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  • Review Article
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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.

Abstract

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.

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Figure 1: Distinct modes of Notch signalling.
Figure 2: The Notch signalling pathway.
Figure 3: Sequential addition of O-linked glycans to EGF domains in CHO cells.
Figure 4: Analysing the requirements for O-fucose glycans in Notch signalling in cultured cells.
Figure 5: Analysing the requirements for O-fucose glycans in Notch signalling in the developing Drosophila wing.
Figure 6: Evolutionary conservation of sites for O-fucosylation, O-glucosylation and β-hydroxylation.
Figure 7: Models for the action of O-fucose glycans.

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Acknowledgements

We thank N. Baker, J. Chen, R. Haltiwanger and P. Stanley for comments on the manuscript. Research in K.D.I.'s laboratory is supported by the Howard Hughes Medical Institute and by the National Institutes of Health.

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Correspondence to Kenneth D. Irvine.

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DATABASES

LocusLink

Cripto

CSL

Delta

fringe connection

Jagged

Notch

Ofut1

POFUT1

presenilin

scabrous

Serrate

Swiss-Prot

β4GalT-1

Fringe

lex-1

L-Fng

M-Fng

Notch1

R-Fng

FURTHER INFORMATION

Kenneth Irvine's laboratory

Glossary

NEUROBLAST

A primary Drosophila neural precursor that gives rise to neural and glial cells only. It divides asymmetrically in a stem-cell-like mode into another neuroblast and a ganglion mother cell.

GLYCOSYLTRANSFERASE

An enzyme that catalyses the transfer of a sugar from a nucleoside sugar-donor substrate to an acceptor substrate. Most glycosyltransferases are highly specific for a particular donor sugar, acceptor sugar or amino acid, and for the type of linkage created between the two substrates. The linkages are named according to the carbon atom on each sugar, and the enantiomeric configuration (α or β).

EGF DOMAIN

A widespread structural motif with 40 amino acids, including six cysteine residues and a mainly β-sheet structure. Ligands for ERBB/EGF receptors contain single EGF domains, but many other protein families contain multiple, repeated EGF-like domains.

FIBRINOLYSIS

The proteolysis of fibrin by plasmin in blood cells.

RNA INTERFERENCE

(rnai). A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation — through nucleases — of the homologous endogenous transcripts, mimicking the effect of the reduction, or loss, of gene activity.

N-LINKED GLYCANS

Sugars that are attached to a protein substrate through linkage at the amide groups of asparagine residues.

O-LINKED GLYCANS

Sugars that are attached to a protein substrate through linkage at the hydroxyl groups of serine or threonine residues.

PRESOMITIC MESODERM

Unsegmented paraxial mesoderm, which is subdivided by segmentation into somites.

CELL AUTONOMOUS

Autonomy, in genetic terms, is a description of the spatial relationship between genotype and phenotype. Autonomy is assessed in genetic mosaics, and a gene is said to influence a phenotype cell-autonomously if there is a precise correspondence between the genotype and phenotype of a cell.

EPISTASIS

Epistasis is a description of the relationship between alleles of different genes, and is often used by geneticists to order genes in a pathway. When an animal that is a double mutant for two different genes displays the phenotype of one of the single mutants and not the other, the gene whose phenotype is observed is said to be epistatic.

LECTIN

A protein that binds to sugars without modifying them. Lectins usually recognize specific carbohydrate moieties and form multivalent attachments.

HEPARIN SULPHATE PROTEOGLYCAN

A protein extensively modified with glycosaminoglycans, the basic structure of which consists of repeating disaccharides of glucuronic acid and N-acetylglucosamine. They are essential for the function of several signalling pathways.

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Haines, N., Irvine, K. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 4, 786–797 (2003). https://doi.org/10.1038/nrm1228

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