title: Galactose differentially modulates lunatic and manic fringe effects on Delta1-induced NOTCH signaling.
abstract: NOTCH signaling induced by Delta1 (DLL1) and Jagged1 (JAG1) NOTCH ligands is modulated by the β3N-acetylglucosaminyl transferase Fringe. LFNG (Lunatic Fringe) and MFNG (Manic Fringe) transfer N-acetylglucosamine (GlcNAc) to O-fucose attached to EGF-like repeats of NOTCH receptors. In co-culture NOTCH signaling assays, LFNG generally enhances DLL1-induced, but inhibits JAG1-induced, NOTCH signaling. In mutant Chinese hamster ovary (CHO) cells that do not add galactose (Gal) to the GlcNAc transferred by Fringe, JAG1-induced NOTCH signaling is not inhibited by LFNG or MFNG. In mouse embryos lacking B4galt1, NOTCH signaling is subtly reduced during somitogenesis. Here we show that DLL1-induced NOTCH signaling in CHO cells was enhanced by LFNG, but this did not occur in either Lec8 or Lec20 CHO mutants lacking Gal on O-fucose glycans. Lec20 mutants corrected with a B4galt1 cDNA became responsive to LFNG. By contrast, MFNG promoted DLL1-induced NOTCH signaling better in the absence of Gal than in its presence. This effect was reversed in Lec8 cells corrected by expression of a UDP-Gal transporter cDNA. The MFNG effect was abolished by a DDD to DDA mutation that inactivates MFNG GlcNAc transferase activity. The binding of soluble NOTCH ligands and NOTCH1/EGF1-36 generally reflected changes in NOTCH signaling caused by LFNG and MFNG. Therefore, the presence of Gal on O-fucose glycans differentially affects DLL1-induced NOTCH signaling modulated by LFNG versus MFNG. Gal enhances the effect of LFNG but inhibits the effect of MFNG on DLL1-induced NOTCH signaling, with functional consequences for regulating the strength of NOTCH signaling.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, New York 10461.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, New York 10461.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tashima
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, New York 10461. Electronic address: pamela.stanley@einstein.yu.edu.
authors.forename: Pamela
authors.initials: P
authors.lastname: Stanley
mesh_terms: D000818:Animals; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004815:Epidermal Growth Factor / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005690:Galactose / Q000378:metabolism*; D005964:Glucosyltransferases; D016695:Glycosyltransferases / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D011134:Polysaccharides / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D012995:Solubility
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011134:Polysaccharides; D011506:Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D004815:Epidermal Growth Factor; D016695:Glycosyltransferases; D005964:Glucosyltransferases; C498392:Lfng protein, mouse; C486343:Mfng protein, mouse; D005690:Galactose
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