The bisecting GlcNAc on N-glycans inhibits growth factor signaling and retards mammary tumor progression.
The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration, and hepatoma formation. Here, we show that Chinese hamster ovary cells expressing Mgat3 and the polyoma middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in mouse mammary tumor virus (MMTV)/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly and have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway and reduced amounts of functionally glycosylated alpha-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus, the addition of the bisecting GlcNAc to complex N-glycans of mammary tumor cell glycoprotein receptors is a cell autonomous mechanism serving to retard tumor progression by reducing growth factor signaling.
Song
Yinghui
Y
Department of Cell Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
Aglipay
Jason A
JA
Bernstein
Joshua D
JD
Goswami
Sumanta
S
Stanley
Pamela
P
D000117:Acetylglucosamine / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018450:Disease Progression; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009362:Neoplasm Metastasis; D011134:Polysaccharides / Q000737:chemistry*; D015398:Signal Transduction
D036341:Intercellular Signaling Peptides and Proteins; D011134:Polysaccharides; D049030:Dystroglycans; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; D000117:Acetylglucosamine
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