InterPro domain: IPR003378

The Notch receptor is a large, cell surface transmembrane protein involved in a wide variety of developmental processes in higher organisms [ 1 ]. It becomes activated when its extracellular region binds to ligands located on adjacent cells. Much of this extracellular region is composed of EGF-like repeats, many of which can be O-fucosylated. A number of these O-fucosylated repeats can in turn be further modified by the action of a beta-1,3-N-acetylglucosaminyltransferase enzyme known as Fringe [ 2 ]. Fringe potentiates the activation of Notch by Delta ligands, while inhibiting activation by Serrate/Jagged ligands. This regulation of Notch signalling by Fringe is important in many processes [ 3 ].

Four distinct Fringe proteins have so far been studied in detail; Drosophila Fringe (Dfng) and its three mammalian homologues Lunatic Fringe (Lfng), Radical Fringe (Rfng) and Manic Fringe (Mfng). Dfng, Lfng and Rfng have all been shown to play important roles in developmental processes within their host, though the phenotype of mutants can vary between species e.g. Rfng mutants are retarded in wing development in chickens, but have no obvious phenotype in mice [ 4 , 5 , 6 ]. Mfng mutants have not, so far, been charcterised. Biochemical studies indicate that the Fringe proteins are fucose-specific transferases requiring manganese for activity and utilising UDP-N-acetylglucosamine as a donor substrate [ 7 ]. The three mammalian proteins show distinct variations in their catalytic efficiencies with different substrates.

Dfng is a glucosaminyltransferase that controls the response of the Notch receptor to specific ligands which is localised to the Golgi apparatus [ 8 ] (not secreted as previously thought). Modification of Notch occurs through glycosylation by Dfng.

This entry consists of Fringe proteins and related glycosyltransferase enzymes including:

• Beta-1,3-glucosyltransferase, which glucosylates O-linked fucosylglycan on thrombospondin type 1 repeat domains [ 9 ].
• Core 1 beta1,3-galactosyltransferase 1, generates the core T antigen, which is a precursor for many extended O-glycans in glycoproteins and plays a central role in many processes, such as angiogenesis, thrombopoiesis and kidney homeostasis development [ 10 ].

1. Notch signaling: cell fate control and signal integration in development. Science 284, 770-6
2. Modulation of receptor signaling by glycosylation: fringe is an O-fucose-beta1,3-N-acetylglucosaminyltransferase. Biochim. Biophys. Acta 1573, 328-35
3. Glycosylation regulates Notch signalling. Nat. Rev. Mol. Cell Biol. 4, 786-97
4. fringe, a Boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79, 595-606
5. Segmentation defects of Notch pathway mutants and absence of a synergistic phenotype in lunatic fringe/radical fringe double mutant mice. Genesis 33, 21-8
6. Radical fringe positions the apical ectodermal ridge at the dorsoventral boundary of the vertebrate limb. Nature 386, 360-6
7. Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. J. Biol. Chem. 280, 42454-63
8. The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD. Curr. Biol. 10, 813-20
9. Molecular cloning and characterization of a novel human beta1,3-glucosyltransferase, which is localized at the endoplasmic reticulum and glucosylates O-linked fucosylglycan on thrombospondin type 1 repeat domain. Glycobiology 16, 1194-206
10. Purification, characterization, and subunit structure of rat core 1 Beta1,3-galactosyltransferase. J. Biol. Chem. 277, 169-77