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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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“To verify the respective roles of thesemolecular players versus direct nuclear force, we seeded cells on stiff substrates and abrogated YAP nuclear localization, focal adhesions, and cytoskeletal force transmission by either depolymerizing actin with 2 mM cytochalasin D (Figures S2A–S2F) or depleting talin (Elosegui-A…”
InfluentialIntegrins as biomechanical sensors of the microenvironment
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“Interestingly, under cyclic stretch, MRTF–SRF activation precedes and facilitates YAP/ JCB • Volume 215 • NumBer 4 • 2016452 TAZ activation, suggesting that MRTF–SRF activation is responsible for immediate transcriptional response to mechanical stimulus (Cui et al., 2015).”
BackgroundInfluential
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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