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Regulation of mTORC1 signaling by pH
- Source :
- PLoS ONE, PLoS ONE, Vol 6, Iss 6, p e21549 (2011)
- Publication Year :
- 2011
-
Abstract
- Background Acidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is activated by various growth-stimulating signals and inactivated by starvation conditions. Whether mTORC1 can also respond to changes in extracellular or cytoplasmic pH and play a role in limiting anabolic processes in acidic conditions is not known. Methodology/Findings We examined the effects of acidifying the extracellular medium from pH 7.4 to 6.4 on human breast carcinoma MCF-7 cells and immortalized mouse embryo fibroblasts. Decreasing the extracellular pH caused intracellular acidification and rapid, graded and reversible inhibition of mTORC1, assessed by measuring the phosphorylation of the mTORC1 substrate S6K. Fibroblasts deleted of the tuberous sclerosis complex TSC2 gene, a major negative regulator of mTORC1, were unable to inhibit mTORC1 in acidic extracellular conditions, showing that the TSC1–TSC2 complex is required for this response. Examination of the major upstream pathways converging on the TSC1–TSC2 complex showed that Akt signaling was unaffected by pH but that the Raf/MEK/ERK pathway was inhibited. Inhibition of MEK with drugs caused only modest mTORC1 inhibition, implying that other unidentified pathways also play major roles. Conclusions This study reveals a novel role for the TSC1/TSC2 complex and mTORC1 in sensing variations in ambient pH. As a common feature of low tissue perfusion, low glucose availability and high energy expenditure, acidic pH may serve as a signal for mTORC1 to downregulate energy-consuming anabolic processes such as protein synthesis as an adaptive response to metabolically stressful conditions.
- Subjects :
- MAPK/ERK pathway
lcsh:Medicine
mTORC1
Signal transduction
ERK signaling cascade
Biochemistry
Tuberous Sclerosis Complex 1 Protein
Molecular cell biology
Signal Initiation
Akt signaling cascade
Membrane Receptor Signaling
Phosphorylation
lcsh:Science
Second Messenger System
Protein kinase signaling cascade
Cellular Stress Responses
Multidisciplinary
TOR Serine-Threonine Kinases
Mechanisms of Signal Transduction
Signaling cascades
Tor signaling
Hydrogen-Ion Concentration
Hormone Receptor Signaling
Cell biology
Mitogenic signaling
biological phenomena, cell phenomena, and immunity
Research Article
MAPK signaling cascades
Signaling in cellular processes
P70-S6 Kinase 1
Biology
Mechanistic Target of Rapamycin Complex 1
Signaling Pathways
Cell Growth
Cell Line
Cell Line, Tumor
Tuberous Sclerosis Complex 2 Protein
Extracellular
Animals
Humans
Protein kinase A
Protein kinase B
GTPase signaling
Glucose signaling
Tumor Suppressor Proteins
lcsh:R
Proteins
Signal Termination
Multiprotein Complexes
lcsh:Q
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 6
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....51920fdc06dab2211799d19fc76c0fef