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Sci. STKE, 29 November 2005
Vol. 2005, Issue 312, p. re13
[DOI: 10.1126/stke.3122005re13]
REVIEWS
The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code"
Dona C. Love and
John A. Hanover*
Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
Abstract:
A dynamic cycle of addition and removal of O-linked N-acetylglucosamine (O-GlcNAc) at serine and threonine residues is emerging as a key regulator of nuclear and cytoplasmic protein activity. Like phosphorylation, protein O-GlcNAcylation dramatically alters the posttranslational fate and function of target proteins. Indeed, O-GlcNAcylation may compete with phosphorylation for certain Ser/Thr target sites. Like kinases and phosphatases, the enzymes of O-GlcNAc metabolism are highly compartmentalized and regulated. Yet, O-GlcNAc addition is subject to an additional and unique level of metabolic control. O-GlcNAc transfer is the terminal step in a "hexosamine signaling pathway" (HSP). In the HSP, levels of uridine 5'-diphosphate (UDP)-GlcNAc respond to nutrient excess to activate O-GlcNAcylation. Removal of O-GlcNAc may also be under similar metabolic regulation. Differentially targeted isoforms of the enzymes of O-GlcNAc metabolism allow the participation of O-GlcNAc in diverse intracellular functions. O-GlcNAc addition and removal are key to histone remodeling, transcription, proliferation, apoptosis, and proteasomal degradation. This nutrient-responsive signaling pathway also modulates important cellular pathways, including the insulin signaling cascade in animals and the gibberellin signaling pathway in plants. Alterations in O-GlcNAc metabolism are associated with various human diseases including diabetes mellitus and neurodegeneration. This review will focus on current approaches to deciphering the "O-GlcNAc code" in order to elucidate how O-GlcNAc participates in its diverse functions. This ongoing effort requires analysis of the enzymes of O-GlcNAc metabolism, their many targets, and how the O-GlcNAc modification may be regulated.
Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease.
F. Liu, J. Shi, H. Tanimukai, J. Gu, J. Gu, I. Grundke-Iqbal, K. Iqbal, and C.-X. Gong (2009)
Brain
132, 1820-1832
|Abstract »|Full Text »|PDF »
Identification of protein O-GlcNAcylation sites using electron transfer dissociation mass spectrometry on native peptides.
R. J. Chalkley, A. Thalhammer, R. Schoepfer, and A. L. Burlingame (2009)
PNAS
106, 8894-8899
|Abstract »|Full Text »|PDF »
A PGC-1{alpha}-O-GlcNAc Transferase Complex Regulates FoxO Transcription Factor Activity in Response to Glucose.
M. P. Housley, N. D. Udeshi, J. T. Rodgers, J. Shabanowitz, P. Puigserver, D. F. Hunt, and G. W. Hart (2009)
J. Biol. Chem.
284, 5148-5157
|Abstract »|Full Text »|PDF »
Up-regulation of O-GlcNAc Transferase with Glucose Deprivation in HepG2 Cells Is Mediated by Decreased Hexosamine Pathway Flux.
R. P. Taylor, T. S. Geisler, J. H. Chambers, and D. A. McClain (2009)
J. Biol. Chem.
284, 3425-3432
|Abstract »|Full Text »|PDF »
Site-Specific GlcNAcylation of Human Erythrocyte Proteins: Potential Biomarker(s) for Diabetes.
Z. Wang, K. Park, F. Comer, L. C. Hsieh-Wilson, C. D. Saudek, and G. W. Hart (2009)
Diabetes
58, 309-317
|Abstract »|Full Text »|PDF »
Glucosamine improves cardiac function following trauma-hemorrhage by increased protein O-GlcNAcylation and attenuation of NF-{kappa}B signaling.
L. Zou, S. Yang, V. Champattanachai, S. Hu, I. H. Chaudry, R. B. Marchase, and J. C. Chatham (2009)
Am J Physiol Heart Circ Physiol
296, H515-H523
|Abstract »|Full Text »|PDF »
NF{kappa}B activation is associated with its O-GlcNAcylation state under hyperglycemic conditions.
W. H. Yang, S. Y. Park, H. W. Nam, D. H. Kim, J. G. Kang, E. S. Kang, Y. S. Kim, H. C. Lee, K. S. Kim, and J. W. Cho (2008)
PNAS
105, 17345-17350
|Abstract »|Full Text »|PDF »
Identification of Structural and Functional O-Linked N-Acetylglucosamine-bearing Proteins in Xenopus laevis Oocyte.
V. Dehennaut, M.-C. Slomianny, A. Page, A.-S. Vercoutter-Edouart, C. Jessus, J.-C. Michalski, J.-P. Vilain, J.-F. Bodart, and T. Lefebvre (2008)
Mol. Cell. Proteomics
7, 2229-2245
|Abstract »|Full Text »|PDF »
O-GlcNAc Regulates FoxO Activation in Response to Glucose.
M. P. Housley, J. T. Rodgers, N. D. Udeshi, T. J. Kelly, J. Shabanowitz, D. F. Hunt, P. Puigserver, and G. W. Hart (2008)
J. Biol. Chem.
283, 16283-16292
|Abstract »|Full Text »|PDF »
An Extracellular Glycoprotein Is Implicated in Cell-Cell Contacts in the Toxic Cyanobacterium Microcystis aeruginosa PCC 7806.
Y. Zilliges, J.-C. Kehr, S. Mikkat, C. Bouchier, N. T. de Marsac, T. Borner, and E. Dittmann (2008)
J. Bacteriol.
190, 2871-2879
|Abstract »|Full Text »|PDF »
Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells.
B. Luo, Y. Soesanto, and D. A. McClain (2008)
Arterioscler Thromb Vasc Biol
28, 651-657
|Abstract »|Full Text »|PDF »
Functional Analysis of SPINDLY in Gibberellin Signaling in Arabidopsis.
A. L. Silverstone, T.-S. Tseng, S. M. Swain, A. Dill, S. Y. Jeong, N. E. Olszewski, and T.-p. Sun (2007)
Plant Physiology
143, 987-1000
|Abstract »|Full Text »|PDF »
Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system.
N. Fulop, R. B. Marchase, and J. C. Chatham (2007)
Cardiovasc Res
73, 288-297
|Abstract »|Full Text »|PDF »
delayed flowering1 Encodes a Basic Leucine Zipper Protein That Mediates Floral Inductive Signals at the Shoot Apex in Maize.
M. G. Muszynski, T. Dam, B. Li, D. M. Shirbroun, Z. Hou, E. Bruggemann, R. Archibald, E. V. Ananiev, and O. N. Danilevskaya (2006)
Plant Physiology
142, 1523-1536
|Abstract »|Full Text »|PDF »
Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer.
