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

Jin Seok Park, Deok Ho Kim, Sagar R. Shah, Hong Nam Kim, Kshitiz, Peter Kim, Alfredo Quinones-Hinojosa, Andre Levchenko

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number2797
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

rho GTP-Binding Proteins
Epithelial-Mesenchymal Transition
GTP Phosphohydrolases
switches
Neurofibromin 2
Switches
Feedback
augmentation
Cadherins
Transcription
cells
Topography
Tumors
Cell Movement
Wilms Tumor
Kidney Neoplasms
EH-101 helicopter
Proteins
Cell Communication
cancer

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and Rho-family GTPases. / Park, Jin Seok; Kim, Deok Ho; Shah, Sagar R.; Kim, Hong Nam; Kshitiz; Kim, Peter; Quinones-Hinojosa, Alfredo; Levchenko, Andre.

In: Nature communications, Vol. 10, No. 1, 2797, 01.12.2019.

Research output: Contribution to journalArticle

Park, Jin Seok ; Kim, Deok Ho ; Shah, Sagar R. ; Kim, Hong Nam ; Kshitiz ; Kim, Peter ; Quinones-Hinojosa, Alfredo ; Levchenko, Andre. / Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and Rho-family GTPases. In: Nature communications. 2019 ; Vol. 10, No. 1.
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