Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and Rho-family GTPases
- Authors
- Park, JinSeok; Kim, Deok-Ho; Shah, Sagar R.; Kim, Hong-Nam; Kshitiz; Kim, Peter; Quinones-Hinojosa, Alfredo; Levchenko, Andre
- Issue Date
- 2019-06
- Publisher
- Nature Publishing Group
- Citation
- Nature Communications, v.10
- 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.
- Keywords
- COLLECTIVE CELL-MIGRATION; MEDIATES CONTACT INHIBITION; E-CADHERIN; MECHANICAL-PROPERTIES; TOPOGRAPHIC GUIDANCE; FOCAL ADHESIONS; WILMS-TUMOR; ACTIVATION; COMPLEX; YAP/TAZ
- ISSN
- 2041-1723
- URI
- https://pubs.kist.re.kr/handle/201004/119961
- DOI
- 10.1038/s41467-019-10729-5
- Appears in Collections:
- KIST Article > 2019
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