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

Nature Cell Biology volume 18, pages 540548 (2016) | Download Citation

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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Acknowledgements

We acknowledge support from the Spanish Ministry for Economy and Competitiveness (BFU2011-23111, BFU2012-38146 and BFU2014-52586-REDT), a Career Integration Grant within the seventh European Community Framework Programme (PCIG10-GA-2011-303848), the European Research Council (Grant Agreements 242993 and 240487), the Generalitat de Catalunya, Fundació La Caixa, Fundació la Marató de TV3 (project 20133330), and the National Institutes of Health (US NIH R01AI044902). A.E.-A., R.O. and C.P.-G. were supported respectively by a Juan de la Cierva Fellowship (Spanish Ministry of Economy and Competitiveness), a FI fellowship (Generalitat de Catalunya), and the fundació ‘La Caixa’. We thank R. Sunyer, J. Alcaraz, E. Bazellières, F. Rico, S. Garcia-Manyes, N. Bate, N. Berrow and the members of the P.R.-C. and X.T. laboratories for technical assistance and discussions.

Author information

Affiliations

  1. Institute for Bioengineering of Catalonia, Barcelona 08028, Spain

    • Alberto Elosegui-Artola
    • , Roger Oria
    • , Anita Kosmalska
    • , Carlos Pérez-González
    • , Natalia Castro
    • , Xavier Trepat
    •  & Pere Roca-Cusachs
  2. University of Barcelona, Barcelona 08028, Spain

    • Roger Oria
    • , Anita Kosmalska
    • , Carlos Pérez-González
    • , Xavier Trepat
    •  & Pere Roca-Cusachs
  3. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    • Yunfeng Chen
    •  & Cheng Zhu
  4. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    • Yunfeng Chen
    •  & Cheng Zhu
  5. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    • Cheng Zhu
  6. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain

    • Xavier Trepat
  7. Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid 28029, Spain

    • Xavier Trepat

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Contributions

A.E.-A. and P.R.-C. conceived the study, A.E.-A., C.Z., X.T. and P.R.-C. designed the experiments, A.E.-A., R.O., Y.C., A.K., C.P.-G. and N.C. performed the experiments, P.R.-C. carried out the theoretical modelling, and A.E.-A. and P.R.-C. wrote the paper.

Competing interests

The results have been protected under a patent application.

Corresponding author

Correspondence to Pere Roca-Cusachs.

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DOI

https://doi.org/10.1038/ncb3336

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