Biological Functions of Glycosyltransferase Genes Involved in O-fucose Glycan Synthesis

Abstract

Rare types of glycosylation often occur in a domain-specific manner and are involved in specific biological processes. Well-known examples of such modification are O-linked fucose (O-fucose) and O-linked glucose (O-glucose) glycans on epidermal growth factor (EGF) domains. In particular, O-fucose glycans are reported to regulate the functions of EGF domain-containing proteins such as urinary-type plasminogen activator and Notch receptors. Two glycosyltransferases catalyze the initiation and elongation of O-fucose glycans. The initiation process is catalyzed by O-fucosyltransferase 1, which is essential for Notch signalling in both Drosophila and mice. O-fucosyltransferase 1 can affect the folding, ligand interaction and endocytosis of Notch receptors, and both the glycosyltransferase and non-catalytic activities of O-fucosyltransferase 1 have been reported. The elongation of O-fucose monosaccharide is catalyzed by Fringe-related genes, which differentially modulate the interaction between Notch and two classes of ligands, namely, Delta and Serrate/Jagged. In this article, we have reviewed the recent reports addressing the distinctive features of the glycosyltransferases and O-glycans present on the EGF domains.

Roles of Pofut1 and O-Fucose in Mammalian Notch Signaling

“…Some combination of these effects presumably allows stable cell surface expression of mammalian Notch receptors in the absence of Pofut1. The combined results emphasize the fact that conclusions drawn from studies of Drosophila Notch (18,61,62), cannot necessarily be applied to mammalian Notch receptors. Another example of a substantial difference between mammals and Drosophila is in the in vivo consequences of eliminating the O-fucose site in the Notch1 ligand binding domain.…”

“…Experiments in cultured Drosophila wing discs also suggest that Ofut1 may not be required for trafficking of Notch to the cell surface, although it is required for stable cell surface expression of Notch (17,37). However, there are technical concerns that may affect the interpretation of these experiments (18,61,62). Interestingly, Drosophila Notch lacking O-glucose in the rumi mutant is functionally inactive at 25°C but is expressed well at the cell surface (63).…”

O-Linked N-Acetylglucosamine Is Present on the Extracellular Domain of Notch Receptors

“…Identification of other O-GlcNAcylated peptides and determination of the consensus sequence for O-GlcNAc modification on EGF domains will be required to address these questions. In addition to Notch receptors, Factors VII, IX, and XII, plasminogen activators, and Protein Z are reported to be O-fucosylated or O-glucosylated (34). Interestingly, with the exception of Factor XII, these plasma glycoproteins do not contain potentially O-GlcNAcylated Ser/Thr residues.…”

Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells

“…This selective activation of specific Notch paralogs can result from interaction with specific ligands, such as selective activation of Notch2 by Jagged family members in the presence of Fringe, a glycosyltransferase that mediates differential receptor activation by unique ligands in both Drosophila and mammals (21)(22)(23)(24)(25). Overall, these studies have raised questions of distinct function of individual Notch paralogs in HSC function.…”