Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes

Whelan, Stephen A.; Dias, Wagner B.; Thiruneelakantapillai, Lakshmanan; Lane, M. Daniel; Hart, Gerald W.

doi:10.1074/jbc.m109.077818

Cited by 156 publications

(133 citation statements)

References 58 publications

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“…One such pathway is the hexosamine-signaling pathway, as 2-5% of the total intracellular glucose is converted to UDP-GlcNAc, the substrate for OGT-1 ( Figure 1D) (Bouche et al 2004). A consequence of glucose toxicity in mammalian cells is an increase in flux through the hexosamine signaling pathway, and insulin treatment increases the O-GlcNAcylation of key proteins in the insulin-signaling pathway (Whelan et al 2010).…”

Section: Resultsmentioning

confidence: 99%

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

et al. 2011

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In a variety of organisms, including worms, flies, and mammals, glucose homeostasis is maintained by insulin-like signaling in a robust network of opposing and complementary signaling pathways. The hexosamine signaling pathway, terminating in O-linked-N-acetylglucosamine (O-GlcNAc) cycling, is a key sensor of nutrient status and has been genetically linked to the regulation of insulin signaling in Caenorhabditis elegans. Here we demonstrate that O-GlcNAc cycling and insulin signaling are both essential components of the C. elegans response to glucose stress. A number of insulin-dependent processes were found to be sensitive to glucose stress, including fertility, reproductive timing, and dauer formation, yet each of these differed in their threshold of sensitivity to glucose excess. Our findings suggest that O-GlcNAc cycling and insulin signaling are both required for a robust and adaptable response to glucose stress, but these two pathways show complex and interdependent roles in the maintenance of glucose-insulin homeostasis.

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Section: Resultsmentioning

confidence: 99%

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

et al. 2011

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“…Furthermore, conditional deletion of OGT results in cellular senescence and apoptosis in numerous cell types, including T cells (25). Considering that abnormal O-GlcNAc levels, possibly stemming from alterations in metabolism (26)(27)(28)(29), may contribute to the pathology of several diseases, including cancer, diabetes, and neurodegeneration (29)(30)(31)(32)(33)(34)(35)(36), a greater understanding of O-GlcNAc biology in T cells could help to explain the impact of metabolic health on the function of the immune system.making the relevance to primary T cells unclear. Furthermore, only a selected few proteins were surveyed.…”

mentioning

confidence: 99%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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T cell activation in response to Ag is largely regulated by protein posttranslational modifications. Although phosphorylation has been extensively characterized in T cells, much less is known about the glycosylation of serine/threonine residues by O-linked N-acetylglucosamine (O-GlcNAc). Given that O-GlcNAc appears to regulate cell signaling pathways and protein activity similarly to phosphorylation, we performed a comprehensive analysis of O-GlcNAc during T cell activation to address the functional importance of this modification and to identify the modified proteins. Activation of T cells through the TCR resulted in a global elevation of O-GlcNAc levels and in the absence of O-GlcNAc, IL-2 production and proliferation were compromised. T cell activation also led to changes in the relative expression of O-GlcNAc transferase (OGT) isoforms and accumulation of OGT at the immunological synapse of murine T cells. Using a glycoproteomics approach, we identified >200 O-GlcNAc proteins in human T cells. Many of the identified proteins had a functional relationship to RNA metabolism, and consistent with a connection between O-GlcNAc and RNA, inhibition of OGT impaired nascent RNA synthesis upon T cell activation. Overall, our studies provide a global analysis of O-GlcNAc dynamics during T cell activation and the first characterization, to our knowledge, of the O-GlcNAc glycoproteome in human T cells.

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“…Dynamic cycling of O-GlcNAc is necessary for normal development, and cycling defects are implicated in metabolic syndromes such as diabetes, cancer, and neurodegeneration. [3][4][5][6][7] Importantly, O-GlcNAc cycling defects have profound consequences for cell cycle progression. 8 Early studies in Xenopus oocytes demonstrated important roles for O-GlcNAc during progesterone mediated maturation.…”

Section: Introductionmentioning

confidence: 99%

Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects

et al. 2016

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Alterations in O-GlcNAc cycling, the addition and removal of O-GlcNAc, lead to mitotic defects and increased aneuploidy. Herein, we generated stable O-GlcNAcase (OGA, the enzyme that removes OGlcNAc) knockdown HeLa cell lines and characterized the effect of the reduction in OGA activity on cell cycle progression. After release from G 1 /S, the OGA knockdown cells progressed normally through S phase but demonstrated mitotic exit defects. Cyclin A was increased in the knockdown cells while Cyclin B and D expression was reduced. Retinoblastoma protein (RB) phosphorylation was also increased in the knockdown compared to control. At M phase, the knockdown cells showed more compact spindle chromatids than control cells and had a greater percentage of cells with multipolar spindles. Furthermore, the timing of the inhibitory tyrosine phosphorylation of Cyclin Dependent Kinase 1 (CDK1) was altered in the OGA knockdown cells. Although expression and localization of the chromosomal passenger protein complex (CPC) was unchanged, histone H3 threonine 3 phosphorylation was decreased in one of the OGA knockdown cell lines. The Ewing Sarcoma Breakpoint Region 1 Protein (EWS) participates in organizing the CPC at the spindle and is a known substrate for O-GlcNAc transferase (OGT, the enzyme that adds OGlcNAc). EWS O-GlcNAcylation was significantly increased in the OGA knockdown cells promoting uneven localization of the mitotic midzone. Our data suggests that O-GlcNAc cycling is an essential mechanism for proper mitotic signaling and spindle formation, and alterations in the rate of O-GlcNAc cycling produces aberrant spindles and promotes aneuploidy.

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Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes

Cited by 156 publications

References 58 publications

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects

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