Multifaceted regulation of Notch signaling by glycosylation

To build a complex body composed of various cell types and tissues and to maintain tissue homeostasis in the postembryonic period, animals use a small number of highly conserved intercellular communication pathways. Among these is the Notch signaling pathway, which is mediated via the interaction of transmembrane Notch receptors and ligands usually expressed by neighboring cells. Maintaining optimal Notch pathway activity is essential for normal development, as evidenced by various human diseases caused by decreased and increased Notch signaling. It is therefore not surprising that multiple mechanisms are used to control the activation of this pathway in time and space. Over the last 20 years, protein glycosylation has been recognized as a major regulatory mechanism for Notch signaling. In this review, we will provide a summary of the various types of glycan that have been shown to modulate Notch signaling. Building on recent advances in the biochemistry, structural biology, cell biology and genetics of Notch receptors and the glycosyltransferases that modify them, we will provide a detailed discussion on how various steps during Notch activation are regulated by glycans. Our hope is that the current review article will stimulate additional research in the field of Notch glycobiology and will potentially be of benefit to investigators examining the contribution of glycosylation to other developmental processes.