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Science 1 October 2004:
Vol. 306. no. 5693, pp. 120 - 124
DOI: 10.1126/science.1102109
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Reports

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*

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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