Effects of Notch glycosylation on health and diseases

Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell‐fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch‐modifying glycosyltransferase. Since then, glycosylation—a post‐translational modification involving literal sugars—on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse O‐glycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor‐like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation. Notch receptors are heavily decorated with structurally diverse glycans. Glycosylation of Notch extracellular domain has come to be noted as a critical mechanism for regulation of Notch signaling, and dysregulation of Notch signaling leads to various human diseases.