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The role of O‐fucosylated glycans in Notch signaling
Author(s) -
Shim Jeongsup,
Petryniak Bronislawa,
Lowe John B.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.825.1
Subject(s) - notch signaling pathway , notch proteins , microbiology and biotechnology , glycosylation , receptor , signal transduction , cyclin dependent kinase 8 , hes3 signaling axis , biology , egf like domain , chemistry , biochemistry , binding site , binding domain
Signaling from the Notch receptor family is important in development, and its role in disease has assigned the Notch signaling pathway as a therapeutic target. Mammalian Notch receptors are single‐pass transmembrane glycoproteins containing 29–36 EGF‐like repeats. Notch receptors on “receiving” cells signal when they interact with Notch ligands expressed on “sending” cells. Glycosylation of some Notch EGF‐like repeats modulates Notch‐dependent signaling. EGF repeat glycosylation includes constitutive fucosylation of some EGF repeat‐localized serine/threonine residues, and elongation of fucose‐initiated glycans regulated by the Fringe family of glycosyltransferases. To understand how glycosylation controls Notch signaling, we sought to determine how O‐fucosylated glycans modulate Notch receptor‐ligand interactions, using (1) surface plasmon resonance, (2) cell‐based binding assays, and (3) cell‐based Notch signaling assays. We find that lunatic Fringe modification of Notch1 receptors enhances Dll1 and Dll4 binding affinities and signaling, while it reduces Jag1‐mediated binding affinity and signaling. Fringe modification of Notch1 does not significantly alter Jag2‐mediated binding affinity and signaling. We also find that Dll1 binding and signaling is enhanced by lunatic Fringe primarily when Notch1 expression is low, and this enhancement is blunted when Notch1 expression is high.