Focal adhesions as mechanosensors: A physical mechanism

^{Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; and}^{; and Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel}

^{To whom correspondence should be addressed. E-mail:}li.ca.uat.tsop@khcim.

Edited by Marc W. Kirschner, Harvard Medical School, Boston, MA, and approved July 12, 2005

Received 2005 Jan 12

Abstract

Focal adhesions (FA) are large, multiprotein complexes that provide a mechanical link between the cytoskeletal contractile machinery and the extracellular matrix. FA exhibit mechanosensitive properties; they self-assemble and elongate upon application of pulling forces and dissociate when these forces are decreased. We propose a thermodynamic model for the mechanosensitivity of FA, according to which a molecular aggregate, subjected to pulling forces, tends to grow in the direction of force application by incorporating additional molecules. We demonstrate that this principle is consistent with the phenomenology of FA dynamics by considering a one-dimensional protein aggregate subjected to pulling forces and anchored to the substrate. Depending on the force level, force distribution along the aggregate, and the character of its anchoring to the substrate, the aggregate is predicted to exhibit distinct modes of assembly that are largely consistent with the experimentally observed FA behavior. We define here specific conditions that can lead to the different regimes of FA assembly, including growth, steady state, and disassembly.

Keywords: elasticity, mechanosensitivity, elastic stress, self-assembly

Abstract

Mechanosensitive behavior of focal adhesions (FA) is an important component of cell ability to spread and move along substrates (1–3). The basic observation underlying FA mechanosensitivity is that alterations in the mechanical force applied to these adhesion sites either by the contractile machinery of the cell or after an external perturbation have a dramatic effect on FA properties (1). Although the molecular mechanism of this phenomenon is still obscure, the recent progress in characterizing the molecular organization and complexity of the integrin-mediated FA (4, 5) stimulated several attempts toward investigating the physical principles governing FA dynamics (6, 7, 32). The present work proposes a previously undescribed mechanism of FA mechanosensitivity based on thermodynamic properties of self-assembly under tension.

Acknowledgments

We thank Sam Safran, Robin Bruinsma, and Michael Urbakh for discussions. B.G. is the E. Neter Professor for Cell and Tumor Biology and was supported by the Cell Migration Consortium of the National Institutes of Health and the Minerva Foundation (Munich). A.D.B. holds the Joseph Moss Chair of Biomedical Research and was supported by the Israel Science Foundation, the Binational United States–Israel Foundation, the Minerva Foundation, and the Clore Center for Biological Physics. M.M.K. was supported by the Israel Science Foundation, the Binational United States–Israel Foundation, and the Human Frontier Science Program Organization.

Acknowledgments

Notes

Author contributions: B.G., A.D.B., and M.M.K. designed research; T.S. and M.M.K. performed research; and T.S., B.G., A.D.B., and M.M.K. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office. Abbreviation: FA, focal adhesions.

Notes

Author contributions: B.G., A.D.B., and M.M.K. designed research; T.S. and M.M.K. performed research; and T.S., B.G., A.D.B., and M.M.K. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office. Abbreviation: FA, focal adhesions.

Footnotes

^{Hu, K., Ji, L., Ginsberg, M., Danuser, G. & Waterman-Storer, C. M. (2004)}Mol. Biol. Cell15, Suppl., 177a (abstr.).

Footnotes

References

1. Bershadsky, A. D., Balaban, N. Q. & Geiger, B. (2003) Annu. Rev. Cell Dev. Biol.19, 677–695. [[PubMed]
2. Geiger, B. & Bershadsky, A. (2001) Curr. Opin. Cell Biol.13, 584–592. [[PubMed]
3. Geiger, B. & Bershadsky, A. (2002) Cell110, 139–142. [[PubMed]
4. Zamir, E. & Geiger, B. (2001) J. Cell Sci.114, 3583–3590. [[PubMed]
5. Zamir, E. & Geiger, B. (2001) J. Cell Sci.114, 3577–3579. [[PubMed]
6. Nicolas, A., Geiger, B. & Safran, S. (2004) Proc. Natl. Acad. Sci. USA101, 12520–12525.
7. Novak, I. L., Slepchenko, B. M., Mogilner, A. & Loew, L. M. (2004) Phys. Rev. Lett.93, 268109. [[PubMed]
8. Bresnick, A. R. (1999) Curr. Opin. Cell Biol.11, 26–33. [[PubMed]
9. Somlyo, A. P. & Somlyo, A. V. (2000) J. Physiol.522, 177–185.
10. Geiger, B., Bershadsky, A., Pankov, R. & Yamada, K. M. (2001) Nat. Rev. Mol. Cell. Biol.2, 793–805. [[PubMed]
11. Smilenov, L. B., Mikhailov, A., Pelham, R. J., Marcantonio, E. E. & Gundersen, G. G. (1999) Science286, 1172–1174. [[PubMed]
12. Zamir, E., Katz, M., Posen, Y., Erez, N., Yamada, K. M., Katz, B. Z., Lin, S., Lin, D. C., Bershadsky, A., Kam, Z. & Geiger, B. (2000) Nat. Cell Biol.2, 191–196. [[PubMed]
13. Wehrle-Haller, B. & Imhof, B. (2002) Trends Cell Biol.12, 382–389. [[PubMed]
14. Webb, D. J., Parsons, J. T. & Horwitz, A. F. (2002) Nat. Cell Biol.4, E97–E100. [[PubMed]
15. Small, J. V. & Kaverina, I. (2003) Curr. Opin. Cell Biol.15, 40–47. [[PubMed]
16. Ballestrem, C., Hinz, B., Imhof, B. A. & Wehrle-Haller, B. (2001) J. Cell Biol.155, 1319–1332.
17. Tsuruta, D., Gonzales, M., Hopkinson, S. B., Otey, C., Khuon, S., Goldman, R. D. & Jones, J. C. (2002) FASEB J.16, 866–868. [[PubMed]
18. Riveline, D., Zamir, E., Balaban, N. Q., Schwarz, U. S., Ishizaki, T., Narumiya, S., Kam, Z., Geiger, B. & Bershadsky, A. D. (2001) J. Cell Biol.153, 1175–1186.
19. Balaban, N. Q., Schwarz, U. S., Riveline, D., Goichberg, P., Tzur, G., Sabanay, I., Mahalu, D., Safran, S., Bershadsky, A., Addadi, L. & Geiger, B. (2001) Nat. Cell Biol.3, 466–472. [[PubMed]
20. Hill, T. L. (1987) Linear Aggregation Theory in Cell Biology (Springer, New York).
21. von Wichert, G., Haimovich, B., Feng, G. S. & Sheetz, M. P. (2003) EMBO J.22, 5023–5035.
22. Munevar, S., Wang, Y. L. & Dembo, M. (2004) J. Cell Sci.117, 85–92. [[PubMed]
23. Reif, F(1965) Fundamentals of Statistical and Thermal Physics (McGraw, New York).[Google Scholar]
24. Gibbs, J. W. (1961) The Scientific Papers (Dover, New York).
25. Hill, T. L. & Kirschner, M. W. (1982) Int. Rev. Cytol.78, 1–125. [[PubMed]
26. Helfman, D. M., Levy, E. T., Berthier, C., Shtutman, M., Riveline, D., Grosheva, I., Lachish-Zalait, A., Elbaum, M. & Bershadsky, A. D. (1999) Mol. Biol. Cell10, 3097–3112.
27. Chrzanowska-Wodnicka, M. & Burridge, K. (1996) J. Cell Biol.133, 1403–1415.
28. Kozlov, M. M. & Bershadsky, A. D. (2004) J. Cell Biol.167, 1011–1017.
29. Springer, T. A. & Wang, J. H. (2004) Adv. Protein Chem.68, 29–63. [[PubMed]
30. Hynes, R. O. (2002) Cell110, 673–687. [[PubMed]
31. Izard, T., Evans, G., Borgon, R. A., Rush, C. L., Bricogne, G. & Bois, P. R. (2004) Nature427, 171–175. [[PubMed]
32. Bruinsma, R(2005) Biophys. J.89, 87–94. [Google Scholar]