Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and Rho-family GTPases

Nat Commun. 2019 Jun 26;10(1):2797. doi: 10.1038/s41467-019-10729-5.


Collective cell migration occurs in many patho-physiological states, including wound healing and invasive cancer growth. The integrity of the expanding epithelial sheets depends on extracellular cues, including cell-cell and cell-matrix interactions. We show that the nano-scale topography of the extracellular matrix underlying epithelial cell layers can strongly affect the speed and morphology of the fronts of the expanding sheet, triggering partial and complete epithelial-mesenchymal transitions (EMTs). We further demonstrate that this behavior depends on the mechano-sensitivity of the transcription regulator YAP and two new YAP-mediated cross-regulating feedback mechanisms: Wilms Tumor-1-YAP-mediated downregulation of E-cadherin, loosening cell-cell contacts, and YAP-TRIO-Merlin mediated regulation of Rho GTPase family proteins, enhancing cell migration. These YAP-dependent feedback loops result in a switch-like change in the signaling and the expression of EMT-related markers, leading to a robust enhancement in invasive cell spread, which may lead to a worsened clinical outcome in renal and other cancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Dogs
  • Epithelial Cells / physiology*
  • Epithelial-Mesenchymal Transition / physiology*
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins / metabolism
  • Madin Darby Canine Kidney Cells
  • Nanostructures*
  • Surface Properties
  • WT1 Proteins / genetics
  • WT1 Proteins / metabolism*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • WT1 Proteins
  • Green Fluorescent Proteins
  • rho GTP-Binding Proteins