title: 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.
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Elosegui-Artola
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|University of Barcelona, Barcelona 08028, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Oria
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.|Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|University of Barcelona, Barcelona 08028, Spain.
authors.forename: Anita
authors.initials: A
authors.lastname: Kosmalska
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|University of Barcelona, Barcelona 08028, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-González
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Castro
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.|Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.|Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|University of Barcelona, Barcelona 08028, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.|Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Madrid 28029, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Trepat
authors.affiliation: Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.|University of Barcelona, Barcelona 08028, Spain.
authors.forename: Pere
authors.identifier: 0000-0001-6947-961X
authors.initials: P
authors.lastname: Roca-Cusachs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D022502:Stress Fibers / Q000378:metabolism; D016608:Talin / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D005353:Fibronectins; D016023:Integrins; D010750:Phosphoproteins; D016608:Talin; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D016596:Vinculin; D051416:Focal Adhesion Protein-Tyrosine Kinases