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Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity
Abstract
Cell function depends on tissue rigidity, which cells probe by applying and transmitting forces to their extracellular matrix, and then transducing them into biochemical signals. Here we show that in response to matrix rigidity and density, force transmission and transduction are explained by the mechanical properties of the actin-talin-integrin-fibronectin clutch. We demonstrate that force transmission is regulated by a dynamic clutch mechanism, which unveils its fundamental biphasic force/rigidity relationship on talin depletion. Force transduction is triggered by talin unfolding above a stiffness threshold. Below this threshold, integrins unbind and release force before talin can unfold. Above the threshold, talin unfolds and binds to vinculin, leading to adhesion growth and YAP nuclear translocation. Matrix density, myosin contractility, integrin ligation and talin mechanical stability differently and nonlinearly regulate both force transmission and the transduction threshold. In all cases, coupling of talin unfolding dynamics to a theoretical clutch model quantitatively predicts cell response.
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“However, beyond acting as a physical barrier, ECM stiffness also triggers mechanotransduction pathways that profoundly influence tumor cell behavior [91,92]. Mechanical cues generated by a stiffened matrix are sensed through integrin-based focal adhesions and transmitted via cytoskeletal tension to activate intracellular signaling cascades, including Yes-associated protein/Transcriptional coactiv”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [93]
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“We developed a modified motor-clutch model that includes force-dependent recruitment of adhesion components in response to substrate stiffness, similar to recently proposed models (Elosegui-Artola et al., 2014, 2016).”
BackgroundMethodArgentati, C., Morena, F., Tortorella, I., Bazzucchi, M., Porcellati, S., Emiliani, C., & Martino, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215337 · Cited by 143
Lamellipodium is a myosin-independent mechanosensor
Oakes, P. W., Bidone, T. C., Beckham, Y., Skeeters, A. V., Juan, G. R. R.-S., Winter, S. P., Voth, G. A., & Gardel, M. L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1715869115 · Cited by 133
“Conceptually, this framework is similar to the general motorclutch model (54) that has been suggested as a mechanism for understanding mechanosensitivity (23, 24, 26, 27).”
ResultExtracellular matrix type modulates mechanotransduction of stem cells
Stanton, A. E., Tong, X., & Yang, F. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.06.048 · Cited by 132
“To characterize YAP localization in a quantitative manner, we employed a method [21] which reports the ratio of nuclear YAP intensity vs.”
MethodAdjustable viscoelasticity allows for efficient collective cell migration
Barriga, E. H., & Mayor, R. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.05.027 · Cited by 131
d’Angelo, M., Benedetti, E., Tupone, M. G., Catanesi, M., Castelli, V., Antonosante, A., & Cimini, A. (2019) · Cells · doi:10.3390/cells8091036 · Cited by 132
Cell monolayers sense curvature by exploiting active mechanics and nuclear mechanoadaptation
Luciano, M., Xue, S.-L., Vos, W. H. D., Redondo‐Morata, L., Surin, M., Lafont, F., Hannezo, É., & Gabriele, S. (2021) · Nature Physics · doi:10.1038/s41567-021-01374-1 · Cited by 128
Actomyosin contractility-dependent matrix stretch and recoil induces rapid cell migration
Wang, W. Y., Davidson, C. D., Lin, D., & Baker, B. M. (2019) · Nature Communications · doi:10.1038/s41467-019-09121-0 · Cited by 134
Fiore, V. F., Wong, S. S., Tran, C., Tan, C., Xu, W., Sulchek, T., White, E. S., Hagood, J. S., & Barker, T. H. (2018) · JCI Insight · doi:10.1172/jci.insight.97597 · Cited by 126
Andreu, I., Falcones, B., Hurst, S., Chahare, N. R., Quiroga, X., Roux, A. L., Kechagia, Z., Beedle, A. E. M., Elósegui-Artola, A., Trepat, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24383-3 · Cited by 121
Graham, D. M., Andersen, T., Sharek, L., Uzer, G., Rothenberg, K. E., Hoffman, B. D., Rubin, J. E., Balland, M., Bear, J. E., & Burridge, K. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201706097 · Cited by 119
“During the past few years, much has been learned about how tension exerted on the clutch affects the properties and interactions of components mediating adhesion (Elosegui-Artola et al., 2016).”
BackgroundPutra, V. D. L., Kilian, K. A., & Tate, M. L. K. (2023) · Communications Biology · doi:10.1038/s42003-022-04320-w · Cited by 121
The Plot Thickens: The Emerging Role of Matrix Viscosity in Cell Mechanotransduction
Cantini, M., Donnelly, H., Dalby, M. J., & Salmerón‐Sánchez, M. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201901259 · Cited by 119
Miller, A. E., Hu, P., & Barker, T. H. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.201901445 · Cited by 119
Single Molecule Force Measurements in Living Cells Reveal a Minimally Tensioned Integrin State
Chang, A. C., Mekhdjian, A. H., Morimatsu, M., Denisin, A. K., Pruitt, B. L., & Dunn, A. R. (2016) · ACS Nano · doi:10.1021/acsnano.6b03314 · Cited by 115
Extracellular fluid viscosity enhances liver cancer cell mechanosensing and migration
Gonzalez‐Molina, J., Zhang, X., Borghesan, M., da Silva, J. M., Awan, M., Fuller, B. J., Gavara, N., & Selden, C. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.05.058 · Cited by 115
“This model explains rigidity sensing considering the differences in integrin-ECM bond lifetime and force loading rates in soft and stiff substrates determining force transmission to the intracellular protein talin, which leads to adhesion reinforcement and mechanotransduction pathway activation [24].”
BackgroundMechanics in the nervous system: From development to disease
Pillai, E. K., & Franze, K. (2023) · Neuron · doi:10.1016/j.neuron.2023.10.005 · Cited by 126
“58 Furthermore, integrins form catch bonds with their ECM binding partners, 59 and the life-times of these bonds increase with the tensile force applied.”
Cao, X. D., Ban, E., Baker, B. M., Lin, Y., Burdick, J. A., Chen, C. S., & Shenoy, V. B. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620486114 · Cited by 109
“It is well known that the bonds formed between integrins and ECM are highly dynamic (9, 20, 40).”
BackgroundInfluentialExtracellular matrix plasticity as a driver of cell spreading
Grolman, J. M., Weinand, P., & Mooney, D. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008801117 · Cited by 115
“These cues include cell–cell interactions (5), soluble signaling molecules (6), and adhesion to the extracellular matrix (ECM) via transmembrane receptors (7, 8); the physical properties of the ECM, particularly its stiffness (9) and rate of stress relaxation, are known to regulate the ability of a variety of cell typ…”
BackgroundResultZhou, D. W., Lee, T. T., Weng, S., Fu, J., & Garcı́a, A. J. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-02-0116 · Cited by 119
“Indeed, this is consistent with recent work showing that increases in substrate stiffness promote talin’s ability to unfold and bind vinculin to promote force transmission (Elosegui-Artola et al., 2016).”
BackgroundExtracellular Matrix Components and Mechanosensing Pathways in Health and Disease
Berdiaki, A., Neagu, M. T., Tzanakakis, P., Spyridaki, I., Pérez, S., & Nikitovic, D. (2024) · Biomolecules · doi:10.3390/biom14091186 · Cited by 117
Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading
Cruz, J. O. L., Nardone, G., Vrbský, J., Pompeiano, A., Perestrelo, A. R., Capradossi, F., Melajová, K., Filipenský, P., & Forte, G. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.03.009 · Cited by 111
“Hydrogels of di ff erent sti ff nesses were obtained by mixing di ff erent proportions of thrombin and fi brinogen according to previously published data [27], in order to produce compliant (300 Pa) and sti ff (5 kPa) hydrogels able to di ff erentially control YAP nuclear localization [56].”
Chirality Controls Mesenchymal Stem Cell Lineage Diversification through Mechanoresponses
Wei, Y. Q., Jiang, S., Si, M., Zhang, X., Liu, J., Wang, Z., Cao, C., Huang, J., Huang, H., Chen, L., et al. (2019) · Advanced Materials · doi:10.1002/adma.201900582 · Cited by 110
Hippo signalling during development
Davis, J. R., & Tapon, N. (2019) · Development · doi:10.1242/dev.167106 · Cited by 113
“When cells are cultured on soft substrates (<3 kPa) YAP/TAZ are cytoplasmic; however, their nuclear localisation increases when cultured on rigid substrates (>10 kPa) (Dupont et al., 2011; Elosegui-Artola et al., 2016).”
BackgroundTraction force microscopy – Measuring the forces exerted by cells
Lekka, M., Gnanachandran, K., Kubiak, A., Zieliński, T., & Zemła, J. (2021) · Micron · doi:10.1016/j.micron.2021.103138 · Cited by 115
Vinculin Force-Sensitive Dynamics at Focal Adhesions Enable Effective Directed Cell Migration
Rothenberg, K. E., Scott, D. W., Christoforou, N., & Hoffman, B. D. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.02.019 · Cited by 110
“Based on these results, it has been suggested that either talin, vinculin, or the interaction of talin and vinculin, is the key component of the molecular clutch or the crucial element in force-induced FA strengthening (15,25,30,45,47).”
BackgroundResultCell-Extracellular Matrix Dynamics
Doyle, A., Nazari, S. S., & Yamada, K. M. (2021) · Physical Biology · doi:10.1088/1478-3975/ac4390 · Cited by 88
Actin polymerization downstream of integrins: signaling pathways and mechanotransduction
Romero, S., Clainche, C. L., & Gautreau, A. M. (2020) · Biochemical Journal · doi:10.1042/bcj20170719 · Cited by 111
Integrating Chemistry and Mechanics: The Forces Driving Axon Growth
Franze, K. (2020) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100818-125157 · Cited by 106
Metadata
- Authors
- Elosegui-Artola, A., Oria, R., Chen, Y., Kosmalska, A., Pérez-González, C., Castro, N., Zhu, C., Trepat, X., & Roca-Cusachs, P.
- Affiliations
- Institute for Bioengineering of Catalonia (ES)
- Georgia Institute of Technology (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Venue
- Nature Cell Biology
- Published
- 2016-04-11
- Volume
- 18
- Issue
- 5
- Pages
- 540-548
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2327893020
- Cited by
- 858
- References
- 57
- Citations by year
- 2026: 72 · 2025: 101 · 2024: 87 · 2023: 93 · 2022: 103 · 2021: 93 · 2020: 96 · 2019: 71 · 2018: 67 · 2017: 60 · 2016: 15
- FWCI
- 48.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI044902)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Force Microscopy Techniques and Applications
- Keywords
- molecular clutch, matrix rigidity, force transmission, mechanotransduction, vinculin, YAP nuclear translocation, cell adhesion, extracellular matrix stiffness, myosin contractility, actin cytoskeleton, fibronectin
- MeSH terms
- YAP-Signaling Proteins, Animals, Biomechanical Phenomena, Cell Adhesion, Cell Nucleus, Cytoskeleton, Extracellular Matrix, Fibronectins, Phosphoproteins, Phosphorylation, Protein Binding, Integrins, Vinculin, Talin, Cell Cycle Proteins, Protein Transport, Stress Fibers, Mechanotransduction, Cellular, Adaptor Proteins, Signal Transducing, Mice, Focal Adhesion Protein-Tyrosine Kinases
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