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MBC in Press, published online ahead of print December 1, 2004
Mol. Biol. Cell 10.1091/mbc.E04-07-0614

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Submitted on July 21, 2004
Accepted on November 19, 2004

Fringe Glycosyltransferases Differentially Modulate Notch1 Proteolysis Induced by Delta1 and Jagged1

Liang-Tung Yang,* James T. Nichols,* Christine Yao,* Jennifer O. Manilay,{dagger} Ellen A. Robey,{dagger} and Gerry Weinmaster*{ddagger}{sect}

*Department of Biological Chemistry and {ddagger}Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1737; {dagger}Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720

Monitoring Editor: Reid Gilmore

Fringe O-fucose-{beta}1,3-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. Even though 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. Although our data support the idea that fringe glycosylation increases Delta1 binding to potentiate signaling, we propose that while 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.

{sect}Corresponding author. E-mail: gweinmaster{at}mednet.ucla.edu






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