Cross-talk between GlcNAcylation and phosphorylation: Roles in insulin resistance and glucose toxicity

Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205-2185, USA.
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 08/2008; 295(1):E17-28. DOI: 10.1152/ajpendo.90281.2008
Source: PubMed


O-linked beta-N-acetylglucosamine (O-GlcNAc) is a dynamic posttranslational modification that, analogous to phosphorylation, cycles on and off serine and/or threonine hydroxyl groups. Cycling of O-GlcNAc is regulated by the concerted actions of O-GlcNAc transferase and O-GlcNAcase. GlcNAcylation is a nutrient/stress-sensitive modification that regulates proteins involved in a wide array of biological processes, including transcription, signaling, and metabolism. GlcNAcylation is involved in the etiology of glucose toxicity and chronic hyperglycemia-induced insulin resistance, a major hallmark of type 2 diabetes. Several reports demonstrate a strong positive correlation between GlcNAcylation and the development of insulin resistance. However, recent studies suggest that inhibiting GlcNAcylation does not prevent hyperglycemia-induced insulin resistance, suggesting that other mechanisms must also be involved. To date, proteomic analyses have identified more than 600 GlcNAcylated proteins in diverse functional classes. However, O-GlcNAc sites have been mapped on only a small percentage (<15%) of these proteins, most of which were isolated from brain or spinal cord tissue and not from other metabolically relevant tissues. Mapping the sites of GlcNAcylation is not only necessary to elucidate the complex cross-talk between GlcNAcylation and phosphorylation but is also key to the design of site-specific mutational studies and necessary for the generation of site-specific antibodies, both of which will help further decipher O-GlcNAc's functional roles. Recent technical advances in O-GlcNAc site-mapping methods should now finally allow for a much-needed increase in site-specific analyses to address the functional significance of O-GlcNAc in insulin resistance and glucose toxicity as well as other major biological processes.

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    • "The role of O-GlcNAcylation in regulation of PI3K/Akt signaling pathway was extensively studied especially in adipocytes and muscle cells (41–45). It was shown that overexpression of OGT and increased O-GlcNAcylation in muscle, adipocytes, or liver cells inhibited insulin signaling (23, 43, 46, 47). However, studies using OGA inhibitors gave contradictory results. "
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    • "In recent years, cross-talk between O-linked glycosylation and phosphorylation has been proposed as the basis for hyperglycemia-induced insulin resistance [35]. The serine and threonine residues of a protein are susceptible to post-translational modifications including phosphorylation and O-linked glycosylation [36]. "
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