Protease-activated receptor 2 signaling modulates susceptibility of colonic epithelium to injury through stabilization of YAP in vivo

Cell Death & Disease
Longmei HeHongying Wang

Abstract

Hippo signaling plays critical roles in intestinal regeneration. However, the mechanisms which regulate its activity in vivo are largely unknown. We hypothesize that protease-activated receptor 2 (PAR2) signaling, which could be activated by trypsin, might affect YAP activity in the setting of tissue damage and regeneration. It is found that knockout of PAR2 severely aggravates the mucosal damage induced by dextran sodium sulfate (DSS) in mouse, which correlated with notable repression of YAP protein in colonic epithelial cells. Although the cytokine expression is reduced, the damage of colonic crypt is more severe after DSS-induced colitis in PAR2-/- mouse. In vitro, PAR2 activation causes the accumulation of YAP, while knockdown of PAR2 with shRNA dramatically represses the expression of YAP protein in different intestinal epithelial cell lines. Moreover, forced expression of YAP significantly reduces the production of reactive oxygen species (ROS) and the sensitivity to nitric oxide-induced apoptosis in PAR2-deficient condition. Further studies show that PAR2 signaling stabilizes YAP protein but independent of Lats. Nevertheless PAR2 activation increased the binding of YAP with protein phosphatase PP1. Inhibition of PP1 with...Continue Reading

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Citations

Sep 9, 2019·The FEBS Journal·Giulia PontarolloChristoph Reinhardt
Jan 28, 2021·Cells·Claire Racaud-Sultan, Nathalie Vergnolle
Nov 5, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Ji Yun HerEunok Im
Mar 4, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Derek B McMahonRobert J Lee
May 29, 2021·Microbial Pathogenesis·Jun-Jie HouBang-Mao Wang

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Methods Mentioned

BETA
transfection
flow cytometry
protein assay
Antibody
immunoprecipitation
PCR
flow
transfect

Software Mentioned

plus
image
pro
GeneSpring
GraphPad Prism5

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