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PMID:15574878

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Citation

Yang, LT, Nichols, JT, Yao, C, Manilay, JO, Robey, EA and Weinmaster, G (2005) Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1. Mol. Biol. Cell 16:927-42

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.

Links

PubMed PMC545923 Online version:10.1091/mbc.E04-07-0614

Keywords

Alkaline Phosphatase/analysis; Animals; Biotinylation; Calcium-Binding Proteins; Cell Line; Coculture Techniques; Drosophila Proteins/metabolism; Edetic Acid/pharmacology; Fibroblasts/drug effects; Genes, Reporter; Glycosyltransferases/metabolism; Humans; Hydrolysis; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Ligands; Luciferases/metabolism; Membrane Proteins/antagonists & inhibitors; Membrane Proteins/metabolism; Mice; Models, Biological; N-Acetylglucosaminyltransferases/metabolism; NIH 3T3 Cells; Receptor, Notch1; Receptors, Cell Surface/metabolism; Signal Transduction; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MFNG

acts_upstream_of_or_within

GO:0032092: positive regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MFNG

acts_upstream_of_or_within

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RFNG

acts_upstream_of_or_within

GO:0032092: positive regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RFNG

acts_upstream_of_or_within

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LFNG

acts_upstream_of_or_within

GO:0032092: positive regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LFNG

acts_upstream_of_or_within

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ADAM7

enables

GO:0004175: endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NOTC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61483
PR:Q9QXX0
PR:Q9Z0F8

F

Seeded From UniProt

complete

MOUSE:NOTC1

part_of

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DLL1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q01705

F

Seeded From UniProt

complete

MOUSE:DLL1

acts_upstream_of_or_within

GO:0045747: positive regulation of Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:JAG1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q01705

F

Seeded From UniProt

complete

MOUSE:JAG1

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TMM59

enables

GO:0004175: endopeptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ADA17

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q01705

F

Seeded From UniProt

complete


See also

References

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