Abstract
V-ATPases are proton pumps that function to acidify intracellular compartments in all eukaryotic cells, and to transport protons across the plasma membrane of certain specialized cells. V-ATPases function in many normal and disease processes, including membrane traffic, protein degradation, pathogen entry, and cancer cell invasion. An important mechanism of regulating V-ATPase activity in vivo is regulated assembly, which is the reversible dissociation of the ATP-hydrolytic V1 domain from the proton-conducting V0 domain. Regulated assembly is highly conserved and occurs in response to various nutrient cues, suggesting that it plays an important role in cellular homeostasis. We have recently found that starvation of mammalian cells for either amino acids or glucose increases V-ATPase assembly on lysosomes, possibly to increase protein degradation (for amino acid homeostasis) or for the utilization of alternative energy sources (during glucose starvation). While regulation of assembly in response to amino acid starvation does not involve PI3K or mTORC1, glucose-regulated assembly involves both PI3K and AMPK. Another important form of V-ATPase regulation is the targeting of the enzyme to different cellular membranes, which is controlled by isoforms of subunit a. We have shown that V-ATPases are localized to the plasma membrane of highly invasive breast cancer cells, where they promote cell migration and invasion. Furthermore, overexpression of the a3 isoform is responsible for plasma membrane targeting of V-ATPases in breast tumor cells leading to their increased invasiveness.
Highlights
Our laboratory has shown that regulated assembly of the yeast V-ATPase in response to changes in glucose availability is controlled by the Ras/cAMP/PKA pathway (Bond and Forgac, 2008)
We identified Ira2p, a Ras GAP which is inhibited by elevated glucose, as a protein whose disruption leads to V-ATPase assembly even in the absence of glucose (Bond and Forgac, 2008)
This study found that V-ATPase inhibition blocked EGFstimulated mTORC1 activation but not activation of PI3K or Ras substrates (Xu Y. et al, 2012)
Summary
Vacuolar H+-ATPases (V-ATPases) are ATP-dependent proton pumps present in intracellular membranes in all eukaryotes and at the plasma membrane of certain specialized cells (Forgac, 2007; Kane, 2012; Breton and Brown, 2013; Marshansky et al, 2014; Cotter et al, 2015b; McGuire et al, 2017). While the low pH of the lysosome is essential for proteolysis, the proton gradient imposed by the V-ATPase drives the coupled export of amino acids into the cytoplasm (Xu and Ren, 2015) V-ATPases are localized to the plasma membrane of certain specialized mammalian cells where they function to transport protons from the cytosol to the extracellular space. Regulated assembly occurs in response to various nutrient cues, and the section of this review will focus on the role of regulated assembly in nutrient sensing Another important form of V-ATPase regulation is the targeting of V-ATPases to different cellular membranes, which is controlled by isoforms of subunit a. The final section of this review will cover recent developments from our lab on the role of a subunit isoforms in cancer cell migration and invasion
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