Multiple roles for O-glycans in Notch signalling

Abstract

Notch signalling regulates a plethora of developmental processes and is also essential for the maintenance of tissue homeostasis in adults. Therefore, fine-tuning of Notch signalling strength needs to be tightly regulated. Of key importance for the regulation of Notch signalling are O-fucose, O-GlcNAc and O-glucose glycans attached to the extracellular domain of Notch receptors. The EGF repeats of the Notch receptor extracellular domain harbour consensus sites for addition of the different types of O-glycan to Ser or Thr, which takes place in the endoplasmic reticulum. Studies from Drosophila to mammals have demonstrated the multifaceted roles of O-glycosylation in regulating Notch signalling. O-glycosylation modulates different aspects of Notch signalling including recognition by Notch ligands, the strength of ligand binding, Notch receptor trafficking, stability and activation at the cell surface. Defects in O-glycosylation of Notch receptors give rise to pathologies in humans. This Review summarizes the nature of the O-glycans on Notch receptors and their differential effects on Notch signalling.

Keywords: Notch signalling; O-GlcNAc; O-fucose; O-glucose; glycosylation; glycosyltransferases.

Figure 1.

Representation of mouse NOTCH1 extracellular domain depicting EGF repeats with different O-glycan consensus sites that may be modified with the O-glycans shown. One of the EGF domains is magnified to show the consensus site for each type of O-glycan. Different O-glycans, their respective differential extension with sugars (+/−), and the glycosyltransferases responsible for the transfer of each sugar are shown below the diagram. The transfer of O-glucose by POGLUT2 or POGLUT3 occurs only on EGF11 in NOTCH1. The consensus site is between Cys³ and Cys⁴, indicated by the different location of the glucose symbol in EGF11 in the diagram.

Figure 2.

The human mutations and pathologies associated with glycosyltransferases that modify Notch receptors. The diagram of each glycosyltransferase represents protein size, with the signal peptide or transmembrane domain identified by a grey box and each ER retention sequence given at the C-terminus. The human mutations identified so far are mentioned below each protein diagram, with the corresponding pathologies referred to in the disease column.