Figure 8.

Notch/Wnt signaling pathways. Notch signaling is initiated by ligand binding to Notch receptor (1) leading to receptor endocytosis (2). The receptor is cleaved by γ-secretase in a V-ATPase-dependent manner (3) allowing the cytoplasmic domain to translocate to the nucleus (4) and activate target genes (5). Inhibition of V-ATPase-mediated acidification with bafilomycin blocks this process. Furthermore, V-ATPase-dependent lysosomal degradation of the receptor decreases Notch signaling. Wnt signaling is initiated by Wnt ligand binding to the Frizzled and low-density lipoprotein (LRP) receptors (1) leading to internalization of the receptors into V-ATPase-containing endosomes where they associate with the V-ATPase via the ATP6AP2 accessory protein (2). A multiprotein signaling pathway then inhibits a “destruction complex” that normally degrades β-catenin, leading to an increase in cytoplasmic accumulation and translocation of β-catenin to the nucleus (3), where it activates target genes (4). Created with BioRender.com.