Abstract
Notch signaling, which was initially identified in Drosophila wing morphogenesis, plays pivotal roles in cell development and differentiation. Optimal Notch pathway activity is essential for normal development and dysregulation of Notch signaling leads to various human diseases, including many types of cancers. In hematopoietic cancers, such as T-cell acute lymphoblastic leukemia, Notch plays an oncogenic role, while in acute myeloid leukemia, it has a tumor-suppressive role. In solid tumors, such as hepatocellular carcinoma and medulloblastoma, Notch may have either an oncogenic or tumor-suppressive role, depending on the context. Aberrant expression of Notch receptors or ligands can alter the ligand-dependent Notch signaling and changes in trafficking can lead to ligand-independent signaling. Defects in any of the two signaling pathways can lead to tumorigenesis and tumor progression. Strikingly, O-glycosylation is one such process that modulates ligand–receptor binding and trafficking. Three types of O-linked modifications on the extracellular epidermal growth factor-like (EGF) repeats of Notch receptors are observed, namely O-glucosylation, O-fucosylation, and O-N-acetylglucosamine (GlcNAc) modifications. In addition, O-GalNAc mucin-type O-glycosylation outside the EGF repeats also appears to occur in Notch receptors. In this review, we first briefly summarize the basics of Notch signaling, describe the latest information on O-glycosylation of Notch receptors classified on a structural basis, and finally describe the regulation of Notch signaling by O-glycosylation in cancer.
Highlights
Introduction to Notch SignalingNotch signaling is a highly conserved cell signaling system in metazoans, as it controls multiple processes involved in the development of multicellular organisms, tissue homeostasis, and stem cell maintenance [1]
Dysregulation of Notch signaling in many cellular contexts is related to tumorigenesis, in which the Notch signaling pathway acts as a tumor suppressor, such as in small-cell lung cancer, and exhibits oncogenic functions, such as in T-cell acute lymphoblastic leukemia (T-ALL) [4]
O-Fucose modification was first discovered after the isolation of amino acid fucosides from human urine in 1975 [51] and later found on the epidermal growth factor-like (EGF) repeats in NOTCH1 derived from Chinese hamster ovary (CHO) cells [52]
Summary
Protein glycosylation can occur both co-translationally or post-translationally and contributes to the structural and functional characteristics of a large number of glycosylated proteins. It usually occurs in the ER and Golgi apparatus for secreted and transmembrane proteins and involves the addition of different forms of glycan to specific sites of proteins. Each O-glycosylation reaction occurs at specific positions only in properly folded EGF repeats in Notch receptors or DSL ligands via specific glycosyltransferases. O-Glycans play critical and multiple roles in the activation of Notch receptors, including protein folding/stability, trafficking, and ligand binding. Several human diseases are related to mutations in genes encoding the Notch-modifying glycosyltransferases
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