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      YAP regulates cell mechanics by controlling focal adhesion assembly

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          Abstract

          Hippo effectors YAP/TAZ act as on–off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described by a hierarchical model in which elements of Hippo pathway are under the control of focal adhesions (FAs). Here we unveil the molecular mechanism by which cell spreading and RhoA GTPase activity control FA formation through YAP to stabilize the anchorage of the actin cytoskeleton to the cell membrane. This mechanism requires YAP co-transcriptional function and involves the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity leads to the modification of cell mechanics, force development and adhesion strength, and determines cell shape, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify this Hippo effector as the key determinant of cell mechanics in response to ECM cues.

          Abstract

          The transcriptional co-activator YAP is known to operate downstream of mechanical signals arising from the cell niche. Here the authors demonstrate that YAP controls cell mechanics, force development and adhesion strength by promoting the transcription of genes related to focal adhesions.

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          Most cited references35

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          YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

          The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Random versus directionally persistent cell migration.

            Directional migration is an important component of cell motility. Although the basic mechanisms of random cell movement are well characterized, no single model explains the complex regulation of directional migration. Multiple factors operate at each step of cell migration to stabilize lamellipodia and maintain directional migration. Factors such as the topography of the extracellular matrix, the cellular polarity machinery, receptor signalling, integrin trafficking, integrin co-receptors and actomyosin contraction converge on regulation of the Rho family of GTPases and the control of lamellipodial protrusions to promote directional migration.
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              Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization.

              Rac is a small GTPase of the Rho family that mediates stimulus-induced actin cytoskeletal reorganization to generate lamellipodia. Little is known about the signalling pathways that link Rac activation to changes in actin filament dynamics. Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3; however, the kinases responsible for this phosphorylation have not been identified. Here we show that LIM-kinase 1 (LIMK-1), a serine/threonine kinase containing LIM and PDZ domains, phosphorylates cofilin at Ser 3, both in vitro and in vivo. When expressed in cultured cells, LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization. Expression of an inactive form of LIMK-1 suppresses lamellipodium formation induced by Rac or insulin. Furthermore, insulin and an active form of Rac increase the activity of LIMK-1. Taken together, our results indicate that LIMK-1 participates in Rac-mediated actin cytoskeletal reorganization, probably by phosphorylating cofilin.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                15 May 2017
                2017
                : 8
                : 15321
                Affiliations
                [1 ]International Clinical Research Center (ICRC), St Anne's University Hospital , CZ-65691 Brno, Czech Republic
                [2 ]CEITEC MU, Masaryk University , CZ-65691 Brno, Czech Republic
                [3 ]Faculty of Medicine, Department of Biology, Masaryk University , CZ-62500 Brno, Czech Republic
                [4 ]Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc , Hněvotínská 1333/5, CZ-77515 Olomouc, Czech Republic
                [5 ]Faculty of Pharmacy, Division of Pharmaceutical Biosciences, University of Helsinki , Viikinkaari 5 E, FI-00014 Helsinki, Finland
                [6 ]Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo JP-162-8666, Japan
                [7 ]Laboratory of Bio-inspired and Graphene Nanomechanics, Department of Civil, Environmental and Mechanical Engineering, University of Trento , I-38123 Trento, Italy
                [8 ] Ket-Lab, Italian Space Agency, Via del Politecnico snc , 00133 Rome, Italy
                [9 ]School of Engineering and Materials Science, Queen Mary University of London , Mile End Road, UK-E1 4NS London, UK
                [10 ]Department of Biomaterials Science, Institute of Dentistry, University of Turku , FI-20014 Turku, Finland
                Author notes
                [*]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-1341-1023
                Article
                ncomms15321
                10.1038/ncomms15321
                5440673
                28504269
                c5a6bc95-6fc7-41df-8909-8e873c292c90
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 08 November 2016
                : 10 March 2017
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