The curious case of vacuolar ATPase: regulation of signaling pathways

Abstract

The Vacuolar ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. The structure of V-ATPase has been highly conserved among all eukaryotic cells and is involved in diverse functions across species. V-ATPase is best known for its acidification of endosomes and lysosomes and is also important for luminal acidification of specialized cells. Several reports have suggested the involvement of V-ATPase in maintaining an alkaline intracellular and acidic extracellular pH thereby aiding in proliferation and metastasis of cancer cells respectively. Increased expression of V-ATPase and relocation to the plasma membrane aids in cancer modulates key tumorigenic cell processes like autophagy, Warburg effect, immunomoduation, drug resistance and most importantly cancer cell signaling. In this review, we discuss the direct role of V-ATPase in acidification and indirect regulation of signaling pathways, particularly Notch Signaling.

Keywords: Autophagy; Cancer; Drug resistance; Notch signaling; TGF-β; V-ATPase; WNT; Warburg effect; mTOR.

Fig. 1

Physiological role of V-ATPase in luminal acidification. The involvement of V-ATPase is involved in numerous specialized cell processes including bone resorption, renal function, sperm maturation, innate immune responses and neurotransmission is outlined. a Bone resorption: V-ATPase located on the plasma membrane of osteoclasts mediates extracellular acidification for bone demineralization during bone resorption. b Renal function: In the kidney, intercalated cells maintain systemic acidosis and achieve urinary acidification by proton pumping activity of V-ATPases expressed on apical membrane. c Sperm maturation: In the epididymis, V-ATPase expressing clear cells acidify the lumen, a process that is crucial for the proper maturation and motility of spermatozoa. d Innate immune responses: V-ATPases mediated vesicular acidification has an important role in trafficking and exocytosis of neutrophil granules V-ATPase is constitutively expressed on the plasma membrane of monocytes and activated lymphocytes and contributes to pH related inflammatory responses. e Neurotransmission: V-ATPase provides the crucial proton motive force necessary for the formation of synaptic vesicles and subsequent accumulation of neurotransmitters. V-ATPase provides the crucial electrochemical potential necessary for accumulation of neurotransmitters in the secretory synaptic vesicles

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