O-GlcNAc modification: why so intimately associated with phosphorylation?

Abstract

Post-translational modification of proteins at serine and threonine side chains by β-N-acetylglucosamine (O-GlcNAc) mediated by the enzyme β-N-acetylglucosamine transferase has been emerging as a fundamental regulatory mechanism encompassing a wide range of proteins involved in cell division, metabolism, transcription and cell signaling. Furthermore, an extensive interplay between O-GlcNAc modification and serine/threonine phosphorylation in a variety of proteins has been reported to exist. However, our understanding of the regulatory mechanisms involved in O-GlcNAc modification and its interplay with serine/threonine phosphorylation in proteins is still elusive. Recent success in the mapping of O-GlcNAc modification sites in proteins as a result of technological advancement in mass spectrometry have revealed two important clues which may be inherently connected to the regulation of O-GlcNAc modification and its interplay with phosphorylation in proteins. First, almost all O-GlcNAc modified proteins are known phospho proteins. Second, the prevalence of tyrosine phosphorylation among O-GlcNAc modified proteins is exceptionally higher (~68%) than its normal occurrence (~2%) alone. We hypothesize that phosphorylation may be a requisite for O-GlcNAc modification and tyrosine phosphorylation plays a role in the interplay between O-GlcNAc modification and serine/threonine phosphorylation in proteins. In other words, the interplay between O-GlcNAc modification and phosphorylation is not limited to serine/threonine phosphorylation but also includes tyrosine phosphorylation. Our hypothesis provides an opportunity to understand the underlying mechanism involved in O-GlcNAc modification and its interplay with serine/threonine phosphorylation in proteins. Furthermore, implication of our hypothesis extends to tyrosine kinase signaling.

Alternating Phosphorylation with O-GlcNAc Modification: Another Way to Control Protein Function

“…Based on the higher prevalence of Tyr phosphorylation among O-GlcNAc-modified proteins (~68% vs. ~2% in non-O-GlcNAc-modified proteins), Mishra and colleagues suggested that Tyr phosphorylation plays a role in the interplay between O-GlcNAc modification and Ser/Thr phosphorylation in proteins (Mishra et al, 2011). This clearly shows that the interplay between O-GlcNAcylation and phosphorylation is both complex and very extensive.…”

Reprogrammed Cellular Metabolism and O -GlcNAc Modification in Cancer

“…Furthermore, such hypothesis is not tenable to explain the simultaneous downregulation of O-GlcNAc modification in a number of proteins in cancer cells [30]. Although not well understood, such findings are not surprising, keeping in mind that O-GlcNAc modification in protein is a highly regulated process and involved not only O-GlcNAc level, O-GlcNAc cycling enzymes OGT and OGA but also their interacting proteins and various modification status of the substrate itself [9,15]. Delineating the role of O-GlcNAc modification in relation cancer cell metabolism and function would require not only protein specific but also modification site specific approaches, as proteins are often subjected to a number of posttranslational modifications, often with very different and even opposite functional consequences.…”

“…Together, OGT and OGA dynamically alter the post-translational state and function of proteins in response to cellular signals [9]. O-GlcNAc modification is involved in extensive crosstalk with other posttranslational modifications, such as phosphorylation including tyrosine phosphorylation and virtually all O-GlcNAc modified proteins are phosphoproteins [9,14,15]. As many of the processes that are perturbed in the pathogenesis and progression of cancer involved altered protein phosphorylation, changes in O-GlcNAc modification are likely to have effect on them.…”

The Role of O-Linked -N-Acetylglucosamine (GlcNAc) Modification in Cell Signaling

“…Protein glycosylation traditionally refers to the covalent attachment of complex oligosaccharides to proteins in intraluminal compartments or cellular membranes, or in proteins that are destined for secretion. In contrast, O-GlcNAcylation is abundant in cytoplasmic and nuclear proteins, which are modified with a single β-N-acetylglucosamine monosaccharide moiety through an O-β-glycosydic attachment to serine and/or threonine side chains of the polypeptide backbone [2].…”

“…However, unlike phosphorylation, which is regulated by hundreds of kinases and phosphatases, O-GlcNAc cycling has only two mediators: the enzymes O-GlcNAc transferase (OGT), and O-GlcNAc amidase (OGA) [2]. The addition and removal of O-GlcNAc is mediated by the concerted action of these two enzymes.…”