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


ABSTRACT: Dysfunctions in Wnt signaling increase ?-catenin stability and are associated with cancers, including colorectal cancer. In addition, ?-catenin degradation is decreased by nutrient-dependent O-GlcNAcylation. Human colon tumors and colons from mice fed high-carbohydrate diets exhibited higher amounts of ?-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 ?-catenin. By ETD-MS/MS, we identified 4 O-GlcNAcylation sites at the N terminus of ?-catenin (S23/T40/T41/T112). Furthermore, mutation of serine and threonine residues within the D box of ?-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 ?-catenin stability. Analyses of ?-catenin O-GlcNAcylation mutants reinforced T41 as the most crucial residue that controls the ?-catenin degradation rate. Finally, inhibiting O-GlcNAcylation decreased the ?-catenin/?-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 ?-catenin, but also affects its localization at the level of adherens junctions. Accordingly, we propose that O-GlcNAcylation of ?-catenin is a missing link between the glucose metabolism deregulation observed in metabolic disorders and the development of cancer.

SUBMITTER: Olivier-Van Stichelen S 

PROVIDER: S-EPMC4101651 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Olivier-Van Stichelen Stéphanie S   Dehennaut Vanessa V   Buzy Armelle A   Zachayus Jean-Luc JL   Guinez Céline C   Mir Anne-Marie AM   El Yazidi-Belkoura Ikram I   Copin Marie-Christine MC   Boureme Didier D   Loyaux Denis D   Ferrara Pascual P   Lefebvre Tony T  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140417 8


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-  ...[more]

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