Extracellular O-linked β-N-acetylglucosamine: Its biology and relationship to human disease

Figure 1 Extracellular O-linked β-N-acetylglucosamine. A: The O-linked β-N-acetylglucosamine (O-GlcNAc)ylation of extracellular protein domains is a newly identified translational modification of epidermal growth factor (EGF) domains, including Notch, HSPG2, Pamr1, and Lama5. Extracellular O-GlcNAc is mediated by EOGT in the endoplasmic reticulum (ER). Mutations in EOGT were recently identified in patients with Adams-Oliver syndrome (AOS). The role of EOGT in the pathogenesis of AOS is currently unknown. Given that RBPJ, a transcriptional factor for Notch signaling, is a causative gene for AOS, O-GlcNAcylation of Notch receptors by EOGT might regulate Notch receptor trafficking or Notch-ligand interactions. ARHGAP31 or DOCK6, another causative gene for AOS, affects the actin cytoskeleton by regulating Cdc42 and Rac1 activity. Thus, another possibility is that the O-GlcNAcylation of unidentified cell adhesion molecules by EOGT affects actin dynamics. It should be noted, however, that Dumpy homologues are not present in mammals. The O-GlcNAcylation of Notch ligands was reported in Drosophila. The causative genes for AOS are shown by asterisks; B: Summary of proteins with extracellular O-GlcNAc identified to date.