title: Role of YAP/TAZ in mechanotransduction.
abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
authors.affiliation: Department of Histology, Microbiology and Medical Biotechnologies, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy. dupont@bio.unipd.it
authors.forename: Sirio
authors.initials: S
authors.lastname: Dupont
authors.forename: Leonardo
authors.initials: L
authors.lastname: Morsut
authors.forename: Mariaceleste
authors.initials: M
authors.lastname: Aragona
authors.forename: Elena
authors.initials: E
authors.lastname: Enzo
authors.forename: Stefano
authors.initials: S
authors.lastname: Giulitti
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cordenonsi
authors.forename: Francesca
authors.initials: F
authors.lastname: Zanconato
authors.forename: Jimmy
authors.initials: J
authors.lastname: Le Digabel
authors.forename: Mattia
authors.initials: M
authors.lastname: Forcato
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.forename: Nicola
authors.initials: N
authors.lastname: Elvassore
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D048430:Cell Shape; D002470:Cell Survival; D003463:Cues; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C456659:YY1AP1 protein, human; C486223:Yap1 protein, mouse