The Notch signaling pathway is involved in a wide variety of highly conserved 
developmental processes in mammals. Importantly, mutations of the Notch protein 
and components of its signaling pathway have been implicated in an array of 
human diseases (T-cell leukemia and other cancers, Multiple Sclerosis, CADASIL, 
Alagille Syndrome, Spondylocostal Dysostosis). In mammals, Notch becomes 
activated upon binding of its extracellular domain to ligands (Delta and 
Jagged/Serrate) that are present on the surface of apposed cells. The 
extracellular domain of Notch contains up to 36 tandem Epidermal Growth 
Factor-like (EGF) repeats. Many of these EGF repeats are modified at 
evolutionarily-conserved consensus sites by an unusual form of O-glycosylation 
called O-fucose. Work from several groups indicates that O-fucosylation plays an 
important role in ligand mediated Notch signaling. Recent evidence also suggests 
that the enzyme responsible for addition of O-fucose to Notch, protein 
O-fucosyltransferase-1 (POFUT1), may serve a quality control function in the 
endoplasmic reticulum. Additionally, some of the O-fucose moieties are further 
elongated by the action of members of the Fringe family of 
beta-1,3-N-acetylglucosaminyltransferases. The alteration in O-fucose saccharide 
structure caused by Fringe modulates the response of Notch to its ligands. Thus, 
glycosylation serves an important role in regulating Notch activity. This review 
focuses on the role of glycosylation in the normal functioning of the Notch 
pathway. As well, potential roles for glycosylation in Notch-related human 
diseases, and possible roles for therapeutic targeting of POFUT1 and Fringe in 
Notch-related human diseases, are discussed.