What are the Real Functions of O-Glycan Modifications of Notch?

Abstract

Notch is a transmembrane protein receptor that mediates direct cell–cell interactions and controls various cell-fate specifications in metazoans. The extracellular domain of Notch contains 36 tandem epidermal growth factor (EGF)-like repeats, most of which have O-linked glycan modifications: O-glucose, O-fucose, and O-GlcNAc. The function of these individual glycans in Notch signaling activation has been investigated by elimination of single modification sites and by knockout of individual glycosyltransferases. Single site mutants show weaker phenotypes compared with glycosyltransferases knockouts in Notch signaling activation. Thus, the collaboration between two or more glycan modifications appears to be essential for full Notch activation. In this review, we describe the history of Notch’s glycan modifications, the individual functions of the modifications, and how glycan modifications might collaborate in regulating Notch function.