Dynamic interplay between O-glycosylation and O-phosphorylation of nucleocytoplasmic proteins: a new paradigm for metabolic control of signal transduction and transcription

Abstract

The glycosylation of serine and threonine residues with beta-O-linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslational modification of nuclear and cytoplasmic proteins in multicellular eukaryotes. This highly dynamic glycosylation/deglycosylation of protein is catalyzed by the nucleocytoplasmic enzymes, UDP-G1cNAc: polypeptide O-beta-N-acetylglucosaminyltransferase (OGT)/O-beta-N-acetylglucosaminidase. OGT is required for embryonic stem cell viability and mouse ontogeny, thus O-GlcNAc is essential for the life of eukaryotes. The gene encoding O-GlcNAcase maps to a locus important to late-onset Alzheimer's disease. All known O-GlcNAc-modified proteins are also phosphoproteins that form reversible multimeric protein complexes. There is both a global and often site-specific reciprocal relationship between O-GlcNAc and O-phosphate in many cellular responses to stimuli. Thus, regulation of the protein-protein interaction(s) and/or protein function by dynamic glycosylation/phosphorylation has been hypothesized. In this chapter, we will review the current status of dynamic glycosylation/phosphorylation of several important regulatory proteins including c-Myc, estrogen receptors, Sp1, endothelial nitric oxide synthase, and beta-catenin. Various aspects of subcellular localization, association with binding partners, activity, and/or turnover of these proteins appear to be regulated by dynamic glycosylation/ phosphorylation in response to cellular signals or stages.