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.
Erika Ishihara  1 ,  Yuya Nagaoka  1 ,  Toshiaki Okuno  2 ,  Satoshi Kofuji  1 ,  Mari Ishigami-Yuasa  3 ,  Hiroyuki Kagechika  3 ,  Kenya Kamimura  4 ,  Shuji Terai  4 ,  Takehiko Yokomizo  2 ,  Yukihiko Sugimoto  5 ,  Yasuyuki Fujita  6 ,  Akira Suzuki  7 ,  Hiroshi Nishina  1
Affiliations
  • 1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • 2. Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  • 3. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • 4. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
  • 5. Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
  • 6. Division of Molecular Oncology, Institute for Genetic Medicine, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Japan.
  • 7. Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
PMID: 31989743 DOI: 10.1111/gtc.12750
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.
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