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

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.
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https://hal.univ-lille.fr/hal-03284998
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Soumis le : mardi 13 juillet 2021 - 08:42:09
Dernière modification le : mardi 19 octobre 2021 - 11:33:30

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Stéphanie Olivier-van Stichelen, Vanessa Dehennaut, Armelle Buzy, Jean-Luc Zachayus, Celine Guinez, et al.. O-GlcNAcylation stabilizes β-catenin through direct competition with phosphorylation at threonine 41. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014, The FASEB Journal, 28 (8), pp.3325-3338. ⟨10.1096/fj.13-243535⟩. ⟨hal-03284998⟩

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