et al. Sheath cell invasion and trans-differentiation repair mechanical damage caused by loss of caveolae in the zebrafish notochord. Curr. Biol. 27, 1982–1989.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lim, Y.-W. et al. Caveolae protect notochord cells against catastrophic mechanical failure during development. Curr. Biol. 27, 1968–1981.e7 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Lo, H. P., Hall, T. E. & Parton, R. G. Mechanoprotection by skeletal muscle caveolae. Bioarchitecture 6, 22–27 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Dewulf, M. et al. Dystrophy-associated caveolin-3 mutations reveal that caveolae couple IL6/STAT3 signaling with mechanosensing in human muscle cells. Nat. Commun. 10, 1974 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Baker, N. & Tuan, R. S. The less-often-traveled surface of stem cells: caveolin-1 and caveolae in stem cells, tissue repair and regeneration. Stem Cell Res. Ther. 4, 90 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Strippoli, R. et al. Caveolin-1 deficiency induces a MEK–ERK1/2–Snail-1-dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis. EMBO Mol. Med. 7, 102–123 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Baker, N., Zhang, G., You, Y. & Tuan, R. S. Caveolin-1 regulates proliferation and osteogenic differentiation of human mesenchymal stem cells. J. Cell Biochem. 113, 3773–3787 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Tahir, S. A. et al. Caveolin-1–LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer Res. 73, 1900–1911 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Del Galdo, F., Lisanti, M. P. & Jimenez, S. A. Caveolin-1, TGF-β receptor internalization, and the pathogenesis of systemic sclerosis. Curr. Opin. Rheumatol. 20, 713–719 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Raucher, D. & Sheetz, M. P. Characteristics of a membrane reservoir buffering membrane tension. Biophys. J. 77, 1992–2002 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lavi, I. et al. Cellular blebs and membrane invaginations are coupled through membrane tension buffering. Biophys. J. 117, 1485–1495 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Antonny, B. Mechanisms of membrane curvature sensing. Annu. Rev. Biochem. 80, 101–123 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Carman, P. J. & Dominguez, R. BAR domain proteins — a linkage between cellular membranes, signaling pathways, and the actin cytoskeleton. Biophys. Rev. 10, 1587–1604 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. McMahon, H. T. & Boucrot, E. Membrane curvature at a glance. J. Cell Sci. 128, 1065–1070 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Mim, C. & Unger, V. M. Membrane curvature and its generation by BAR proteins. Trends Biochem. Sci. 37, 526–533 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhao, H. et al. Membrane-sculpting BAR domains generate stable lipid microdomains. Cell Rep. 4, 1213–1223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Goudarzi, M. et al. Bleb expansion in migrating cells depends on supply of membrane from cell surface invaginations. Dev. Cell 43, 577–587.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zobel, T. et al. Cooperative functions of the two F-BAR proteins Cip4 and Nostrin in the regulation of E-cadherin in epithelial morphogenesis. J. Cell Sci. 128, 499–515 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. Ogi, S. et al. Syndapin constricts microvillar necks to form a united rhabdomere in Drosophila photoreceptors. Development 146, dev169292 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Bisi, S. et al. IRSp53 controls plasma membrane shape and polarized transport at the nascent lumen in epithelial tubules. Nat. Commun. 11, 3516 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Saengsawang, W. et al. The F-BAR protein CIP4 inhibits neurite formation by producing lamellipodial protrusions. Curr. Biol. 22, 494–501 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Galic, M. et al. Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons. eLife 3, e03116 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Dalby, M. J. Harnessing nanotopography and integrin–matrix interactions to influence stem cell fate. Nat. Mater. 13, 12 (2014).

    Article  CAS  Google Scholar 

  154. Zhang, W., Yang, Y. & Cui, B. New perspectives on the roles of nanoscale surface topography in modulating intracellular signaling. Curr. Opin. Solid State Mater. Sci. 25, 100873 (2021).

    Article  CAS  PubMed  Google Scholar 

  155. Figard, L., Wang, M., Zheng, L., Golding, I. & Sokac, A. M. Membrane supply and demand regulates F-actin in a cell surface reservoir. Dev. Cell 37, 267–278 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Davis, J. R. & Tapon, N. Hippo signalling during development. Development 146, dev167106 (2019).

    Article  CAS  PubMed  Google Scholar 

  157. Dorn, T. et al. Interplay of cell–cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity. EMBO J. 37, e98133 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Velasquez, L. S. et al. Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc. Natl Acad. Sci. USA 110, 16850–16855 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Simunovic, M., Evergren, E., Callan-Jones, A. & Bassereau, P. Curving cells inside and out: roles of BAR domain proteins in membrane shaping and its cellular implications. Annu. Rev. Cell Dev. Biol. 35, 111–129 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Sandilands, E. et al. Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors. EMBO Rep. 8, 1162–1169 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Auciello, G., Cunningham, D. L., Tatar, T., Heath, J. K. & Rappoport, J. Z. Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8. J. Cell Sci. 126, 613–624 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Leyton-Puig, D. et al. Flat clathrin lattices are dynamic actin-controlled hubs for clathrin-mediated endocytosis and signalling of specific receptors. Nat. Commun. 8, 16068 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zuidema, A. et al. Mechanisms of integrin αVβ5 clustering in flat clathrin lattices. J. Cell Sci. 131, jcs221317 (2018).

    Article  PubMed  CAS  Google Scholar 

  164. Diz-Muñoz, A. et al. Membrane tension acts through PLD2 and mTORC2 to limit actin network assembly during neutrophil migration. PLoS Biol. 14, e1002474 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Riggi, M. et al. Decrease in plasma membrane tension triggers PtdIns(4,5)P2 phase separation to inactivate TORC2. Nat. Cell Biol. 20, 1043–1051 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Friedrich, E. E. et al. Endothelial cell Piezo1 mediates pressure-induced lung vascular hyperpermeability via disruption of adherens junctions. Proc. Natl Acad. Sci. USA 116, 12980–12985 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Nourse, J. L. & Pathak, M. M. How cells channel their stress: interplay between Piezo1 and the cytoskeleton. Semin. Cell Dev. Biol. 71, 3–12 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Ariotti, N. et al. Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling. J. Cell Biol. 204, 777–792 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Rausch, V. et al. The Hippo pathway regulates caveolae expression and mediates flow response via caveolae. Curr. Biol. 29, 242–255.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Hamouda, M. S., Labouesse, C. & Chalut, K. J. Nuclear mechanotransduction in stem cells. Curr. Opin. Cell Biol. 64, 97–104 (2020).

    Article  CAS  PubMed  Google Scholar 

  171. Colom, A. et al. A fluorescent membrane tension probe. Nat. Chem. 10, 1118–1125 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Royer, C. et al. ASPP2 maintains the integrity of mechanically stressed pseudostratified epithelia during morphogenesis. Nat. Commun. 13, 1–19 (2022).

    Article  CAS  Google Scholar 

  173. Träber, N. et al. Polyacrylamide bead sensors for in vivo quantification of cell-scale stress in zebrafish development. Sci. Rep. 9, 17031 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Mongera, A. et al. A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561, 401–405 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Campàs, O. A toolbox to explore the mechanics of living embryonic tissues. Semin. Cell Dev. Biol. 55, 119–130 (2016). This work reviews the various techniques allowing the study of mechanics in embryonic tissues.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Roca-Cusachs, P., Conte, V. & Trepat, X. Quantifying forces in cell biology. Nat. Cell Biol. 19, 742–751 (2017).

    Article  CAS  PubMed  Google Scholar 

  177. Gauthier, N. C., Masters, T. A. & Sheetz, M. P. Mechanical feedback between membrane tension and dynamics. Trends Cell Biol. 22, 527–535 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Pontes, B., Monzo, P. & Gauthier, N. C. Membrane tension: a challenging but universal physical parameter in cell biology. Semin. Cell Dev. Biol. 71, 30–41 (2017).

    Article  CAS  PubMed  Google Scholar 

  179. Sitarska, E. & Diz-Muñoz, A. Pay attention to membrane tension: mechanobiology of the cell surface. Curr. Opin. Cell Biol. 66, 11–18 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Diz-Muñoz, A., Fletcher, D. A. & Weiner, O. D. Use the force: membrane tension as an organizer of cell shape and motility. Trends Cell Biol. 23, 47–53 (2013).

    Article  PubMed  CAS  Google Scholar 

  181. Diz-Muñoz, A. et al. Control of directed cell migration in vivo by membrane-to-cortex attachment. PLoS Biol. 8, e1000544 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Rouven Brückner, B., Pietuch, A., Nehls, S., Rother, J. & Janshoff, A. Ezrin is a major regulator of membrane tension in epithelial cells. Sci. Rep. 5, 14700 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Bergert, M. et al. Cell surface mechanics gate embryonic stem cell differentiation. Cell Stem Cell 28, 209–216 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Peukes, J. & Betz, T. Direct measurement of the cortical tension during the growth of membrane blebs. Biophys. J. 107, 1810–1820 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Kariuki, S. N. et al. Red blood cell tension protects against severe malaria in the Dantu blood group. Nature 585, 579–583 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Li, W. et al. A membrane-bound biosensor visualizes shear stress-induced inhomogeneous alteration of cell membrane tension. iScience 7, 180–190 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Houk, A. R. et al. Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration. Cell 148, 175–188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Lieber, A. D., Yehudai-Resheff, S., Barnhart, E. L., Theriot, J. A. & Keren, K. Membrane tension in rapidly moving cells is determined by cytoskeletal forces. Curr. Biol. 23, 1409–1417 (2013).

    Article  CAS  PubMed  Google Scholar 

  189. Cohen, A. E. & Shi, Z. Do cell membranes flow like honey or jiggle like jello? BioEssays 42, 1900142 (2020).

    Article  Google Scholar 

  190. Rawicz, W., Olbrich, K. C., McIntosh, T., Needham, D. & Evans, E. Effect of chain length and unsaturation on elasticity of lipid bilayers. Biophys. J. 79, 328–339 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Le Roux, A.-L., Quiroga, X., Walani, N., Arroyo, M. & Roca-Cusachs, P. The plasma membrane as a mechanochemical transducer. Philos. Trans. R. Soc. B Biol. Sci. 374, 20180221 (2019).

    Article  CAS  Google Scholar 

  192. Sezgin, E., Levental, I., Mayor, S. & Eggeling, C. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat. Rev. Mol. Cell Biol. 18, 361–374 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Honigmann, A. & Pralle, A. Compartmentalization of the cell membrane. J. Mol. Biol. 428, 4739–4748 (2016).

    Article  CAS  PubMed  Google Scholar 

  194. Fletcher, D. A. & Mullins, R. D. Cell mechanics and the cytoskeleton. Nature 463, 485–492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Koenderink, G. H. & Paluch, E. K. Architecture shapes contractility in actomyosin networks. Curr. Opin. Cell Biol. 50, 79–85 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Svitkina, T. M. Actin cell cortex: structure and molecular organization. Trends Cell Biol. 30, 556–565 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Fischer, R. S., Lam, P.-Y., Huttenlocher, A. & Waterman, C. M. Filopodia and focal adhesions: an integrated system driving branching morphogenesis in neuronal pathfinding and angiogenesis. Dev. Biol. 451, 86–95 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Oakes, P. W. et al. Lamellipodium is a myosin-independent mechanosensor. Proc. Natl Acad. Sci. USA 115, 2646–2651 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Wolfenson, H. et al. Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices. Nat. Cell Biol. 18, 33–42 (2016).

    Article  CAS  PubMed  Google Scholar 

  200. Lee, S. & Kumar, S. Actomyosin stress fiber mechanosensing in 2D and 3D. F1000Res 5, 2261 (2016).

    Article  CAS  Google Scholar 

  201. Burridge, K. & Wittchen, E. S. The tension mounts: stress fibers as force-generating mechanotransducers. J. Cell Biol. 200, 9–19 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Chugh, P. & Paluch, E. K. The actin cortex at a glance. J. Cell Sci. 131, jcs186254 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Kelkar, M., Bohec, P. & Charras, G. Mechanics of the cellular actin cortex: from signalling to shape change. Curr. Opin. Cell Biol. 66, 69–78 (2020).

    Article  CAS  PubMed  Google Scholar 

  204. Luo, T., Mohan, K., Iglesias, P. A. & Robinson, D. N. Molecular mechanisms of cellular mechanosensing. Nat. Mater. 12, 1064–1071 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Sigismund, S., Lanzetti, L., Scita, G. & Di Fiore, P. P. Endocytosis in the context-dependent regulation of individual and collective cell properties. Nat. Rev. Mol. Cell Biol 22, 625–643 (2021).

    Article  CAS  PubMed  Google Scholar 

  206. Sanz-Moreno, V. & Marshall, C. J. The plasticity of cytoskeletal dynamics underlying neoplastic cell migration. Curr. Opin. Cell Biol. 22, 690–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Sanz-Moreno, V. et al. Rac activation and inactivation control plasticity of tumor cell movement. Cell 135, 510–523 (2008).

    Article  CAS  PubMed  Google Scholar 

  208. Maddox, A. S. & Burridge, K. RhoA is required for cortical retraction and rigidity during mitotic cell rounding. J. Cell Biol. 160, 255–265 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Ridley, A. J. & Hall, A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70, 389–399 (1992).

    Article  CAS  PubMed  Google Scholar 

  210. Watanabe, N., Kato, T., Fujita, A., Ishizaki, T. & Narumiya, S. Cooperation between mDia1 and ROCK in Rho-induced actin reorganization. Nat. Cell Biol. 1, 136–143 (1999).

    Article  CAS  PubMed  Google Scholar 

  211. Sumi, T., Matsumoto, K., Takai, Y. & Nakamura, T. Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho- and Cdc42-activated LIM-kinase 2. J. Cell Biol. 147, 1519–1532 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Tsuji, T. et al. ROCK and mDia1 antagonize in Rho-dependent Rac activation in Swiss 3T3 fibroblasts. J. Cell Biol. 157, 819–830 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Sailem, H., Bousgouni, V., Cooper, S. & Bakal, C. Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity. Open. Biol. 4, 130132 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Holmes, W. R. & Edelstein-Keshet, L. Analysis of a minimal Rho-GTPase circuit regulating cell shape. Phys. Biol. 13, 046001 (2016).

    Article  PubMed  CAS  Google Scholar 

  215. Matsui, T. et al. Rho-kinase phosphorylates COOH-terminal threonines of Ezrin/Radixin/Moesin (ERM) proteins and regulates their head-to-tail association. J. Cell Biol. 140, 647–657 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Nijhara, R. et al. Rac1 mediates collapse of microvilli on chemokine-activated T lymphocytes. J. Immunol. 173, 4985–4993 (2004).

    Article  CAS  PubMed  Google Scholar 

  217. Staser, K. et al. A Pak1–PP2A–ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp. Hematol. 41, 56–66.e2 (2013).

    Article  CAS  PubMed  Google Scholar 

  218. Hokanson, D. E., Laakso, J. M., Lin, T., Sept, D. & Ostap, E. M. Myo1c binds phosphoinositides through a putative pleckstrin homology domain. MBoC 17, 4856–4865 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. McClatchey, A. I. ERM proteins at a glance. J. Cell Sci. 127, 3199–3204 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Lien, E. C., Dibble, C. C. & Toker, A. PI3K signaling in cancer: beyond AKT. Curr. Opin. Cell Biol. 45, 62–71 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Weiner, O. D. et al. A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity. Nat. Cell Biol. 4, 509–513 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Li, Z. et al. Regulation of PTEN by Rho small GTPases. Nat. Cell Biol. 7, 399–404 (2005).

    Article  CAS  PubMed  Google Scholar 

  223. Torrino, S. et al. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. J. Cell Biol. 217, 4092–4105 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank A. Stubb, S. Saha and C. Lamaze for feedback on the manuscript. The authors acknowledge funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 641639 (ITN Biopol, to H.D.B. and E.K.P.), European Molecular Biology Organization (EMBO) ALTF 203-2021 (to H.D.B) and the European Research Council (Consolidator Grants 820188-NanoMechShape to E.K.P. and 772798-CellFateTech to K.J.C.).

Author information

Author notes

  1. Henry De Belly

    Present address: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA

  2. Henry De Belly

    Present address: Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA

Authors and Affiliations

  1. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

    Henry De Belly, Ewa K. Paluch & Kevin J. Chalut

  2. Wellcome/MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    Kevin J. Chalut

Authors
  1. Henry De Belly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ewa K. Paluch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin J. Chalut
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to the writing and revisions of the article.

Corresponding authors

Correspondence to Ewa K. Paluch or Kevin J. Chalut.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Integrin

A transmembrane receptor mediating cell adhesions such as cell–extracellular matrix (ECM) adhesion.

YAP/TAZ

A protein whose function and localization, either cytoplasmic or nuclear, is regulated by mechanical cues.

PIEZO1

A transmembrane mechanosensitive ion channel that is actuated by an increase in membrane tension.

Hydrogel

A 3D water-retaining network of polymers.

Formin

A family of proteins that are actin polymerization regulators.

Cell delamination

The process by which cells detach from their original tissue.

Laminin

An extracellular matrix (ECM) protein found in most tissues and organs.

Syndecans

Heavily glycosylated transmembrane proteins interacting with various ligands, often acting as co-receptors of many different proteins including, for example, G protein-coupled receptors (GPCRs).

SH2 domain

A protein domain interacting with phosphorylated tyrosine present on other proteins.

Focal adhesions

Large protein complexes that mechanically link the actin cytoskeleton and the extracellular matrix (ECM).

Extrusion

A mechanically induced increase in actomyosin contraction leading to the cell squeezing itself out of the tissue.

Remyelination

The production of layers of myelin, which help electric transmission of electric action potential, around neuronal axons.

CLIC/GEEC endocytic pathway

A clathrin-independent endocytic pathway, involved in pinocytosis and large bulk membrane uptakes.

Membrane blebs

Spherical cellular protrusions driven by hydrostatic pressure and cytoplasmic flows.

Rhabdomere

A phosphosensory structure consisting of a microvilli bundle.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De Belly, H., Paluch, E.K. & Chalut, K.J. Interplay between mechanics and signalling in regulating cell fate. Nat Rev Mol Cell Biol 23, 465–480 (2022). https://doi.org/10.1038/s41580-022-00472-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-022-00472-z

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