Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2.
Proteins encoded by the fringe family of genes are required to modulate Notch signalling in a wide range of developmental contexts. Using a cell co-culture assay, we find that mammalian Lunatic fringe (Lfng) inhibits Jagged1-mediated signalling and potentiates Delta1-mediated signalling through Notch1. Lfng localizes to the Golgi, and Lfng-dependent modulation of Notch signalling requires both expression of Lfng in the Notch-responsive cell and the Notch extracellular domain. Lfng does not prevent binding of soluble Jagged1 or Delta1 to Notch1-expressing cells. Lfng potentiates both Jagged1- and Delta1-mediated signalling via Notch2, in contrast to its actions with Notch1. Our data suggest that Fringe-dependent differential modulation of the interaction of Delta/Serrate/Lag2 (DSL) ligands with their Notch receptors is likely to have a significant role in the combinatorial repertoire of Notch signalling in mammals.
Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, California 90095-1737, USA.
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Hicks
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Johnston
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diSibio
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Collazo
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Vogt
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Weinmaster
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D018920:Coculture Techniques; D005347:Fibroblasts; D005964:Glucosyltransferases; D016695:Glycosyltransferases; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D011506:Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; C064045:delta protein; D016695:Glycosyltransferases; D005964:Glucosyltransferases; C498392:Lfng protein, mouse; C486343:Mfng protein, mouse; D000469:Alkaline Phosphatase