Ozalp Ozgun, Cark Ozge, Azbazdar Yagmur, Haykir Betul, Cucun Gokhan, Kucukaylak Ismail, Alkan-Yesilyurt Gozde, Sezgin Erdinc, Ozhan Gunes
Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey.
Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey.
Biomolecules. 2021 Jan 14;11(1):100. doi: 10.3390/biom11010100.
Wnt/β-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), as a negative regulator of Wnt/β-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/β-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/β-catenin signaling during development.
Wnt/β-连环蛋白信号通路控制着许多生物学过程，这些过程对于发育和体内平衡期间正常组织大小、组织和功能的产生及维持至关重要。因此，Wnt信号通路成分和调节因子的突变会引发疾病，包括遗传性疾病和癌症。针对与该通路相关疾病的靶向治疗需要详细了解微调Wnt信号的调控机制。在此，我们鉴定出神经生长因子受体相关死亡结构域（Nradd），它是p75神经生长因子受体（p75）的同源物，是斑马鱼胚胎和哺乳动物细胞中Wnt/β-连环蛋白信号通路的负调节因子。在斑马鱼原肠胚形成过程中，Nradd显著抑制Wnt8介导的中胚层和神经外胚层的模式形成。Nradd定位于质膜，与Wnt受体复合物发生物理相互作用，并与Wnt/β-连环蛋白信号通路协同增强细胞凋亡。我们的功能分析表明，N-糖基化的N端和含死亡结构域的C端区域对于抑制Wnt信号和细胞凋亡都是必需的。最后，Nradd可在哺乳动物细胞中诱导细胞凋亡。因此，在发育过程中，Nradd作为Wnt/β-连环蛋白信号通路的修饰因子调节细胞死亡。
