Spatial-temporal regulation of the prostanoid receptor EP2 co-ordinates PGE2-mediated cAMP signaling in decidualizing human endometrium
Paul J. Brighton,
Abigail R. Walker,
Oliver Mann,
Chow-Seng Kong,
Emma S. Lucas,
Pavle Vrljicak,
Jan J. Brosens,
Aylin C. Hanyaloglu
Affiliations
Paul J. Brighton
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Corresponding author
Abigail R. Walker
Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
Oliver Mann
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK
Chow-Seng Kong
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK
Emma S. Lucas
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Division of Clinical Medicine, School of Medicine & Population Health, Faculty of Health, University of Sheffield, Sheffield S10 2SF, UK
Pavle Vrljicak
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK
Jan J. Brosens
Division of Biomedical Sciences, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK; Centre for Early Life, University of Warwick, Coventry CV4 7AL, UK; Tommy’s National Centre for Miscarriage Research, University Hospitals Coventry & Warwickshire NHS Trust, Coventry CV2 2DX, UK
Aylin C. Hanyaloglu
Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
Summary: Decidualization denotes the differentiation of endometrial stromal cells into specialized decidual cells, essential for embryo implantation and pregnancy. The process requires coordination of progesterone and cAMP signaling, which converge on downstream transcription factors. PGE2 and relaxin, acting, respectively, through Gαs-coupled GPCRs EP2 and RXFP1, are putative candidates for generating cAMP in differentiating stromal cells. Here, we show that PGE2 is less efficacious than relaxin in elevating intracellular cAMP levels in primary stromal cells but more effective at driving the expression of decidual genes. PGE2-and relaxin-induced cAMP generation involves receptor internalization, but EP2 is endocytosed into very early endosomes (VEEs). Perturbation of VEE machinery through depletion of key trafficking proteins; APPL1 and GIPC, dysregulates PGE2-dependent cAMP profiles and disrupts key decidual signaling pathways, resulting in a disordered differentiation response. We demonstrate that regulation of EP2 via internalization is essential for coordinated activation of the downstream signaling cascades that govern decidualization.
