Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis.
The Golgi enzyme beta1,6 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-beta 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.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
Emily A
EA
Partridge
Christine
C
Le Roy
Gianni M
GM
Di Guglielmo
Judy
J
Pawling
Pam
P
Cheung
Maria
M
Granovsky
Ivan R
IR
Nabi
Jeffrey L
JL
Wrana
James W
JW
Dennis
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D037502:Galectin 3 / Q000378:metabolism; D005822:Genetic Vectors; D006031:Glycosylation; D006056:Golgi Apparatus / Q000201:enzymology; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010587:Phagocytosis; D011134:Polysaccharides / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction
D037502:Galectin 3; D006133:Growth Substances; D011134:Polysaccharides; D018121:Receptors, Cytokine; D018125:Receptors, Transforming Growth Factor beta; C037199:poly-N-acetyllactosamine; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; D066246:ErbB Receptors