TY - JOUR
T1 - Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity
AU - Elosegui-Artola, Alberto
AU - Oria, Roger
AU - Chen, Yunfeng
AU - Kosmalska, Anita
AU - Pérez-González, Carlos
AU - Castro, Natalia
AU - Zhu, Cheng
AU - Trepat, Xavier
AU - Roca-Cusachs, Pere
N1 - Funding Information:
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. Bazellires, 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.
Publisher Copyright:
© 2016 Macmillan Publishers Limited.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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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U2 - 10.1038/ncb3336
DO - 10.1038/ncb3336
M3 - Article
C2 - 27065098
AN - SCOPUS:84963600077
SN - 1465-7392
VL - 18
SP - 540
EP - 548
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -