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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Capping Proteins / metabolism*
  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Extracellular Matrix / metabolism
  • Humans
  • Mechanical Phenomena
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / metabolism*
  • Signal Transduction*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*

Substances

  • Actin Capping Proteins
  • Actins
  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • TAZ protein, human
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human