title: A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors.
abstract: Key cellular decisions, such as proliferation or growth arrest, typically occur at spatially defined locations within tissues. Loss of this spatial control is a hallmark of many diseases, including cancer. Yet, how these patterns are established is incompletely understood. Here, we report that physical and architectural features of a multicellular sheet inform cells about their proliferative capacity through mechanical regulation of YAP and TAZ, known mediators of Hippo signaling and organ growth. YAP/TAZ activity is confined to cells exposed to mechanical stresses, such as stretching, location at edges/curvatures contouring an epithelial sheet, or stiffness of the surrounding extracellular matrix. We identify the F-actin-capping/severing proteins Cofilin, CapZ, and Gelsolin as essential gatekeepers that limit YAP/TAZ activity in cells experiencing low mechanical stresses, including contact inhibition of proliferation. We propose that mechanical forces are overarching regulators of YAP/TAZ in multicellular contexts, setting responsiveness to Hippo, WNT, and GPCR signaling.
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy.
authors: Mariaceleste
authors: M
authors: Aragona
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy.
authors: Tito
authors: T
authors: Panciera
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy.
authors: Andrea
authors: A
authors: Manfrin
authors: Department of Industrial Engineering (DII), University of Padua, via Marzolo 9, 35131 Padua, Italy.
authors: Stefano
authors: S
authors: Giulitti
authors: Department of Industrial Engineering (DII), University of Padua, via Marzolo 9, 35131 Padua, Italy.
authors: Federica
authors: F
authors: Michielin
authors: Department of Industrial Engineering (DII), University of Padua, via Marzolo 9, 35131 Padua, Italy.
authors: Nicola
authors: N
authors: Elvassore
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy. Electronic address: dupont@bio.unipd.it.
authors: Sirio
authors: S
authors: Dupont
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy. Electronic address: piccolo@bio.unipd.it.
authors: Stefano
authors: S
authors: Piccolo
mesh_terms: D051344:Actin Capping Proteins / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D055595:Mechanical Phenomena; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D051344:Actin Capping Proteins; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human