Site‐specific interplay between O‐GlcNAcylation and phosphorylation in cellular regulation

Abstract

Ser(Thr)‐O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) is a ubiquitous modification of nucleocytoplasmic proteins. Extensive crosstalk exists between O‐GlcNAcylation and phosphorylation, which regulates signaling in response to nutrients/stress. The development of novel O‐GlcNAc detection and enrichment methods has improved our understanding of O‐GlcNAc functions. Mass spectrometry has revealed O‐GlcNAc's many interactions with phosphorylation‐mediated signaling. However, mechanisms regulating O‐GlcNAcylation and phosphorylation are quite different. Phosphorylation is catalyzed by hundreds of distinct kinases. In contrast, in mammals, uridine diphospho‐N‐acetylglucosamine:polypeptide β‐N‐acetylglucosaminyl transferase (OGT) and β‐D‐N‐acetylglucosaminidase (OGA) are encoded by single highly conserved genes. Both OGT's and OGA's specificities are determined by their transient associations with many other proteins to create a multitude of specific holoenzymes. The extensive crosstalk between O‐GlcNAcylation and phosphorylation represents a new paradigm for cellular signaling.