Cytosolic pH Regulates Cell Growth through Distinct GTPases, Arf1 and Gtr1, to Promote Ras/PKA and TORC1 Activity

Dechant, Reinhard; Saad, Shady; Ibáñez, Alfredo J.; Peter, Matthias

doi:10.1016/j.molcel.2014.06.002

Cited by 123 publications

(160 citation statements)

References 56 publications

Supporting

Mentioning

150

Contrasting

Order By: Relevance

“…Pharmacological inhibition of V-ATPase or knockdown of genes encoding V-ATPase components also prevents amino acid-induced mTORC1 activation [47]. Furthermore, Gtr1 interacts with V-ATPase in yeast, and deletion of a V-ATPase component (vma2∆) inhibits TORC1 activity [49]. These data suggest that the V-ATPase is an evolutionarily conserved upstream regulator of TORC1.…”

Section: Ragulator a Gef For Raga/bmentioning

confidence: 94%

“…These data suggest that the V-ATPase is an evolutionarily conserved upstream regulator of TORC1. Although it is not clear whether the V-ATPase in yeast is required for TORC1 activation in response to amino acids, this is likely the case since the growth defect of vma2∆ cells is partially reversed by overexpression of Gtr1-GTP [49].…”

Section: Ragulator a Gef For Raga/bmentioning

confidence: 99%

See 1 more Smart Citation

Multiple amino acid sensing inputs to mTORC1

2015

View full text Add to dashboard Cite

The evolutionarily conserved target of rapamycin complex 1 (TORC1) is a master regulator of cell growth and metabolism. In mammals, growth factors and cellular energy stimulate mTORC1 activity through inhibition of the TSC complex (TSC1-TSC2-TBC1D7), a negative regulator of mTORC1. Amino acids signal to mTORC1 independently of the TSC complex. Here, we review recently identified regulators that link amino acid sufficiency to mTORC1 activity and how mutations affecting these regulators cause human disease.

show abstract

Section: Ragulator a Gef For Raga/bmentioning

confidence: 94%

Section: Ragulator a Gef For Raga/bmentioning

confidence: 99%

Multiple amino acid sensing inputs to mTORC1

2015

View full text Add to dashboard Cite

show abstract

“…Recently it has been reported that Pma1 activation increases intracellular pH and this activates TORC1 (Dechant et al, 2014). Together with our results this suggest that there is cross activation between TORC1 and Pma1, the two cellular systems responding to nutrients.…”

Section: Torc1 Kinase Is a Positive Regulator Of Pma1 Activitysupporting

confidence: 88%

“…that Pma1, promoting progression through the START or restriction point of the G1 phase of the cell division cycle Sutton et al, 1991;Johnson and Skotheim, 2013;Dechant et al, 2014).…”

Section: Upstream Of Torc2mentioning

confidence: 99%

Protein kinases and phosphatases regulating the yeast proton pump

Hamouda¹

View full text Add to dashboard Cite

“…However, the cellular mechanisms governing V-ATPase regulation by reversible disassembly are not well understood. In yeast, V-ATPase reversible disassembly is intertwined with cytosol pH changes (14,15) the RAS/cAMP/PKA pathway (16), and glycolysis (3).…”

Section: Vacuolar Hmentioning

confidence: 99%

Regulation of Vacuolar H+-ATPase (V-ATPase) Reassembly by Glycolysis Flow in 6-Phosphofructo-1-kinase (PFK-1)-deficient Yeast Cells

Chan¹,

Dominguez

Parra

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Vacuolar H ϩ -ATPase (V-ATPase) 3 is a highly conserved ATP-driven proton pump distributed throughout the endomembrane system. Intracellular V-ATPase generates and maintains the acidic organelle luminal pH necessary for membrane trafficking, protein sorting and processing, and zymogen activation (1-5). V-ATPase is also present at the plasma membrane of cells specialized for active proton transport. Kidney intercalated cells (6), bone osteoclasts (7), and epididymis clear cells (6) express V-ATPases at the plasma membrane, which are necessary for systemic acid-base balance, bone resorption, and sperm maturation, respectively.V-ATPase consists of two multisubunit domains, V 1 and V o , that are responsible for ATP hydrolysis and proton transport, respectively (8, 9). Peripheral subunits form V 1 , the catalytic domain attached to the cytosolic side of the membrane. V 1 is bound to V o , the integral membrane domain that forms the path for proton transport. During catalysis, ATP hydrolysis within V 1 drives active transport of protons from the cytosol to the other side of the membrane via rotation of a proteolipid ring structure in V o . Detachment of V 1 from V o is an important mechanism that inhibits V-ATPase proton transport (3, 10, 11). Disassembly and reassembly of V 1 V o has been observed in yeast, insects, and mammalian cells (3,(11)(12)(13). However, the cellular mechanisms governing V-ATPase regulation by reversible disassembly are not well understood. In yeast, V-ATPase reversible disassembly is intertwined with cytosol pH changes (14, 15) the RAS/cAMP/PKA pathway (16), and glycolysis (3).Disassembly of the yeast V 1 V o complex occurs when glucose is not available. Upon glucose depletion, V 1 subunit C is released into the cytoplasm, causing the rest of the V 1 domain to dissociate from V o (10,17,18). Disassembly completely inactivates V-ATPase pumps because V 1 without V o cannot hydrolyze ATP, and V o without V 1 cannot transport protons (2). Consequently, protons cannot not be redistributed from the cytosol into the vacuole, which alkalinizes the vacuolar lumen and acidifies the cytosol (19,20). Disassembly is reversed by readdition of glucose to yeast cells (10,21). After reassembly, V 1 V o resumes ATP-driven proton transport, which restores vacuolar and cytosol pH homeostasis (20).Complete glucose depletion causes about 75% of the V 1 V o complexes to disassemble (10, 21); the remaining 25% of the pumps maintain the V-ATPase activity necessary to sustain basal cellular functions. Presumably yeast V 1 V o disassembly preserves energy when glucose, the main energy source, is lim-* This work was supported by National Institutes of Health Grant R01GM086495 (to K. J. P.) and American Heart Association Grant 14PRE19020015 (to C. Y. C.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

show abstract

Cytosolic pH Regulates Cell Growth through Distinct GTPases, Arf1 and Gtr1, to Promote Ras/PKA and TORC1 Activity

Cited by 123 publications

References 56 publications

Multiple amino acid sensing inputs to mTORC1

Multiple amino acid sensing inputs to mTORC1

Protein kinases and phosphatases regulating the yeast proton pump

Regulation of Vacuolar H+-ATPase (V-ATPase) Reassembly by Glycolysis Flow in 6-Phosphofructo-1-kinase (PFK-1)-deficient Yeast Cells

Contact Info

Product

Resources

About