title: Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1.
abstract: Fringe O-fucose-beta1,3-N-acetylglucosaminyltransferases modulate Notch signaling by potentiating signaling induced by Delta-like ligands, while inhibiting signaling induced by Serrate/Jagged1 ligands. Based on binding studies, the differential effects of Drosophila fringe (DFng) on Notch signaling are thought to result from alterations in Notch glycosylation that enhance binding of Delta to Notch but reduce Serrate binding. Here, we report that expression of mammalian fringe proteins (Lunatic [LFng], Manic [MFng], or Radical [RFng] Fringe) increased Delta1 binding and activation of Notch1 signaling in 293T and NIH 3T3 cells. Although Jagged1-induced signaling was suppressed by LFng and MFng, RFng enhanced signaling induced by either Delta1 or Jagged1, underscoring the diversity of mammalian fringe glycosyltransferases in regulating signaling downstream of different ligand-receptor combinations. Interestingly, suppression of Jagged1-induced Notch1 signaling did not correlate with changes in Jagged1 binding as found for Delta1. Our data support the idea that fringe glycosylation increases Delta1 binding to potentiate signaling, but we propose that although fringe glycosylation does not reduce Jagged1 binding to Notch1, the resultant ligand-receptor interactions do not effectively promote Notch1 proteolysis required for activation of downstream signaling events.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1737, USA.
authors.forename: Liang-Tung
authors.initials: LT
authors.lastname: Yang
authors.forename: James T
authors.initials: JT
authors.lastname: Nichols
authors.forename: Christine
authors.initials: C
authors.lastname: Yao
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Manilay
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Robey
authors.forename: Gerry
authors.initials: G
authors.lastname: Weinmaster
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D019921:Biotinylation; D002135:Calcium-Binding Proteins; D002460:Cell Line; D018920:Coculture Techniques; D029721:Drosophila Proteins / Q000378:metabolism*; D004492:Edetic Acid / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D017930:Genes, Reporter; D016695:Glycosyltransferases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C064045:delta protein; D004492:Edetic Acid; D008156:Luciferases; D016695:Glycosyltransferases; D017351:N-Acetylglucosaminyltransferases; C090576:fng protein, Drosophila; D000469:Alkaline Phosphatase