Congenital diseases caused by defective O-glycosylation of Notch receptors.

Abstract

The Notch signaling pathway is highly conserved and essential for animal development. It is required for cell differentiation, survival, and proliferation. Regulation of Notch signaling is a crucial process for human health. Ligands initiate a signal cascade by binding to Notch receptors expressed on a neighboring cell. Notch receptors interact with ligands through their epidermal growth factor-like repeats (EGF repeats). Most EGF repeats are modified by O-glycosylation with residues such as O-linked N-acetylglucosamine (O-GlcNAc), O-fucose, and O-glucose. These O-glycan modifications are important for Notch function. Defects in O-glycosylation affect Notch-ligand interaction, trafficking of Notch receptors, and Notch stability on the cell surface. Although the roles of each modification are not fully understood, O-fucose is essential for binding of Notch receptors to their ligands. We reported an EGF domain-specific O-GlcNAc transferase (EOGT) localized in the endoplasmic reticulum. Mutations in genes encoding EOGT or NOTCH1 cause Adams-Oliver syndrome. Dysregulation of Notch signaling because of defects or mutations in Notch receptors or Notch signal-regulating proteins, such as glycosyltransferases, induce a variety of congenital disorders. In this review, we discuss O-glycosylation of Notch receptors and congenital human diseases caused by defects in O-glycans on Notch receptors.

• Authors: Yuko Tashima, Tetsuya Okajima
• Journal: Nagoya journal of medical science (Nagoya J Med Sci) Vol. 80 Issue 3 Pg. 299-307 (Aug 2018) ISSN: 2186-3326 [Electronic] Japan
• PMID: 30214079 (Publication Type: Journal Article, Review)

Chemical References

• Receptors, Notch
• Epidermal Growth Factor
• N-Acetylglucosaminyltransferases

Topics

• Animals
• Ectodermal Dysplasia (metabolism)
• Epidermal Growth Factor (metabolism)
• Glycosylation
• Humans
• Limb Deformities, Congenital (metabolism)
• N-Acetylglucosaminyltransferases (metabolism)
• Receptors, Notch (metabolism)
• Scalp Dermatoses (congenital, metabolism)