<i>O</i>‐GlcNAcylation stabilizes β‐catenin through direct competition with phosphorylation at threonine 41

Stichelen, Stéphanie Olivier-Van; Dehennaut, Vanessa; Buzy, Armelle; Zachayus, Jean-Luc; Guinez, Céline; Mir, Anne-Marie; Yazidi‐Belkoura, Ikram El; Copin, Marie‐Christine; Boureme, D.; Loyaux, Denis; Ferrara, Pascual; Lefebvre, Tony

doi:10.1096/fj.13-243535

Cited by 128 publications

(73 citation statements)

References 43 publications

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“…Insulin mRNA synthesis and translation can be regulated through a variety of mechanisms (3,53,54). Previous work has demonstrated that O-GlcNAc is capable of regulating protein and mRNA stability (55,56). However, this mechanism is unlikely to be at work here, as the half-life of Ins2 mRNA in Min6 cells is greater than 24 h (57).…”

Section: Discussionmentioning

confidence: 92%

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Durning

Flanagan-Steet

Prasad

et al. 2016

Journal of Biological Chemistry

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The post-translational protein modification O-linked ␤-Nacetylglucosamine (O-GlcNAc) is a proposed nutrient sensor that has been shown to regulate multiple biological pathways. This dynamic and inducible enzymatic modification to intracellular proteins utilizes the end product of the nutrient sensing hexosamine biosynthetic pathway, UDP-GlcNAc, as its substrate donor. Type II diabetic patients have elevated O-GlcNAc-modified proteins within pancreatic beta cells due to chronic hyperglycemia-induced glucose overload, but a molecular role for O-GlcNAc within beta cells remains unclear. Using directed pharmacological approaches in the mouse insulinoma-6 (Min6) cell line, we demonstrate that elevating nuclear O-GlcNAc increases intracellular insulin levels and preserves glucose-stimulated insulin secretion during chronic hyperglycemia. The molecular mechanism for these observed changes appears to be, at least in part, due to elevated O-GlcNAcdependent increases in Ins1 and Ins2 mRNA levels via elevations in histone H3 transcriptional activation marks. Furthermore, RNA deep sequencing reveals that this mechanism of altered gene transcription is restricted and that the majority of genes regulated by elevated O-GlcNAc levels are similarly regulated by a shift from euglycemic to hyperglycemic conditions. These findings implicate the O-GlcNAc modification as a potential mechanism for hyperglycemic-regulated gene expression in the beta cell.

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Section: Discussionmentioning

confidence: 92%

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Durning

Flanagan-Steet

Prasad

et al. 2016

Journal of Biological Chemistry

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“…This observation is quite notable because only very few nanobodies are known to bind short linear peptide sequences (30). The recognized epitope is evolutionarily highly conserved and it harbors a central serine residue (Ser23) that is described to be post-translationally modified either upon targeted phosphorylation mediated by GSK3␤ in the same fashion as the SSTS-motif or by addition of O-linked-beta-N-acetylglucosamine (O-GlcNAc) (47,48). For further analyses of the BC2 epitope specificity, we performed binding studies using the identified peptide with a phosphorylated Ser23 residue.…”

Section: Resultsmentioning

confidence: 99%

Monitoring Interactions and Dynamics of Endogenous Beta-catenin With Intracellular Nanobodies in Living Cells*

Traenkle

Emele

Anton

et al. 2015

Molecular & Cellular Proteomics

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“…Phosphorylation of β-catenin clearly influenced its intracellular distribution (1,3), and reversible O-glycosylation may affect its nuclear accumulation and transcriptional action (64)(65)(66). Correct N-glycosylation and trafficking of integrin β1 required BIG1 (30) and BIG2 (28), respectively, but their roles in O-glycosylation are unknown.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals

Kang

Katō

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Multifunctional β-catenin, with critical roles in both cell-cell adhesion and Wnt-signaling pathways, was among HeLa cell proteins coimmunoprecipitated by antibodies against brefeldin A-inhibited guanine nucleotide-exchange factors 1 and 2 (BIG1 or BIG2) that activate ADP-ribosylation factors (Arfs) by accelerating the replacement of bound GDP with GTP. BIG proteins also contain A-kinase anchoring protein (AKAP) sequences that can act as scaffolds for multimolecular assemblies that facilitate and limit cAMP signaling temporally and spatially. Direct interaction of BIG1 N-terminal sequence with β-catenin was confirmed using yeast two-hybrid assays and in vitro synthesized proteins. Depletion of BIG1 and/or BIG2 or overexpression of guanine nucleotide-exchange factor inactive mutant, but not wild-type, proteins interfered with β-catenin trafficking, leading to accumulation at perinuclear Golgi structures. Both phospholipase D activity and vesicular trafficking were required for effects of BIG1 and BIG2 on β-catenin activation. Levels of PKAphosphorylated β-catenin S675 and β-catenin association with PKA, BIG1, and BIG2 were also diminished after BIG1/BIG2 depletion. Inferring a requirement for BIG1 and/or BIG2 AKAP sequence in PKA modification of β-catenin and its effect on transcription activation, we confirmed dependence of S675 phosphorylation and transcription coactivator function on BIG2 AKAP-C sequence.ADP-ribosylation factor | cell migration | AKAP | phospholipase D M ultifunctional β-catenin is an essential component of intercellular adherens junctions (AJs) that link cell surface cadherin and actin cytoskeleton via interactions with both. β-catenin is also a transcriptional coactivator in several pathways, including Wnt-initiated signaling (1, 2), which is critical in embryonic development and tissue homeostasis or pathology (2, 3). In the absence of "canonical" catenin-dependent Wnt signaling, cytoplasmic β-catenin is maintained at low levels via phosphorylations of S45 and S33, S37 and T41 by, respectively, casein kinase-1 and glycogen synthase kinase-3 (GSK-3) (1, 2). Subsequent degradation of β-catenin via an ubiquitin/proteasome pathway involves axin and adenomatous polyposis coli (APC) as scaffold proteins, plus β-transducin repeat-containing protein (β-TrCP), an E3 ubiquitin ligase. In one well-known model, binding of Wnt to Frizzled (Fz) and its coreceptor low-density lipoprotein receptor-like protein 5 or 6 (LRP5/6) resulted in GSK-3 sequestration in multivesicular bodies, thereby reducing its cytosolic level (4, 5). With lower GSK-3 activity, "stabilized" β-catenin (1, 2) entered the nucleus and, along with members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family, activated transcription via Wnt-target gene promoters, including c-myc and cyclin D1 (6-8). In β-catenin knockout mice, embryogenesis was arrested at gastrulation (9) and aberrant Wnt signaling led to tumor development (2, 3).Although relationships between labile and stabilized β-catenin pools remain poorly understood, ...

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

Cited by 128 publications

References 43 publications

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

O-Linked β-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells

Monitoring Interactions and Dynamics of Endogenous Beta-catenin With Intracellular Nanobodies in Living Cells*

Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals

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