Beiyu Xie, Yue Cao, Wenxi Li, Ruihan Chen, Qiujing Zhou, Xin Xie
The spatiotemporal control of Wnt signaling orchestrates embryonic development and tissue homeostasis, while dysregulation of this pathway has been linked to a variety of diseases, including cancer, fibrosis and neurodegeneration. Although nuclear accumulation of β-catenin serves as a hallmark of Wnt pathway hyperactivation, the mechanisms controlling nuclear β-catenin remain obscure and are subjected to some conflicting hypotheses. In this narrative review, we summarize current understanding of the complex interplays fine-tunning the nucleocytoplasmic trafficking and subcellular distribution of β-catenin. We also present computational analysis to explore candidate molecules regulating nuclear β-catenin and suggest new perspectives to future study. Finally, we discuss how these insights could pave the way for mechanism-based approaches to target "undruggable" Wnt signaling for Wnt-driven diseases.