A Mechanical Checkpoint Controls Multicellular Growth through YAP/TAZ Regulation by Actin-Processing Factors

作者：Aragona, Mariaceleste; Panciera, Tito; Manfrin, Andrea; Giulitti, Stefano; Michielin, Federica; Elvassore, Nicola; Dupont, Sirio^*; Piccolo, Stefano

来源：Cell, 2013, 154(5): 1047-1059.

DOI：10.1016/j.cell.2013.07.042

• HIPPO SIGNALING-PATHWAY
• CELL CONTACT INHIBITION
• TISSUE ARCHITECTURE
• YAP PATHWAY
• F-ACTIN
• CANCER
• PROLIFERATION
• TAZ
• TRANSDUCTION
• INACTIVATION

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.

• 出版日期2013-8-29