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Science 323 (5914): 642-644

Copyright © 2009 by the American Association for the Advancement of Science

Mechanically Activated Integrin Switch Controls {alpha}5β1 Function

Julie C. Friedland,1,2* Mark H. Lee,1,2* David Boettiger1,2,3{dagger}

Abstract: The cytoskeleton, integrin-mediated adhesion, and substrate stiffness control a common set of cell functions required for development and homeostasis that are often deranged in cancer. The connection between these mechanical elements and chemical signaling processes is not known. Here, we show that {alpha}5β1 integrin switches between relaxed and tensioned states in response to myosin II–generated cytoskeletal force. Force combines with extracellular matrix stiffness to generate tension that triggers the integrin switch. This switch directly controls the {alpha}5β1-fibronectin bond strength through engaging the synergy site in fibronectin and is required to generate signals through phosphorylation of focal adhesion kinase. In the context of tissues, this integrin switch connects cytoskeleton and extracellular matrix mechanics to adhesion-dependent motility and signaling pathways.

1 Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.

* These authors contributed equally to the work.

{dagger} To whom correspondence should be addressed: E-mail: boettige{at}

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F. L. Miles and R. A. Sikes (2014)
Mol. Cancer Res. 12, 297-312
   Abstract »    Full Text »    PDF »
Mechanosensing through focal adhesion-anchored intermediate filaments.
M. Gregor, S. Osmanagic-Myers, G. Burgstaller, M. Wolfram, I. Fischer, G. Walko, G. P. Resch, A. Jorgl, H. Herrmann, and G. Wiche (2014)
FASEB J 28, 715-729
   Abstract »    Full Text »    PDF »
Engineered Micromechanical Cues Affecting Human Pluripotent Stem Cell Regulations and Fate.
D. Nampe and H. Tsutsui (2013)
Journal of Laboratory Automation 18, 482-493
   Abstract »    Full Text »    PDF »
Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins.
J. Seong, A. Tajik, J. Sun, J.-L. Guan, M. J. Humphries, S. E. Craig, A. Shekaran, A. J. Garcia, S. Lu, M. Z. Lin, et al. (2013)
PNAS 110, 19372-19377
   Abstract »    Full Text »    PDF »
Molecular Biology of Atherosclerosis.
P. N. Hopkins (2013)
Physiol Rev 93, 1317-1542
   Abstract »    Full Text »    PDF »
How vinculin regulates force transmission.
D. W. Dumbauld, T. T. Lee, A. Singh, J. Scrimgeour, C. A. Gersbach, E. A. Zamir, J. Fu, C. S. Chen, J. E. Curtis, S. W. Craig, et al. (2013)
PNAS 110, 9788-9793
   Abstract »    Full Text »    PDF »
Mechanosensitivity and compositional dynamics of cell-matrix adhesions.
H. B. Schiller and R. Fassler (2013)
EMBO Rep. 14, 509-519
   Abstract »    Full Text »    PDF »
Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes.
C. L. Carraher and J. E. Schwarzbauer (2013)
J. Biol. Chem. 288, 14805-14814
   Abstract »    Full Text »    PDF »
Using force to visualize conformational activation of integrins.
D. Boettiger (2012)
J. Cell Biol. 199, 423-424
   Abstract »    Full Text »    PDF »
Direct observation of proteolytic cleavage at the S2 site upon forced unfolding of the Notch negative regulatory region.
N. L. Stephenson and J. M. Avis (2012)
PNAS 109, E2757-E2765
   Abstract »    Full Text »    PDF »
Finding the weakest link - exploring integrin-mediated mechanical molecular pathways.
P. Roca-Cusachs, T. Iskratsch, and M. P. Sheetz (2012)
J. Cell Sci. 125, 3025-3038
   Abstract »    Full Text »    PDF »
Laminin Interactions with Head and Neck Cancer Cells under Low Fluid Shear Conditions Lead to Integrin Activation and Binding.
S. M. Fennewald, C. Kantara, S. K. Sastry, and V. A. Resto (2012)
J. Biol. Chem. 287, 21058-21066
   Abstract »    Full Text »    PDF »
Matrix rigidity regulates a switch between TGF-{beta}1-induced apoptosis and epithelial-mesenchymal transition.
J. L. Leight, M. A. Wozniak, S. Chen, M. L. Lynch, and C. S. Chen (2012)
Mol. Biol. Cell 23, 781-791
   Abstract »    Full Text »    PDF »
Mechanical stress-activated integrin {alpha}5{beta}1 induces opening of connexin 43 hemichannels.
N. Batra, S. Burra, A. J. Siller-Jackson, S. Gu, X. Xia, G. F. Weber, D. DeSimone, L. F. Bonewald, E. M. Lafer, E. Sprague, et al. (2012)
PNAS 109, 3359-3364
   Abstract »    Full Text »    PDF »
Mechanoinduction of lymph vessel expansion.
L. Planas-Paz, B. Strilic, A. Goedecke, G. Breier, R. Fassler, and E. Lammert (2012)
EMBO J. 31, 788-804
   Abstract »    Full Text »    PDF »
Early integrin binding to Arg-Gly-Asp peptide activates actin polymerization and contractile movement that stimulates outward translocation.
C.-h. Yu, J. B. K. Law, M. Suryana, H. Y. Low, and M. P. Sheetz (2011)
PNAS 108, 20585-20590
   Abstract »    Full Text »    PDF »
Integrin adhesion and force coupling are independently regulated by localized PtdIns(4,5)2 synthesis.
K. R. Legate, S. Takahashi, N. Bonakdar, B. Fabry, D. Boettiger, R. Zent, and R. Fassler (2011)
EMBO J. 30, 4539-4553
   Abstract »    Full Text »    PDF »
The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation.
A. C. Newman, M. N. Nakatsu, W. Chou, P. D. Gershon, and C. C. W. Hughes (2011)
Mol. Biol. Cell 22, 3791-3800
   Abstract »    Full Text »    PDF »
Contractile Forces Contribute to Increased Glycosylphosphatidylinositol-anchored Receptor CD24-facilitated Cancer Cell Invasion.
C. T. Mierke, N. Bretz, and P. Altevogt (2011)
J. Biol. Chem. 286, 34858-34871
   Abstract »    Full Text »    PDF »
{beta}1 integrin cytoplasmic tyrosines promote skin tumorigenesis independent of their phosphorylation.
A. Meves, T. Geiger, S. Zanivan, J. DiGiovanni, M. Mann, and R. Fassler (2011)
PNAS 108, 15213-15218
   Abstract »    Full Text »    PDF »
Integrins in Cell Migration.
A. Huttenlocher and A. R. Horwitz (2011)
Cold Spring Harb Perspect Biol 3, a005074
   Abstract »    Full Text »    PDF »
Fibronectins, Their Fibrillogenesis, and In Vivo Functions.
J. E. Schwarzbauer and D. W. DeSimone (2011)
Cold Spring Harb Perspect Biol 3, a005041
   Abstract »    Full Text »    PDF »
Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity.
J. Du, X. Chen, X. Liang, G. Zhang, J. Xu, L. He, Q. Zhan, X.-Q. Feng, S. Chien, and C. Yang (2011)
PNAS 108, 9466-9471
   Abstract »    Full Text »    PDF »
Actomyosin-generated tension controls the molecular kinetics of focal adhesions.
H. Wolfenson, A. Bershadsky, Y. I. Henis, and B. Geiger (2011)
J. Cell Sci. 124, 1425-1432
   Abstract »    Full Text »    PDF »
Molecular Architecture and Function of Matrix Adhesions.
B. Geiger and K. M. Yamada (2011)
Cold Spring Harb Perspect Biol 3, a005033
   Abstract »    Full Text »    PDF »
Myosin IIA/IIB restrict adhesive and protrusive signaling to generate front-back polarity in migrating cells.
M. Vicente-Manzanares, K. Newell-Litwa, A. I. Bachir, L. A. Whitmore, and A. R. Horwitz (2011)
J. Cell Biol. 193, 381-396
   Abstract »    Full Text »    PDF »
Integrin {alpha}5{beta}1 facilitates cancer cell invasion through enhanced contractile forces.
C. T. Mierke, B. Frey, M. Fellner, M. Herrmann, and B. Fabry (2011)
J. Cell Sci. 124, 369-383
   Abstract »    Full Text »    PDF »
Mechanisms of mechanical signaling in development and disease.
P. A. Janmey and R. T. Miller (2011)
J. Cell Sci. 124, 9-18
   Abstract »    Full Text »    PDF »
The extracellular matrix at a glance.
C. Frantz, K. M. Stewart, and V. M. Weaver (2010)
J. Cell Sci. 123, 4195-4200
   Full Text »    PDF »
Integrins and Extracellular Matrix in Mechanotransduction.
M. A. Schwartz (2010)
Cold Spring Harb Perspect Biol 2, a005066
   Abstract »    Full Text »    PDF »
Forcing Switch from Short- to Intermediate- and Long-lived States of the {alpha}A Domain Generates LFA-1/ICAM-1 Catch Bonds.
W. Chen, J. Lou, and C. Zhu (2010)
J. Biol. Chem. 285, 35967-35978
   Abstract »    Full Text »    PDF »
Spatiotemporal organization, regulation, and functions of tractions during neutrophil chemotaxis.
M. E. Shin, Y. He, D. Li, S. Na, F. Chowdhury, Y.-C. Poh, O. Collin, P. Su, P. de Lanerolle, M. A. Schwartz, et al. (2010)
Blood 116, 3297-3310
   Abstract »    Full Text »    PDF »
Tethering of Intercellular Adhesion Molecule on Target Cells Is Required for LFA-1-Dependent NK Cell Adhesion and Granule Polarization.
C. C. Gross, J. A. Brzostowski, D. Liu, and E. O. Long (2010)
J. Immunol. 185, 2918-2926
   Abstract »    Full Text »    PDF »
Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression.
F. Liu, J. D. Mih, B. S. Shea, A. T. Kho, A. S. Sharif, A. M. Tager, and D. J. Tschumperlin (2010)
J. Cell Biol. 190, 693-706
   Abstract »    Full Text »    PDF »
Spatial organization of adhesion: force-dependent regulation and function in tissue morphogenesis.
E. Papusheva and C.-P. Heisenberg (2010)
EMBO J. 29, 2753-2768
   Abstract »    Full Text »    PDF »
The switchable integrin adhesome.
R. Zaidel-Bar and B. Geiger (2010)
J. Cell Sci. 123, 1385-1388
   Full Text »    PDF »
Pericellular fibronectin is required for RhoA-dependent responses to cyclic strain in fibroblasts.
R. Lutz, T. Sakai, and M. Chiquet (2010)
J. Cell Sci. 123, 1511-1521
   Abstract »    Full Text »    PDF »
Focal adhesions are sites of integrin extension.
J. A. Askari, C. J. Tynan, S. E.D. Webb, M. L. Martin-Fernandez, C. Ballestrem, and M. J. Humphries (2010)
J. Cell Biol. 188, 891-903
   Abstract »    Full Text »    PDF »
Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylation.
A. M. Pasapera, I. C. Schneider, E. Rericha, D. D. Schlaepfer, and C. M. Waterman (2010)
J. Cell Biol. 188, 877-890
   Abstract »    Full Text »    PDF »
Targeting of Integrin {beta}1 and Kinesin 2{alpha} by MicroRNA 183.
G. Li, C. Luna, J. Qiu, D. L. Epstein, and P. Gonzalez (2010)
J. Biol. Chem. 285, 5461-5471
   Abstract »    Full Text »    PDF »
Matrix elasticity, cytoskeletal forces and physics of the nucleus: how deeply do cells 'feel' outside and in?.
A. Buxboim, I. L. Ivanovska, and D. E. Discher (2010)
J. Cell Sci. 123, 297-308
   Abstract »    Full Text »    PDF »
Recreation of the terminal events in physiological integrin activation.
F. Ye, G. Hu, D. Taylor, B. Ratnikov, A. A. Bobkov, M. A. McLean, S. G. Sligar, K. A. Taylor, and M. H. Ginsberg (2010)
J. Cell Biol. 188, 157-173
   Abstract »    Full Text »    PDF »
Nanotopographical Control of Stem Cell Differentiation.
L. E. McNamara, R. J. McMurray, M. J. P. Biggs, F. Kantawong, R. O. C. Oreffo, and M. J. Dalby (2010)
Journal of Tissue Engineering 1, 120623
   Abstract »    Full Text »    PDF »
Integrin Activation Dynamics between the RGD-binding Site and the Headpiece Hinge.
E. Puklin-Faucher and V. Vogel (2009)
J. Biol. Chem. 284, 36557-36568
   Abstract »    Full Text »    PDF »
Clustering of {alpha}5{beta}1 integrins determines adhesion strength whereas {alpha}v{beta}3 and talin enable mechanotransduction.
P. Roca-Cusachs, N. C. Gauthier, A. del Rio, and M. P. Sheetz (2009)
PNAS 106, 16245-16250
   Abstract »    Full Text »    PDF »
Proteomic Analysis of Integrin-Associated Complexes Identifies RCC2 as a Dual Regulator of Rac1 and Arf6.
J. D. Humphries, A. Byron, M. D. Bass, S. E. Craig, J. W. Pinney, D. Knight, and M. J. Humphries (2009)
Science Signaling 2, ra51
   Abstract »    Full Text »    PDF »
Demonstration of catch bonds between an integrin and its ligand.
F. Kong, A. J. Garcia, A. P. Mould, M. J. Humphries, and C. Zhu (2009)
J. Cell Biol. 185, 1275-1284
   Abstract »    Full Text »    PDF »
Multiscale Modeling of Form and Function.
A. J. Engler, P. O. Humbert, B. Wehrle-Haller, and V. M. Weaver (2009)
Science 324, 208-212
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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