O‐GlcNAcylation stabilizes β‐catenin through direct competition with phosphorylation at threonine 41

The FASEB JournalVolume 28, Issue 8 p. 3325-3338 Research CommunicationFree to Read O-GlcNAcylation stabilizes β-catenin through direct competition with phosphorylation at threonine 41 Stéphanie Olivier-Van Stichelen, Stéphanie Olivier-Van Stichelen Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceThese authors contributed equally to this work.Search for more papers by this authorVanessa Dehennaut, Vanessa Dehennaut Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceThese authors contributed equally to this work.Search for more papers by this authorArmelle Buzy, Armelle Buzy Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorJean-Luc Zachayus, Jean-Luc Zachayus Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorCéline Guinez, Céline Guinez Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceSearch for more papers by this authorAnne-Marie Mir, Anne-Marie Mir Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceSearch for more papers by this authorIkram El Yazidi-Belkoura, Ikram El Yazidi-Belkoura Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceSearch for more papers by this authorMarie-Christine Copin, Marie-Christine Copin Tumor Bank, Regional Reference Center in Cancer, Centre Hospitalier Régional Universitaire de Lille (CHRU), University of Lille 2, Lille, FranceSearch for more papers by this authorDidier Boureme, Didier Boureme Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorDenis Loyaux, Denis Loyaux Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorPascual Ferrara, Pascual Ferrara Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorTony Lefebvre, Corresponding Author Tony Lefebvre [email protected] Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceCorrespondence: CNRS-UMR 8576, Unit of Structural and Functional Glycobiology, IFR 147, University of Lille 1, 59655 Villeneuve d'Ascq, France. E-mail: [email protected]Search for more papers by this author Stéphanie Olivier-Van Stichelen, Stéphanie Olivier-Van Stichelen Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceThese authors contributed equally to this work.Search for more papers by this authorVanessa Dehennaut, Vanessa Dehennaut Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceThese authors contributed equally to this work.Search for more papers by this authorArmelle Buzy, Armelle Buzy Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorJean-Luc Zachayus, Jean-Luc Zachayus Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorCéline Guinez, Céline Guinez Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceSearch for more papers by this authorAnne-Marie Mir, Anne-Marie Mir Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceSearch for more papers by this authorIkram El Yazidi-Belkoura, Ikram El Yazidi-Belkoura Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceSearch for more papers by this authorMarie-Christine Copin, Marie-Christine Copin Tumor Bank, Regional Reference Center in Cancer, Centre Hospitalier Régional Universitaire de Lille (CHRU), University of Lille 2, Lille, FranceSearch for more papers by this authorDidier Boureme, Didier Boureme Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorDenis Loyaux, Denis Loyaux Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorPascual Ferrara, Pascual Ferrara Exploratory Unit/Systems Biology, Sanofi-Aventis Research and Development, Toulouse, FranceSearch for more papers by this authorTony Lefebvre, Corresponding Author Tony Lefebvre [email protected] Unit of Structural and Functional Glycobiology, Institut Fédératif de Recherche (IFR) 147, Centre National de la Recherche Scientifique-Unité Mixte de Recherche (CNRS-UMR) 8576, University of Lille 1, Villeneuve d'Ascq, FranceCorrespondence: CNRS-UMR 8576, Unit of Structural and Functional Glycobiology, IFR 147, University of Lille 1, 59655 Villeneuve d'Ascq, France. E-mail: [email protected]Search for more papers by this author First published: 17 April 2014 https://doi.org/10.1096/fj.13-243535Citations: 10 This article includes supplemental data. Please visit http://www.fasebj.org to obtain this information. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Dysfunctions in Wnt signaling increase β-catenin stability and are associated with cancers, including colorectal cancer. In addition, β-catenin degradation is decreased by nutrient-dependent O-GlcNAcylation. Human colon tumors and colons from mice fed high-carbohydrate diets exhibited higher amounts of β-catenin and O-GlcNAc relative to healthy tissues and mice fed a standard diet, respectively. Administration of the O-GlcNAcase inhibitor thiamet G to mice also increased colonic expression of β-catenin. By ETD-MS/MS, we identified 4 O-GlcNAcylation sites at the N terminus of β-catenin (S23/T40/T41/T112). Furthermore, mutation of serine and threonine residues within the D box of β-catenin reduced O-GlcNAcylation by 75%. Interestingly, elevating O-GlcNAcylation in human colon cell lines drastically reduced phosphorylation at T41, a key residue of the D box responsible for β-catenin stability. Analyses of β-catenin O-GlcNAcylation mutants reinforced T41 as the most crucial residue that controls the β-catenin degradation rate. Finally, inhibiting O-GlcNAcylation decreased the β-catenin/α-catenin interaction necessary for mucosa integrity, whereas O-GlcNAcase silencing improved this interaction. These results suggest that O-GlcNAcylation regulates not only the stability of β-catenin, but also affects its localization at the level of adherens junctions. Accordingly, we propose that O-GlcNAcylation of β-catenin is a missing link between the glucose metabolism deregulation observed in metabolic disorders and the development of cancer.—Olivier-Van Stichelen, S., Dehennaut, V., Buzy, A., Zachayus, J.-L., Guinez, C., Mir, A-M., El Yazidi-Belkoura, I., Copin, M.-C., Boureme, D., Loyaux, D., Ferrara, P., Lefebvre, T. O-GlcNAcylation stabilizes β-catenin through direct competition with phosphorylation at threonine 41. FASEB J. 28, 3325–3338 (2014). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2028008006-sup-0001.zipZip archive, 182.5 KB Supplementary material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume28, Issue8August 2014Pages 3325-3338 RelatedInformation