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Regulation of Notch Function by O-Glycosylation.
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.
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