title: Epac1 links prostaglandin E2 to β-catenin-dependent transcription during epithelial-to-mesenchymal transition.
abstract: In epithelial cells, β-catenin is localized at cell-cell junctions where it stabilizes adherens junctions. When these junctions are disrupted, β-catenin can translocate to the nucleus where it functions as a transcriptional cofactor. Recent research has indicated that PGE2 enhances the nuclear function of β-catenin through cyclic AMP. Here, we aim to study the role of the cyclic AMP effector Epac in β-catenin activation by PGE2 in non-small cell lung carcinoma cells. We show that PGE2 induces a down-regulation of E-cadherin, promotes cell migration and enhances β-catenin translocation to the nucleus. This results in β-catenin-dependent gene transcription. We also observed increased expression of Epac1. Inhibition of Epac1 activity using the CE3F4 compound or Epac1 siRNA abolished the effects of PGE2 on β-catenin. Further, we observed that Epac1 and β-catenin associate together. Expression of an Epac1 mutant with a deletion in the nuclear pore localization sequence prevents this association. Furthermore, the scaffold protein Ezrin was shown to be required to link Epac1 to β-catenin. This study indicates a novel role for Epac1 in PGE2-induced EMT and subsequent activation of β-catenin.
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.|Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sepp R
authors.initials: SR
authors.lastname: Jansen
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.
authors.forename: Wilfred J
authors.initials: WJ
authors.lastname: Poppinga
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: de Jager
authors.affiliation: Inserm UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III, Toulouse, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Lezoualc'h
authors.affiliation: Department of Integrative Biology & Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas, Houston, TX, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: School of Life Sciences, Heriot-Watt University, Edinburgh, Scotland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yarwood
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy (GRIP), University of Groningen, Groningen, The Netherlands.
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D051176:beta Catenin; D015232:Dinoprostone
keywords: EMT; Epac; Ezrin; PGE2; β-catenin