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O-GlcNAcylation stabilizes I?-catenin through direct competition with phosphorylation at threonine 41. FASEB J 2014 Aug;28(8):3325-38

Date

04/20/2014

Pubmed ID

24744147

Pubmed Central ID

PMC4101651

DOI

10.1096/fj.13-243535

Scopus ID

2-s2.0-84905216343   88 Citations

Abstract

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

Author List

Olivier-Van Stichelen S, Dehennaut V, Buzy A, Zachayus JL, Guinez C, Mir AM, El Yazidi-Belkoura I, Copin MC, Boureme D, Loyaux D, Ferrara P, Lefebvre T

Author

Stephanie Olivier-Van Stichelen PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylglucosamine
Adenocarcinoma
Adherens Junctions
Amino Acid Sequence
Animals
Colon
Colorectal Neoplasms
Dietary Carbohydrates
Enzyme Inhibitors
Glucose
Glycosylation
HEK293 Cells
Humans
Hyperglycemia
Intestinal Mucosa
MCF-7 Cells
Male
Mice
Mice, Inbred C57BL
Molecular Sequence Data
N-Acetylglucosaminyltransferases
Neoplasm Proteins
Phosphorylation
Protein Interaction Mapping
Protein Processing, Post-Translational
Protein Stability
Proteolysis
RNA, Small Interfering
Threonine
Wnt Signaling Pathway
alpha Catenin
beta Catenin
beta-N-Acetylhexosaminidases