Roles of glycosylation in Notch signaling

Notch and the DSL Notch ligands Delta and Serrate/Jagged are glycoproteins with a single transmembrane domain. The extracellular domain (ECD) of both Notch receptors and Notch ligands contains numerous epidermal growth factor (EGF)-like repeats which are post-translationally modified by a variety of glycans. Inactivation of a subset of genes that encode glycosyltransferases which initiate and elongate these glycans inhibits Notch signaling. In the formation of developmental boundaries in Drosophila and mammals, in mouse T-cell and marginal zone B-cell development, and in co-culture Notch signaling assays, the regulation of Notch signaling by glycans is to date a cell-autonomous effect of the Notch-expressing cell. The regulation of Notch signaling by glycans represents a new paradigm of signal transduction. O-fucose glycans modulate the strength of Notch binding to DSL Notch ligands, while O-glucose glycans facilitate juxta-membrane cleavage of Notch, generating the substrate for intramembrane cleavage and Notch activation. Identifying precisely how the addition of particular sugars at specific locations on Notch modifies Notch signaling is a challenge for the future.