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Regulation of Notch Function by O-Glycosylation

  • Beth M. Harvey
  • Robert S. Haltiwanger
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)

Abstract

The Notch receptor initiates a unique intercellular signaling pathway that is evolutionarily conserved across all metazoans and contributes to the development and maintenance of numerous tissues. Consequently, many diseases result from aberrant Notch signaling. Emerging roles for Notch in disease are being uncovered as studies reveal new information regarding various components of this signaling pathway. Notch activity is regulated at several levels, but O-linked glycosylation of Epidermal Growth Factor (EGF) repeats in the Notch extracellular domain has emerged as a major regulator that, depending on context, can increase or decrease Notch activity. Three types of O-linked glycosylation occur at consensus sequences found within the EGF repeats of Notch: O-fucosylation, O-glucosylation, and O-GlcNAcylation. Recent studies have investigated the site occupancy of these types of glycosylation and also defined specific roles for these glycans on Notch structure and function. Nevertheless, there are many functional aspects to each type of O-glycosylation that remain unclear. Here, we will discuss molecular mechanisms of how O-glycosylation regulates Notch signaling and describe disorders associated with defects in Notch O-glycosylation.

Keywords

Notch signaling EGF repeat O-fucose O-glucose O-GlcNAc 

Abbreviations

β4GalT-1

β4-Galactosyltransferase-1

GXYLT

Glucoside α3-Xylosyltransferase

XXYLT

Xyloside α3-Xylosyltransferase

A

Alanine

AOS

Adams-Oliver Syndrome

C

Cysteine

DDD

Dowling-Degos Disease

DLL

Delta-like ligand

DSL

Delta/Serrate/LAG2

ECD

Extracellular Domain

EGF

Epidermal Growth Factor-like

EOGT

EGF-domain-specific O-GlcNAc Transferase

ER

Endoplasmic Reticulum

FNG

Fringe

Fuc

Fucose

G

Glycine

Gal

Galactose

Glc

Glucose

GlcNAc

N-Acetylglucosamine

JAG

Jagged

OGT

O-GlcNAc Transferase

P

Proline

POFUT1

Protein O-Fucosyltransferase 1

POGLUT1

Protein O-Glucosyltransferase 1

S

Ser, Serine; Sia, Sialic Acid

T

Thr, Threonine

Xyl

Xylose

Notes

Acknowledgments

We would like to thank the members of the Haltiwanger laboratory for helpful comments and discussions. Original work was supported by NIH grant GM061126.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Cell BiologyStony Brook UniversityStony BrookUSA
  2. 2.Present Address: Department of Cell and Developmental BiologyUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Complex Carbohydrate Research CenterUniversity of GeorgiaAthensUSA

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