Fig. 2

The mechanistic basis of V-ATPase dependent signaling. V-ATPase (orange) acidifies intracellular vesicles thereby regulating Notch signaling and other pathways like Wnt and TGF-β, which depend on endolysosomal system for sustenance. In Notch Signaling, the Notch receptor (dark pink) is cleaved in Golgi and translocated to the plasma membrane where further cleavage of the receptor occurs in response to Notch ligand (light pink) binding. Cleaved Notch intracellular domain is translocated to nucleus activating Notch target genes. TGF-β (dark green) protein is glycosylated in the Golgi to form mature TGF-β and secreted into the extracellular space. TGF-β bound to its receptor (TGF-βR) (bright green) results in endocytosis and phosphorylation of Smad2 (olive green), which in turn activates TGF-β target genes. During canonical Wnt signaling, the binding of ligands to the Wnt receptor complex (bright yellow) inhibits the phosphorylation of β-catenin (dark yellow) by GSK-3β and directs the translocation of β-catenin into the nucleus where it activates the transcription of target genes Cyclin D1 and oncogene c-Myc. V-ATPase-mediated acidification can affect signaling in the following ways: a Maturation of signaling molecules Notch receptor and TGF-β by furin glycosylation in the golgi vesicles. b Cleavage and activation of pathway mediators by acid-dependent enzyme like matrix metallo proteinases (MMPs) and γ-secretase. c Maintenance of basal signaling by recycling endocytosis of both ligand and receptor. d Degradation of signaling molecules in lysosomes