Dynamic Interplay between O-Glycosylation and O-Phosphorylation of Nucleocytoplasmic Proteins: A New Paradigm for Metabolic Control of Signal Transduction and Transcription

The glycosylation of serine and threonine residues with β-O-linked N-acetylglucosamine (O-GlcNAc) is an abundant posttranslational modification of nuclear and cytoplasmic proteins in multicellular eukaryotes. This highly dynamic glycosylation{plus 45 degree rule}deglycosylation of protein is catalyzed by the nucleocytoplasmic enzymes, UDP-GlcNAc: polypeptide O-β-N-acetylglucosaminyltransferase (OGT){plus 45 degree rule}O-β-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{plus 45 degree rule}or protein function by dynamic glycosylation{plus 45 degree rule}phosphorylation has been hypothesized. In this chapter, we will review the current status of dynamic glycosylation{plus 45 degree rule}phosphorylation of several important regulatory proteins including c-Myc, estrogen receptors, Sp1, endothelial nitric oxide synthase, and β-catenin. Various aspects of subcellular localization, association with binding partners, activity, and{plus 45 degree rule}or turnover of these proteins appear to be regulated by dynamic glycosylation{plus 45 degree rule}phosphorylation in response to cellular signals or stages.