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

M Aragona, T Panciera, A Manfrin, S Giulitti, F Michielin… - Cell, 2013 - cell.com
M Aragona, T Panciera, A Manfrin, S Giulitti, F Michielin, N Elvassore, S Dupont, S Piccolo
Cell, 2013cell.com
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 …
Summary
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.
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