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.

Lysosomes as a therapeutic target

“…Benzolactoneenamides (salicylihalamide A, lobatamides and oximidines; 299 than bafilomycin A1 and concanamycin A, but also much less potent. Further investigations into v ATPase regulation of signalling pathways are needed to identify specific and safe molecules that regulate this vital proton pump 300 .…”

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

“…Intracellular V‐ATPase plays important roles in several key cell signaling pathways 2, 3. For example, in some systems, V‐ATPase is required for optimal signaling downstream of NOTCH receptors as V‐ATPase‐mediated acidification of endosomes enhances γ‐secretase‐mediated proteolysis of NOTCH to generate the active NICD cleavage product 4, 5.…”

Cancer V-ATPase Expression Signatures: A Distinctive Balance of SubunitCIsoforms in Esophageal Carcinoma

“…In recent years, there has been an increasing body of evidence establishing that the V-ATPase proton pump is implicated in several cancer hallmarks (Hanahan and Weinberg 2011), such as, resistance to cell death, increased cell proliferation, invasion and metastasis, induction of angiogenesis, immune system modulation and reprogramming of energy metabolism (Webb, Chimenti et al 2011, Stransky, Cotter et al 2016, Pamarthy, Kulshrestha et al 2018). However, despite the large amount of data accumulated on V-ATPase differential expression in various types of tumors, no clear molecular signature could be related to the carcinogenesis process in general.…”