Glycosylation regulates Notch signalling

Key Points Notch receptor proteins are modified by the addition of two O -linked glycans — O -linked glucose and O -linked fucose — to serine or threonine residues within their epidermal growth factor (EGF) domains. Many Notch receptors contain 36 EGF domains, most of which might be O -glycosylated. The addition of O -linked fucose to Notch is catalysed by a glycosyltransferase, O -FucT-1. Because loss or reduction of O -FucT-1 results in phenotypes that resemble those observed in the complete absence of Notch function, O -linked fucose must be essential for most, or all, Notch signalling. The O -linked fucose monosaccharide can be elongated by the addition of N -acetylglucosamine, in a reaction that is catalysed by the glycosyltransferase Fringe. Developmental regulation of Fringe transcription effectively creates different forms of Notch receptors. Rather than being positively required for all Notch signalling, elongation of O -linked fucose by Fringe potentiates the activation of Notch by Delta ligands, but inhibits the activation of Notch by Serrate/Jagged ligands. The influence of Fringe is also restricted to certain modes of Notch signalling. O -linked fucose glycans can influence binding between Notch and its ligands, and this seems to be an important mechanism by which O -fucosylation influences Notch signalling. However, O -fucosylation might also influence other steps of Notch signalling. Intracellular post-translational modifications such as phosphorylation and ubiquitylation have been well studied for their roles in regulating diverse signalling pathways, but we are only just beginning to understand how differential glycosylation is used to regulate intercellular signalling. Recent studies make clear that extracellular post-translational modifications, in the form of glycosylation, are essential for the Notch signalling pathway, and that differences in the extent of glycosylation are a significant mechanism by which this pathway is regulated.