Wnt signalosomes: What we know that we do not know.

Signaling through the Wnt/β-catenin pathway is relayed through three multiprotein complexes: (1) the membrane-associated signalosome, which includes the activated Wnt receptors, (2) the cytoplasmic destruction complex that regulates turnover of the transcriptional coactivator β-catenin, and (3) the nuclear enhanceosome that mediates pathway-specific transcription. Recent discoveries have revealed that Wnt receptor activities are tightly regulated to maintain proper tissue homeostasis and that aberrant receptor upregulation enhances Wnt signaling to drive tumorigenesis, highlighting the importance of signalosome control. These studies have focused on the detailed process by which Wnt ligands engage their coreceptors, LRP5/6 and Frizzled. However, the components that constitute the signalosome and the regulation of their assembly remain undefined. In this review, we discuss Wnt/β-catenin signalosome composition and the mechanisms that regulate signalosome assembly, including the role of biomolecular condensates and ubiquitylation. We also summarize the evidence for the presence of Wnt ligand-independent signalosome formation.