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Cell. 2013 Aug 29;154(5):1047-59. 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.

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1
Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy.

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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