1.
Bachir, A. I., Horwitz, A. R., Nelson, W. J. & Bianchini, J. M. Actinbased adhesion modules mediate cell interactions with the extracellular matrix and neighboring cells. Cold Spring Harbour Perspect. Biol. 9, a023234 (2017).
2. Sun, Z. Q., Guo, S. S. & Fassler, R. Integrin-mediated mechanotransduction. J. Cell Biol. 215, 445–456 (2016).
3. Yan, J., Yao, M. X., Goult, B. T. & Sheetz, M. P. Talin dependent
mechanosensitivity of cell focal adhesions. Cell Mol. Bioeng. 8,
151–159, https://doi.org/10.1007/s12195-014-0364-5 (2015).
4. Klapholz, B. & Brown, N. H. Talin—the master of integrin adhesions.
J. Cell Sci. 130, 2435–2446 (2017).
5. Goult, B. T., Yan, J. & Schwartz, M. A. Talin as a mechanosensitive
signaling hub. J. Cell Biol. 217, 3776–3784 (2018).
6. del Rio, A. et al. Stretching single talin rod molecules activates
vinculin binding. Science 323, 638–641 (2009).
7. Calderwood, D. A., Campbell, I. D. & Critchley, D. R. Talins and
kindlins: partners in integrin-mediated adhesion. Nat. Rev. Mol. Cell
Biol. 14, 503–517 (2013).
8. Yao, M. X. et al. Mechanical activation of vinculin binding to talin
locks talin in an unfolded conformation. Sci. Rep. 4, 4610 (2014).
9. Yao, M. X. et al. The mechanical response of talin. Nat. Commun. 7,
11966 (2016).
10. Zhang, X. et al. Talin depletion reveals independence of initial cell
spreading from integrin activation and traction. Nat. Cell Biol. 10,
1062–1068 (2008).
12
Article
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Case, L. B. & Waterman, C. M. Integration of actin dynamics and cell
adhesion by a three-dimensional, mechanosensitive molecular
clutch. Nat. Cell Biol. 17, 955–963 (2015).
Atherton, P. et al. Vinculin controls talin engagement with the
actomyosin machinery. Nat. Commun. 6, https://doi.org/10.1038/
ncomms10038 (2015).
Kanchanawong, P. et al. Nanoscale architecture of integrin-based
cell adhesions. Nature 468, 580–584 (2010).
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).
Danuser, G. & Waterman-Storer, C. M. Quantitative fluorescent
speckle microscopy of cytoskeleton dynamics. Annu Rev. Biophys.
Biom. 35, 361–387 (2006).
Yamashiro, S. et al. New single-molecule speckle microscopy
reveals modification of the retrograde actin flow by focal adhesions
at nanometer scales. Mol. Biol. Cell 25, 1010–1024 (2014).
Driscoll, T. P., Ahn, S. J., Huang, B., Kumar, A. & Schwartz, M. A. Actin
flow-dependent and -independent force transmission through
integrins. Proc. Natl Acad. Sci. USA 117, 32413–32422 (2020).
Schwarz, U. S. & Gardel, M. L. United we stand—integrating the
actin cytoskeleton and cell-matrix adhesions in cellular mechanotransduction. J. Cell Sci. 125, 3051–3060 (2012).
Goult, B. T., Brown, N. H. & Schwartz, M. A. Talin in mechanotransduction and mechanomemory at a glance. J. Cell Sci. 134,
jcs258749 (2021).
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).
Mierke, C. T. et al. Vinculin facilitates cell invasion into threedimensional collagen matrices. J. Biol. Chem. 285,
13121–13130 (2010).
Yamashiro, S. & Watanabe, N. A new link between the retrograde
actin flow and focal adhesions. J. Biochem. 156, 239–248 (2014).
Yamashiro, S. & Watanabe, N. An infrared actin probe for deep-cell
electroporation-based single-molecule speckle (eSiMS) microscopy. Sensors 17, 1545 (2017).
Smith, M. B. et al. Interactive, computer-assisted tracking of speckle
trajectories in fluorescence microscopy: application to actin polymerization and membrane fusion. Biophys. J. 101, 1794–1804 (2011).
Dedden, D. et al. The architecture of Talin1 reveals an autoinhibition
mechanism. Cell 179, 120–131.e113 (2019).
Haining, A. W., von Essen, M., Attwood, S. J., Hytönen, V. P. & Del Río
Hernández, A. All subdomains of the talin rod are mechanically
vulnerable and may contribute to cellular mechanosensing. ACS
Nano 10, 6648–6658 (2016).
Liu, J. R. et al. Talin determines the nanoscale architecture of focal
adhesions. Proc. Natl Acad. Sci. USA 112, E4864–E4873 (2015).
Renn, J. P. et al. Mechanical unfolding of spectrin reveals a superexponential dependence of unfolding rate on force. Sci. Rep. 9,
11101 (2019).
Zhu, L. et al. Structure of Rap1b bound to talin reveals a pathway for
triggering integrin activation. Nat. Commun. 8, 1744 (2017).
Tsuji, T., Miyoshi, T., Higashida, C., Narumiya, S. & Watanabe, N. An
order of magnitude faster AIP1-associated actin disruption than
nucleation by the Arp2/3 complex in lamellipodia. PLoS One 4,
e4921 (2009).
Watanabe, N. Brownian ratchet force sensor at the contacting point
between F-actin barbed end and lamellipodium tip plasma membrane. Plasma Membrane Shaping (1st Edition), Elsevier (2022).
Koseki, K. et al. Lamellipodium tip actin barbed ends serve as a
force sensor. Genes Cells 24, 705–718 (2019).
Tan, S. J. et al. Regulation and dynamics of force transmission
at individual cell-matrix adhesion bonds. Sci. Adv. 6,
eaax0317 (2020).
Nature Communications | (2023)14:8468
https://doi.org/10.1038/s41467-023-44018-z
34. Fantner, G. E. et al. Sacrificial bonds and hidden length dissipate
energy as mineralized fibrils separate during bone fracture. Nat.
Mater. 4, 612–616 (2005).
35. Smith, B. L. et al. Molecular mechanistic origin of the toughness of
natural adhesives, fibres and composites. Nature 399,
761–763 (1999).
36. Thompson, J. B. et al. Bone indentation recovery time correlates
with bond reforming time. Nature 414, 773–776 (2001).
37. Fantner, G. E. et al. Sacrificial bonds and hidden length: unraveling
molecular mesostructures in tough materials. Biophys. J. 90,
1411–1418 (2006).
38. Lieou, C. K. C., Elbanna, A. E. & Carlson, J. M. Sacrificial bonds
and hidden length in biomaterials: a kinetic constitutive
description of strength and toughness in bone. Phys. Rev. E 88,
012703 (2013).
39. Brown, C. M. et al. Probing the integrin-actin linkage using highresolution protein velocity mapping. J. Cell Sci. 119,
5204–5214 (2006).
40. Margadant, F. et al. Mechanotransduction in vivo by repeated talin
stretch-relaxation events depends upon vinculin. Plos Biol. 9,
e1001223 (2011).
41. Chenouard, N. et al. Objective comparison of particle tracking
methods. Nat. Methods 11, 281–U247 (2014).
42. Watanabe, N. & Mitchison, T. J. Single-molecule speckle analysis of
actin filament turnover in lamellipodia. Science 295, 1083–1086
(2002).
43. Yamashiro, S., Mizuno, H. & Watanabe, N. An easy-to-use singlemolecule speckle microscopy enabling nanometer-scale flow and
wide-range lifetime measurement of cellular actin filaments.
Method Cell Biol. 125, 43–59 (2015).
44. Watanabe, N. Fluorescence single-molecule imaging of actin
turnover and regulatory mechanisms. Method Enzymol. 505,
219–232 (2012).
45. Mimori-Kiyosue, Y., Matsui, C., Sasaki, H. & Tsukita, S. Adenomatous
polyposis coli (APC) protein regulates epithelial cell migration and
morphogenesis via PDZ domain-based interactions with plasma
membranes. Genes Cells 12, 219–233 (2007).
46. Yamashiro, S. et al. Convection-induced biased distribution of actin
probes in live cells. Biophys. J. 116, 142–150 (2019).
47. Su, T. X. & Purohit, P. K. Mechanics of forced unfolding of proteins.
Acta Biomater. 5, 1855–1863 (2009).
48. Jedynak, R. New facts concerning the approximation of the inverse
Langevin function. J. Non-Newton Fluid 249, 8–25 (2017).
49. Rubinstein, M. & Colby, R. H. Polymer Physics. (Oxford University
Press, 2007).
50. Tapia-Rojo, R., Alonso-Caballero, A. & Fernandez, J. M. Talin folding
as the tuning fork of cellular mechanotransduction. Proc. Natl Acad.
Sci. USA 117, 21346–21353 (2020).
51. 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).
52. Owen, L. M., Bax, N. A., Weis, W. I. & Dunn, A. R. The C-terminal
actin-binding domain of talin forms an asymmetric catch bond with
F-actin. Proc. Natl Acad. Sci. USA 119, e2109329119 (2022).
Acknowledgements
We thank Ayako Kodera and Shu Yamamura for help with data analysis, and Aaron Hall, Danielle Holz and Shu Yamamura for discussions on mathematical simulations. This work was supported by Japan
Society for the Promotion of Science KAKENHI Grant Number
JP21K06150, JP22H04843, and JP21H05780 (S.Y.), JP22H00456
(N.W.), National Institutes of Health Grant R35GM136372, and by the
National Science Foundation Lehigh Physics REU grant PHY-1852010
that supported K.L.
13
Article
Author contributions
S.Y. and Y.L. performed experiments and analyzed data. S.Y. and N.W.
designed experiments. D.R., K.L. and D.V. performed simulations. S.Y.,
D.R., D.V. and N.W. wrote the manuscript. All other authors edited the
manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information The online version contains
supplementary material available at
https://doi.org/10.1038/s41467-023-44018-z.
Correspondence and requests for materials should be addressed to
Sawako Yamashiro.
Peer review information Nature Communications thanks Reinhard
Fässler and the other, anonymous, reviewer(s) for their contribution to
the peer review of this work. A peer review file is available.
Nature Communications | (2023)14:8468
https://doi.org/10.1038/s41467-023-44018-z
Reprints and permissions information is available at
http://www.nature.com/reprints
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons licence, and indicate if
changes were made. The images or other third party material in this
article are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material is not
included in the article’s Creative Commons licence and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this licence, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2023
14
...