Regulation of Notch Function by O-Glycosylation

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


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.


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





Glucoside α3-Xylosyltransferase


Xyloside α3-Xylosyltransferase




Adams-Oliver Syndrome




Dowling-Degos Disease


Delta-like ligand




Extracellular Domain


Epidermal Growth Factor-like


EGF-domain-specific O-GlcNAc Transferase


Endoplasmic Reticulum
















O-GlcNAc Transferase




Protein O-Fucosyltransferase 1


Protein O-Glucosyltransferase 1


Ser, Serine; Sia, Sialic Acid


Thr, Threonine





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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