Skip to main content

Thank you for visiting 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.

Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin A


Mechanical stresses elicit cellular reactions mediated by chemical signals. Defective responses to forces underlie human medical disorders1,2,3,4 such as cardiac failure5 and pulmonary injury6. The actin cytoskeleton’s connectivity enables it to transmit forces rapidly over large distances7, implicating it in these physiological and pathological responses. Despite detailed knowledge of the cytoskeletal structure, the specific molecular switches that convert mechanical stimuli into chemical signals have remained elusive. Here we identify the actin-binding protein filamin A (FLNA)8,9 as a central mechanotransduction element of the cytoskeleton. We reconstituted a minimal system consisting of actin filaments, FLNA and two FLNA-binding partners: the cytoplasmic tail of β-integrin, and FilGAP. Integrins form an essential mechanical linkage between extracellular and intracellular environments, with β-integrin tails connecting to the actin cytoskeleton by binding directly to filamin4. FilGAP is an FLNA-binding GTPase-activating protein specific for RAC, which in vivo regulates cell spreading and bleb formation10. Using fluorescence loss after photoconversion, a novel, high-speed alternative to fluorescence recovery after photobleaching11, we demonstrate that both externally imposed bulk shear and myosin-II-driven forces differentially regulate the binding of these partners to FLNA. Consistent with structural predictions, strain increases β-integrin binding to FLNA, whereas it causes FilGAP to dissociate from FLNA, providing a direct and specific molecular basis for cellular mechanotransduction. These results identify a molecular mechanotransduction element within the actin cytoskeleton, revealing that mechanical strain of key proteins regulates the binding of signalling molecules.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Differential mechanotransduction in FLNA occurs through spatial separation of binding sites and opening cryptic sites.
Figure 2: External bulk shear of F-actin/FLNA networks alters FLNA’s binding affinity for β 7 -integrin and FilGAP.
Figure 3: Myosin II forces applied to F-actin/FLNA networks change FLNA’s binding affinity to β 7 -integrin and FilGAP.


  1. 1

    Ingber, D. E. Mechanobiology and diseases of mechanotransduction. Ann. Med. 35, 564–577 (2003)

    Article  Google Scholar 

  2. 2

    Discher, D. E., Janmey, P. & Wang, Y. L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Moore, S. W., Roca-Cusachs, P. & Sheetz, M. P. Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing. Dev. Cell 19, 194–206 (2010)

    CAS  Article  Google Scholar 

  4. 4

    Hoffman, B. D. et al. Dynamic molecular processes mediate cellular mechanotransduction. Nature 475, 316–323 (2011)

    CAS  Article  Google Scholar 

  5. 5

    Krüger, M. & Linke, W. A. Titin-based mechanical signalling in normal and failing myocardium. J. Mol. Cell. Cardiol. 46, 490–498 (2009)

    Article  Google Scholar 

  6. 6

    Birukov, K. G. Small GTPases in mechanosensitive regulation of endothelial barrier. Microvasc. Res. 77, 46–52 (2009)

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Stossel, T. P. et al. Filamins as integrators of cell mechanics and signalling. Nature Rev. Mol. Cell Biol. 2, 138–145 (2001)

    CAS  Article  Google Scholar 

  9. 9

    Nakamura, F., Stossel, T. P. & Hartwig, J. H. The filamins: organizers of cell structure and function. Cell Adh. Migr. 5, 160–169 (2011)

    Article  Google Scholar 

  10. 10

    Ohta, Y., Hartwig, J. H. & Stossel, T. P. FilGAP, a Rho- and ROCK-regulated GAP for Rac binds filamin A to control actin remodelling. Nature Cell Biol. 8, 803–814 (2006)

    CAS  Article  Google Scholar 

  11. 11

    Sprague, B. L., Pego, R. L., Stavreva, D. A. & McNally, J. G. Analysis of binding reactions by fluorescence recovery after photobleaching. Biophys. J. 86, 3473–3495 (2004)

    CAS  Article  Google Scholar 

  12. 12

    Nakamura, F., Osborn, T. M., Hartemink, C. A., Hartwig, J. H. & Stossel, T. P. Structural basis of filamin A functions. J. Cell Biol. 179, 1011–1025 (2007)

    CAS  Article  Google Scholar 

  13. 13

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

    ADS  CAS  Article  Google Scholar 

  14. 14

    Calderwood, D. A. et al. Increased filamin binding to β-integrin cytoplasmic domains inhibits cell migration. Nature Cell Biol. 3, 1060–1068 (2001)

    CAS  Article  Google Scholar 

  15. 15

    Lad, Y. et al. Structure of three tandem filamin domains reveals auto-inhibition of ligand binding. EMBO J. 26, 3993–4004 (2007)

    CAS  Article  Google Scholar 

  16. 16

    Heikkinen, O. K. et al. Atomic structures of two novel immunoglobulin-like domain pairs in the actin cross-linking protein filamin. J. Biol. Chem. 284, 25450–25458 (2009)

    CAS  Article  Google Scholar 

  17. 17

    Pentikäinen, U. & Ylanne, J. The regulation mechanism for the auto-inhibition of binding of human filamin A to integrin. J. Mol. Biol. 393, 644–657 (2009)

    Article  Google Scholar 

  18. 18

    Chen, H. S., Kolahi, K. S. & Mofrad, M. R. Phosphorylation facilitates the integrin binding of filamin under force. Biophys. J. 97, 3095–3104 (2009)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Nakamura, F. et al. Molecular basis of filamin A-FilGAP interaction and its impairment in congenital disorders associated with filamin A mutations. PLoS ONE 4, e4928 (2009)

    ADS  Article  Google Scholar 

  20. 20

    Koenderink, G. H. et al. An active biopolymer network controlled by molecular motors. Proc. Natl Acad. Sci. USA 106, 15192–15197 (2009)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Humphrey, D., Duggan, C., Saha, D., Smith, D. & Kas, J. Active fluidization of polymer networks through molecular motors. Nature 416, 413–416 (2002)

    ADS  CAS  Article  Google Scholar 

  22. 22

    Smith, D. M. et al. Molecular motor-induced instabilities and crosslinkers determine biopolymer organization. Biophys. J. 93, 4445–4452 (2007)

    ADS  CAS  Article  Google Scholar 

  23. 23

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

    ADS  CAS  Article  Google Scholar 

  24. 24

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

    ADS  CAS  Article  Google Scholar 

  25. 25

    Na, S. et al. Rapid signal transduction in living cells is a unique feature of mechanotransduction. Proc. Natl Acad. Sci. USA 105, 6626–6631 (2008)

    ADS  CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    Shifrin, Y., Arora, P. D., Ohta, Y., Calderwood, D. A. & McCulloch, C. A. The role of FilGAP-filamin A interactions in mechanoprotection. Mol. Biol. Cell 20, 1269–1279 (2009)

    CAS  Article  Google Scholar 

  29. 29

    Johnson, C. P., Tang, H. Y., Carag, C., Speicher, D. W. & Discher, D. E. Forced unfolding of proteins within cells. Science 317, 663–666 (2007)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Krieger, C. C. et al. Cysteine shotgun-mass spectrometry (CS-MS) reveals dynamic sequence of protein structure changes within mutant and stressed cells. Proc. Natl Acad. Sci. USA 108, 8269–8274 (2011)

    ADS  CAS  Article  Google Scholar 

  31. 31

    Fernández-Suárez, M. & Ting, A. Y. Fluorescent probes for super-resolution imaging in living cells. Nature Rev. Mol. Cell Biol. 9, 929–943 (2008)

    Article  Google Scholar 

  32. 32

    van der Flier, A. et al. Different splice variants of filamin-B affect myogenesis, subcellular distribution, and determine binding to integrin β subunits. J. Cell Biol. 156, 361–376 (2002)

    CAS  Article  Google Scholar 

  33. 33

    Nakamura, F., Osborn, E., Janmey, P. A. & Stossel, T. P. Comparison of filamin A-induced cross-linking and Arp2/3 complex-mediated branching on the mechanics of actin filaments. J. Biol. Chem. 277, 9148–9154 (2002)

    CAS  Article  Google Scholar 

  34. 34

    Weissmann, C. et al. Microtubule binding and trapping at the tip of neurites regulate tau motion in living neurons. Traffic 10, 1655–1668 (2009)

    CAS  Article  Google Scholar 

Download references


The authors acknowledge the Harvard Materials Research and Engineering Center (DMR-0820484) for confocal imaging, and M. Ginsberg, J. Lippincott-Schwartz and V. Verkhusha for providing complementary DNA for PA-GFP and PA-mCherry constructs. We thank T. Collins for technical assistance, L. Jawerth and V. Zaburdaev for discussions, and J. Wilking and K. Guenthner for help with the manuscript. This work was supported by grants NIH R01 HL19429 (T.P.S.) and NIH T32 HL07680 (A.J.E.) and by the Harvard University Science and Engineering Committee Seed Fund for Interdisciplinary Science (D.A.W., T.P.S., F.N.).

Author information




The project was initiated by T.P.S., F.N. and D.A.W. Experiments were designed by A.J.E., T.P.S., J.H.H. and F.N. Proteins and materials were synthesized and purified by F.N. and A.J.E. FLAC experiments were performed by A.J.E. and binding assays were performed by F.N. Data was analysed by A.J.E. All authors discussed data and aided in preparing the manuscript. A.J.E. and F.N. contributed equally to this project.

Corresponding authors

Correspondence to A. J. Ehrlicher or F. Nakamura.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-9 with legends. (PDF 3491 kb)

Supplementary Movie 1

The movie shows PA-GFP β7 Integrin binds longer to del41 mutant FLNa than wild type FLNa. (MOV 6767 kb)

Supplementary Movie 2

The movie shows PA-GFP FilGAP binds longer to wild-type FLNa than to M2474E mutant FLNa. (MOV 9969 kb)

Supplementary Movie 3

The movie shows Myosin II deforms actin networks when ATP is available. (MOV 4196 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ehrlicher, A., Nakamura, F., Hartwig, J. et al. Mechanical strain in actin networks regulates FilGAP and integrin binding to filamin A. Nature 478, 260–263 (2011).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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