NRAGE induces β-catenin/Arm O-GlcNAcylation and negatively regulates Wnt signaling

Journal Article · Sat May 27 04:00:00 EDT 2017 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2017.04.080· OSTI ID:22697036

Chen, Yuxin ^[1]; Jin, Lei ^[2]; Xue, Bin; Jin, Dong ^[3]; Sun, Fenyong ^[1]; Wen, Chuanjun ^[3]

---

1. Department of Clinical Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072 (China)
2. College of Allied Health Professions, Shanghai University of Medicine and Health Sciences, Shanghai 201318 (China)
3. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Nanjing Normal University, Nanjing 210097 (China)

The Wnt pathway is crucial for animal development, as well as tumor formation. Understanding the regulation of Wnt signaling will help to elucidate the mechanism of the cell cycle, cell differentiation and tumorigenesis. It is generally accepted that in response to Wnt signals, β-catenin accumulates in the cytoplasm and is imported into the nucleus where it recruits LEF/TCF transcription factors to activate the expression of target genes. In this study, we report that human NRAGE, a neurotrophin receptor p75 (p75NTR) binding protein, markedly suppresses the expression of genes activated by the Wnt pathway. Consistent with this finding, loss of function of NRAGE by RNA interference (RNAi) activates the Wnt pathway. Moreover, NRAGE suppresses the induction of axis duplication by microinjected β-catenin in Xenopus embryos. To our surprise, NRAGE induces nuclear localization of β-catenin and increases its DNA binding ability. Further studies reveal that NRAGE leads to the modification of β-catenin/Arm with O-linked beta-N-acetylglucosamine (O-GlcNAc), and failure of the association between β-catenin/Arm and pygopus(pygo) protein, which is required for transcriptional activation of Wnt target genes. Therefore, our findings suggest a novel mechanism for regulating Wnt signaling. - Highlights: • NRAGE suppresses the expressions of Wnt pathway downstream genes. • NRAGE induces nuclear localization of β-catenin and increases its DNA binding ability. • NRAGE activity leads to the O-GlcNAcylation of β-catenin.

• OSTI ID: 22697036
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 487; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ARMS
CELL CYCLE
CELL DIFFERENTIATION
GENES
REGULATIONS
SIGNALS
TRANSCRIPTION FACTORS