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.
Partridge
Emily A
EA
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
Le Roy
Christine
C
Di Guglielmo
Gianni M
GM
Pawling
Judy
J
Cheung
Pam
P
Granovsky
Maria
M
Nabi
Ivan R
IR
Wrana
Jeffrey L
JL
Dennis
James W
JW
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