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Science 306 (5693): 120-124

Copyright © 2004 by the American Association for the Advancement of Science

Regulation of Cytokine Receptors by Golgi N-Glycan Processing and Endocytosis

Emily A. Partridge,1,3 Christine Le Roy,1 Gianni M. Di Guglielmo,1 Judy Pawling,1 Pam Cheung,1,2 Maria Granovsky,1,2 Ivan R. Nabi,4 Jeffrey L. Wrana,1,2 James W. Dennis1,2,3*

Abstract: The Golgi enzyme ß1,6 N-acetylglucosaminyltransferase V (Mgat5) is up-regulated in carcinomas and promotes the substitution of N-glycan with poly N-acetyllactosamine, the preferred ligand for galectin-3 (Gal-3). Here, we report that expression of Mgat5 sensitized mouse cells to multiple cytokines. Gal-3 cross-linked Mgat5-modified N-glycans on epidermal growth factor and transforming growth factor–ß receptors at the cell surface and delayed their removal by constitutive endocytosis. Mgat5 expression in mammary carcinoma was rate limiting for cytokine signaling and consequently for epithelial-mesenchymal transition, cell motility, and tumor metastasis. Mgat5 also promoted cytokine-mediated leukocyte signaling, phagocytosis, and extravasation in vivo. Thus, conditional regulation of N-glycan processing drives synchronous modification of cytokine receptors, which balances their surface retention against loss via endocytosis.

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
2 Department of Medical Genetics and Microbiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
3 Department of Laboratory Medicine and Pathology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
4 Department of Anatomy, Cell Biology, and Physiology,

* To whom correspondence should be addressed. E-mail: Dennis{at}mshri.on.ca


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S. Watanabe, M. Misawa, T. Matsuzaki, T. Sakurai, T. Muramatsu, T.-a. Yokomine, and M. Sato (2008)
Glycobiology 18, 9-19
   Abstract »    Full Text »    PDF »
Ovarian Cancer is Associated with Changes in Glycosylation in Both Acute-Phase Proteins and IgG.
R. Saldova, L. Royle, C. M Radcliffe, U. M Abd Hamid, R. Evans, J. N Arnold, R. E Banks, R. Hutson, D. J Harvey, R. Antrobus, et al. (2007)
Glycobiology 17, 1344-1356
   Abstract »    Full Text »    PDF »
Lateral Compartmentalization of T Cell Receptor Versus CD45 by Galectin-N-Glycan Binding and Microfilaments Coordinate Basal and Activation Signaling.
I-J. Chen, H.-L. Chen, and M. Demetriou (2007)
J. Biol. Chem. 282, 35361-35372
   Abstract »    Full Text »    PDF »
N-Glycan Processing Deficiency Promotes Spontaneous Inflammatory Demyelination and Neurodegeneration.
S.-U. Lee, A. Grigorian, J. Pawling, I-J. Chen, G. Gao, T. Mozaffar, C. McKerlie, and M. Demetriou (2007)
J. Biol. Chem. 282, 33725-33734
   Abstract »    Full Text »    PDF »
Plasma membrane domain organization regulates EGFR signaling in tumor cells.
P. Lajoie, E. A. Partridge, G. Guay, J. G. Goetz, J. Pawling, A. Lagana, B. Joshi, J. W. Dennis, and I. R. Nabi (2007)
J. Cell Biol. 179, 341-356
   Abstract »    Full Text »    PDF »
Complex N-Glycan and Metabolic Control in Tumor Cells.
R. Mendelsohn, P. Cheung, L. Berger, E. Partridge, K. Lau, A. Datti, J. Pawling, and J. W. Dennis (2007)
Cancer Res. 67, 9771-9780
   Abstract »    Full Text »    PDF »
Biological Applications of a Chimeric Probe for the Assessment of Galectin-3 Ligands.
F. H. M. de Melo, D. Butera, R. S. Medeiros, L. N. de S. Andrade, S. Nonogaki, F. A. Soares, R. A. Alvarez, A. M. M. da Silva, and R. Chammas (2007)
Journal of Histochemistry & Cytochemistry 55, 1015-1026
   Abstract »    Full Text »    PDF »
Intracellular sorting of galectin-8 based on carbohydrate fine specificity.
S. Carlsson, M. C Carlsson, and H. Leffler (2007)
Glycobiology 17, 906-912
   Abstract »    Full Text »    PDF »
A Galectin of Unique Domain Organization from Hemocytes of the Eastern Oyster (Crassostrea virginica) Is a Receptor for the Protistan Parasite Perkinsus marinus.
S. Tasumi and G. R. Vasta (2007)
J. Immunol. 179, 3086-3098
   Abstract »    Full Text »    PDF »
Kinetics of mobilization and differentiation of lymphohematopoietic cells during experimental murine schistosomiasis in galectin-3 / mice.
F. L. Oliveira, P. Frazao, R. Chammas, D. K. Hsu, F. T. Liu, R. Borojevic, C. M. Takiya, and M. C. El-Cheikh (2007)
J. Leukoc. Biol. 82, 300-310
   Abstract »    Full Text »    PDF »
Metabolic homeostasis and tissue renewal are dependent on {beta}1,6GlcNAc-branched N-glycans.
P. Cheung, J. Pawling, E. A Partridge, B. Sukhu, M. Grynpas, and J. W Dennis (2007)
Glycobiology 17, 828-837
   Abstract »    Full Text »    PDF »
Inhibition of a Specific N-Glycosylation Activity Results in Attenuation of Breast Carcinoma Cell Invasiveness-related Phenotypes: INHIBITION OF EPIDERMAL GROWTH FACTOR-INDUCED DEPHOSPHORYLATION OF FOCAL ADHESION KINASE.
H.-B. Guo, M. Randolph, and M. Pierce (2007)
J. Biol. Chem. 282, 22150-22162
   Abstract »    Full Text »    PDF »
Control of T Cell-mediated Autoimmunity by Metabolite Flux to N-Glycan Biosynthesis.
A. Grigorian, S.-U. Lee, W. Tian, I.-J. Chen, G. Gao, R. Mendelsohn, J. W. Dennis, and M. Demetriou (2007)
J. Biol. Chem. 282, 20027-20035
   Abstract »    Full Text »    PDF »

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