ArticlePloS one2011
Regulation of mTORC1 signaling by pH.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 120 citations in OpenAlex.
- SLC4A7/NBCn1 maintains intracellular pH to support mTORC1 activity and antibody-secreting cell differentiation.Nature communications · 2026Article
- Reversible Nucleolar Stress and Cell Growth Arrest Triggered by Acidic pH.Journal of cellular physiology · 2026Article
- Vacuolar ATPase regulates ureteric bud branching morphogenesis during kidney development.American journal of physiology. Regulatory, integrative and comparative physiology · 2026Article
- Lethality is local, but survival is systemic: Temporal and multi-organ responses to chlorine gas exposure in a murine model.Current research in toxicology · 2026Article
- Intracellular pH regulates ubiquitin-mediated degradation of the MAP kinase ERK3.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A lactate related signature for predicting prognosis and tumor microenvironment in lung adenocarcinoma.Discover oncology · 2025Article
- Regulatory dynamics of Sch9 in response to cytosolic acidification: From spatial reconfiguration to cellular adaptation to stresses.iScience · 2025Article
- Integrated Single-Cell and Spatial Transcriptome Reveal Metabolic Gene SLC16A3 as a Key Regulator of Immune Suppression in Hepatocellular Carcinoma.Journal of cellular and molecular medicine · 2024Article
- Acidity suppresses CD8 + T-cell function by perturbing IL-2, mTORC1, and c-Myc signaling.The EMBO journal · 2024Article
- The Emerging Role of Natural Products in Cancer Treatment.Archives of toxicology · 2024Review
- Review
- Prognostic implication of a novel lactate score correlating with immunotherapeutic responses in pan-cancer.Aging · 2024Article
- How lactate affects immune strategies in lymphoma.Frontiers in molecular biosciences · 2024Review
- The Role of microRNAs in Gene Expression and Signaling Response of Tumor Cells to an Acidic Environment.International journal of molecular sciences · 2023Article
- Paraprobiotic Lacticaseibacillus rhamnosus Protects Intestinal Damage in an Experimental Murine Model of Mucositis.Probiotics and antimicrobial proteins · 2023Article
- The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment.Cancers · 2022Article
- Loss of voltage-gated hydrogen channel 1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T cells.JCI insight · 2022Article
- Article
- Detection and quantification of the vacuolar H+ATPase using the Legionella effector protein SidK.The Journal of cell biology · 2022Article
- Role of the mTOR Signalling Pathway During Extracellular Acidosis in Tumour Cells.Advances in experimental medicine and biology · 2022Article
12 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAcidification 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/
findingsWe 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.
conclusionsThis 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.