Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

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.

Gloss: Glycosylation is not usually considered a "signaling" modification. However, 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. More than a hundred proteins have been identified with this modification. Among these diverse targets are transcription factors, cytosolic enzymes, cytoskeletal proteins, and nuclear pore proteins. Like phosphorylation, this unique modification is dynamic and reversible, serving to either enhance or repress target protein activity. Most targets are also phosphoproteins, and the action of glycosylation and phosphorylation may be complementary or mutually exclusive. Whereas phosphorylation is controlled by many unique kinases and phosphatases, O-GlcNAc cycling is controlled by the efficient use of just two genes to produce differentially targeted enzymes. These enzymes are responsive to fluctuations in nutrient stores, allowing real-time control of signaling. This review will begin to answer how the enzymes of O-GlcNAc cycling are regulated and how the cycle may interface with other cellular signaling pathways.

*Corresponding author. E-mail, jah{at}helix.nih.gov

Citation: D. C. Love, J. A. Hanover, The Hexosamine Signaling Pathway: Deciphering the "O-GlcNAc Code". Sci. STKE 2005, re13 (2005).

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
CREB regulates the expression of neuronal glucose transporter 3: a possible mechanism related to impaired brain glucose uptake in Alzheimer's disease.
N. Jin, W. Qian, X. Yin, L. Zhang, K. Iqbal, I. Grundke-Iqbal, C.-X. Gong, and F. Liu (2013)
Nucleic Acids Res. 41, 3240-3256
   Abstract »    Full Text »    PDF »
p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly.
J. Fricke, L. Y. Koo, C. R. Brown, and P. L. Collins (2013)
J. Virol. 87, 1333-1347
   Abstract »    Full Text »    PDF »
Exploring Leukocyte O-GlcNAcylation as a Novel Diagnostic Tool for the Earlier Detection of Type 2 Diabetes Mellitus.
C. Springhorn, T. E. Matsha, R. T. Erasmus, and M. F. Essop (2012)
J. Clin. Endocrinol. Metab. 97, 4640-4649
   Abstract »    Full Text »    PDF »
Glucose Deprivation-induced Increase in Protein O-GlcNAcylation in Cardiomyocytes Is Calcium-dependent.
L. Zou, X. Zhu-Mauldin, R. B. Marchase, A. J. Paterson, J. Liu, Q. Yang, and J. C. Chatham (2012)
J. Biol. Chem. 287, 34419-34431
   Abstract »    Full Text »    PDF »
Glycosylation to Adapt to Stress.
K. R. Mattaini and M. G. Vander Heiden (2012)
Science 337, 925-926
   Abstract »    Full Text »    PDF »
Metabolic labeling enables selective photocrosslinking of O-GlcNAc-modified proteins to their binding partners.
S.-H. Yu, M. Boyce, A. M. Wands, M. R. Bond, C. R. Bertozzi, and J. J. Kohler (2012)
PNAS 109, 4834-4839
   Abstract »    Full Text »    PDF »
A role for O-GlcNAcylation in setting circadian clock speed.
E. Y. Kim, E. H. Jeong, S. Park, H.-J. Jeong, I. Edery, and J. W. Cho (2012)
Genes & Dev. 26, 490-502
   Abstract »    Full Text »    PDF »
O-GlcNAcylation, Novel Post-Translational Modification Linking Myocardial Metabolism and Cardiomyocyte Circadian Clock.
D. J. Durgan, B. M. Pat, B. Laczy, J. A. Bradley, J.-Y. Tsai, M. H. Grenett, W. F. Ratcliffe, R. A. Brewer, J. Nagendran, C. Villegas-Montoya, et al. (2011)
J. Biol. Chem. 286, 44606-44619
   Abstract »    Full Text »    PDF »
SPINDLY, a Negative Regulator of Gibberellic Acid Signaling, Is Involved in the Plant Abiotic Stress Response.
F. Qin, K.-S. Kodaira, K. Maruyama, J. Mizoi, L.-S. P. Tran, Y. Fujita, K. Morimoto, K. Shinozaki, and K. Yamaguchi-Shinozaki (2011)
Plant Physiology 157, 1900-1913
   Abstract »    Full Text »    PDF »
A lipid-droplet-targeted O-GlcNAcase isoform is a key regulator of the proteasome.
C. N. Keembiyehetty, A. Krzeslak, D. C. Love, and J. A. Hanover (2011)
J. Cell Sci. 124, 2851-2860
   Abstract »    Full Text »    PDF »
Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis.
S. N. Yazbek, D. A. Buchner, J. M. Geisinger, L. C. Burrage, S. H. Spiezio, G. E. Zentner, C.-W. Hsieh, P. C. Scacheri, C. M. Croniger, and J. H. Nadeau (2011)
Genome Res. 21, 1065-1073
   Abstract »    Full Text »    PDF »
Polycomb repressive complex 2 is necessary for the normal site-specific O-GlcNAc distribution in mouse embryonic stem cells.
S. A. Myers, B. Panning, and A. L. Burlingame (2011)
PNAS 108, 9490-9495
   Abstract »    Full Text »    PDF »
Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes.
A. Makino, J. Suarez, T. Gawlowski, W. Han, H. Wang, B. T. Scott, and W. H. Dillmann (2011)
Am J Physiol Regulatory Integrative Comp Physiol 300, R1296-R1302
   Abstract »    Full Text »    PDF »
Isoform-specific Regulation of the Inositol 1,4,5-Trisphosphate Receptor by O-Linked Glycosylation.
P. Bimboese, C. J. Gibson, S. Schmidt, W. Xiang, and B. E. Ehrlich (2011)
J. Biol. Chem. 286, 15688-15697
   Abstract »    Full Text »    PDF »
Insights into intermediate filament regulation from development to ageing.
C. L. Hyder, K. O. Isoniemi, E. S. Torvaldson, and J. E. Eriksson (2011)
J. Cell Sci. 124, 1363-1372
   Abstract »    Full Text »    PDF »
O-GlcNAcylation Increases ChREBP Protein Content and Transcriptional Activity in the Liver.
C. Guinez, G. Filhoulaud, F. Rayah-Benhamed, S. Marmier, C. Dubuquoy, R. Dentin, M. Moldes, A.-F. Burnol, X. Yang, T. Lefebvre, et al. (2011)
Diabetes 60, 1399-1413
   Abstract »    Full Text »    PDF »
Muscle-specific overexpression of NCOATGK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy.
P. Huang, S.-R. Ho, K. Wang, B. C. Roessler, F. Zhang, Y. Hu, D. B. Bowe, J. E. Kudlow, and A. J. Paterson (2011)
Am J Physiol Cell Physiol 300, C456-C465
   Abstract »    Full Text »    PDF »
The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism.
K. E. Wellen, C. Lu, A. Mancuso, J. M. S. Lemons, M. Ryczko, J. W. Dennis, J. D. Rabinowitz, H. A. Coller, and C. B. Thompson (2010)
Genes & Dev. 24, 2784-2799
   Abstract »    Full Text »    PDF »
{beta}-N-acetylglucosamine (O-GlcNAc) is part of the histone code.
K. Sakabe, Z. Wang, and G. W. Hart (2010)
PNAS 107, 19915-19920
   Abstract »    Full Text »    PDF »
Glucosamine Treatment-mediated O-GlcNAc Modification of Paxillin Depends on Adhesion State of Rat Insulinoma INS-1 Cells.
T. K. Kwak, H. Kim, O. Jung, S.-A. Lee, M. Kang, H. J. Kim, J.-M. Park, S.-H. Kim, and J. W. Lee (2010)
J. Biol. Chem. 285, 36021-36031
   Abstract »    Full Text »    PDF »
Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity.
D. C. Love, S. Ghosh, M. A. Mondoux, T. Fukushige, P. Wang, M. A. Wilson, W. B. Iser, C. A. Wolkow, M. W. Krause, and J. A. Hanover (2010)
PNAS 107, 7413-7418
   Abstract »    Full Text »    PDF »
Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked {beta}-N-Acetylglucosamine in 3T3-L1 Adipocytes.
S. A. Whelan, W. B. Dias, L. Thiruneelakantapillai, M. D. Lane, and G. W. Hart (2010)
J. Biol. Chem. 285, 5204-5211
   Abstract »    Full Text »    PDF »
O-GlcNAc Protein Modification in Cancer Cells Increases in Response to Glucose Deprivation through Glycogen Degradation.
J. G. Kang, S. Y. Park, S. Ji, I. Jang, S. Park, H. S. Kim, S.-M. Kim, J. I. Yook, Y.-I. Park, J. Roth, et al. (2009)
J. Biol. Chem. 284, 34777-34784
   Abstract »    Full Text »    PDF »
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 »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882