Cited by 862Cellular Mechanics and InteractionsCell Adhesion Molecules ResearchForce Microscopy Techniques and Applications

Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity

Elosegui-Artola, Alberto, Oria, Roger, Chen, Yunfeng, Kosmalska, Anita, Pérez-González, Carlos, Castro, Natalia, Zhu, Cheng, Trepat, Xavier +1 more·2016·Nature Cell Biology

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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  • ECM stiffness triggers mechanotransduction pathways that influence tumor cell behavior, including activation of YAP/TAZ, FAK, and MAPK pathways and modulation of gene expression associated with proliferation, EMT, and drug resistance.

    “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]

    The paper’s opening summary (p. 1) reports that matrix rigidity can trigger talin unfolding, adhesion growth, and YAP nuclear translocation; the Discussion (p. 9) likewise describes a rigidity threshold for YAP signaling. The study uses mouse embryonic fibroblasts, not tumor cells, and the cited passages do not establish activation of FAK or MAPK pathways or changes in genes associated with proliferation, EMT, or drug resistance. (LLM, conf=0.87)

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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
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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