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Cell. 2013 Aug 29;154(5):1047-1059. doi: 10.1016/j.cell.2013.07.042. Epub 2013 Aug 15.

A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors.

Author information

1
Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy.
2
Department of Industrial Engineering (DII), University of Padua, via Marzolo 9, 35131 Padua, Italy.
3
Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy. Electronic address: dupont@bio.unipd.it.
4
Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy. Electronic address: piccolo@bio.unipd.it.

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.

PMID:
23954413
DOI:
10.1016/j.cell.2013.07.042
[Indexed for MEDLINE]
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