Nradd Acts as a Negative Feedback Regulator of Wnt/beta-Catenin Signaling and Promotes Apoptosis

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Ozalp O., Cark O., Azbazdar Y., Haykir B., Cucun G., Kucukaylak I., ...More

BIOMOLECULES, vol.11, no.1, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 11 Issue: 1
  • Publication Date: 2021
  • Doi Number: 10.3390/biom11010100
  • Journal Name: BIOMOLECULES
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: Nradd, p75 neurotrophin receptor, Wnt/beta-catenin signaling, apoptosis, death receptor
  • Dokuz Eylül University Affiliated: Yes


Wnt/beta-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75(NTR)), as a negative regulator of Wnt/beta-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/beta-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/beta-catenin signaling during development.