Cross-Dysregulation of O-GlcNAcylation and PI3K/AKT/mTOR Axis in Human Chronic Diseases.

Ninon Very,Ikram El Yazidi-Belkoura,Anne-Sophie Vercoutter-Edouart,Stéphan Hardivillé,Tony Lefebvre

doi:10.3389/fendo.2018.00602

Abstract

The hexosamine biosynthetic pathway (HBP) and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway are considered as nutrient sensors that regulate several essential biological processes. The hexosamine biosynthetic pathway produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the substrate for O-GlcNAc transferase (OGT), the enzyme that O-GlcNAcylates proteins on serine (Ser) and threonine (Thr) residues. O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and phosphorylation are highly dynamic post-translational modifications occurring at the same or adjacent sites that regulate folding, stability, subcellular localization, partner interaction, or activity of target proteins. Here we review recent evidence of a cross-regulation of PI3K/AKT/mTOR signaling pathway and protein O-GlcNAcylation. Furthermore, we discuss their co-dysregulation in pathological conditions, e.g., cancer, type-2 diabetes (T2D), and cardiovascular, and neurodegenerative diseases.

Highlights

O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a dynamic modification of serine (Ser) and threonine (Thr) amino acids of cytoplasmic, nuclear [1], and mitochondrial [2] proteins with a single residue of N-acetylglucosamine (GlcNAc)
Highlighted by the studies discussed above O-GlcNAcylation and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway appear to be intimately cross-linked
We summarized evidence that O-GlcNAcylation can modulate the activation of the PI3K/AKT/mTOR signaling pathway by targeting different signaling actors, and that, reciprocally; expression, localization and activation of O-GlcNAc transferase (OGT) are regulated by these signaling pathways (Figure 1)

Summary

Introduction

O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a dynamic modification of serine (Ser) and threonine (Thr) amino acids of cytoplasmic, nuclear [1], and mitochondrial [2] proteins with a single residue of N-acetylglucosamine (GlcNAc). This mini-review summarizes and discusses recent evidence linking cross-regulation and co-dysregulation of O-GlcNAcylation and PI3K/AKT/mTOR signaling pathway in physiological conditions and in human chronic diseases, respectively.

Results

Conclusion