Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition

Genes Cells. 2020 Mar;25(3):197-214. doi: 10.1111/gtc.12750. Epub 2020 Feb 7.

Abstract

Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin-Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP-expressing cells was unknown. Here, we used high-throughput chemical compound screening to identify cyclooxygenase-2 (COX-2) as a key molecule triggering cell competition. Our work shows that COX-2-mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase-cyclic AMP-PKA pathway that, in the presence of active YAP, induces E-cadherin internalization leading to apical extrusion. Thus, COX-2-induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.

Keywords: COX-2; E-cadherin internalization; PGE2; YAP; cell competition.

MeSH terms

  • Animals
  • Cell Competition*
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism*
  • Dogs
  • High-Throughput Screening Assays
  • Humans
  • Madin Darby Canine Kidney Cells / metabolism
  • Receptors, Prostaglandin E, EP2 Subtype / metabolism*
  • Signal Transduction*
  • Transcription Factors / metabolism*

Substances

  • Cell Cycle Proteins
  • Receptors, Prostaglandin E, EP2 Subtype
  • Transcription Factors
  • YY1AP1 protein, human
  • Cyclooxygenase 2
  • Dinoprostone