ArticleProceedings of the National Academy of Sciences of the United States of America2008
Phospholipase D1 is an effector of Rheb in the mTOR pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers.
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Who cites it
102 citing papers in PubMed, 176 citations in OpenAlex.
- Phospholipase D: emerging therapeutic targets in signaling, metabolism, and immune-oncology.Cell communication and signaling : CCS · 2025Review
- Effects of phospholipase D1-inhibitory peptide on the growth and metastasis of gastric cancer cells.Molecules and cells · 2024Article
- Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.International journal of molecular sciences · 2024Review
- Activity-based directed evolution of a membrane editor in mammalian cells.Nature chemistry · 2023Article
- Regulation of mTOR by phosphatidic acid.Trends in endocrinology and metabolism: TEM · 2023Review
- Mechanistic Target of Rapamycin Complex 1: From a Nutrient Sensor to a Key Regulator of Metabolism and Health.Advances in nutrition (Bethesda, Md.) · 2022Article
- Regulation of mTORC1 by amino acids in mammalian cells: A general picture of recent advances.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2021Review
- AMPK-mTOR Signaling and Cellular Adaptations in Hypoxia.International journal of molecular sciences · 2021Review
- Structure and regulation of human phospholipase D.Advances in biological regulation · 2021Review
- Amino Acids in Autophagy: Regulation and Function.Advances in experimental medicine and biology · 2021Article
- Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity.Molecular cell · 2020Article
- Regulation of Body Size and Growth Control.Genetics · 2020Review
- Mammalian phospholipase D: Function, and therapeutics.Progress in lipid research · 2020Review
- Phosphatidic acid drives mTORC1 lysosomal translocation in the absence of amino acids.The Journal of biological chemistry · 2020Article
- Phospholipase D-dependent mTOR complex 1 (mTORC1) activation by glutamine.The Journal of biological chemistry · 2018Article
- Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin.Cancer science · 2018Article
- A Unique Homeostatic Signaling Pathway Links Synaptic Inactivity to Postsynaptic mTORC1.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation.BMC cancer · 2018Article
- mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential.NPJ breast cancer · 2018Article
- Emerging Roles for the Lysosome in Lipid Metabolism.Trends in cell biology · 2017Review
42 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The mammalian target of rapamycin (mTOR) assembles a signaling network essential for the regulation of cell growth, which has emerged as a major target of anticancer therapies. The tuberous sclerosis complex 1 and 2 (TSC1/2) proteins and their target, the small GTPase Rheb, constitute a key regulatory pathway upstream of mTOR. Phospholipase D (PLD) and its product phosphatidic acid are also upstream regulators of the mitogenic mTOR signaling. However, how the TSC/Rheb and PLD pathways interact or integrate in the rapamycin-sensitive signaling network has not been examined before. Here, we find that PLD1, but not PLD2, is required for Rheb activation of the mTOR pathway, as demonstrated by the effects of RNAi. The overexpression of Rheb activates PLD1 in cells in the absence of mitogenic stimulation, and the knockdown of Rheb impairs serum stimulation of PLD activation. Furthermore, the overexpression of TSC2 suppresses PLD1 activation, whereas the knockdown or deletion of TSC2 leads to elevated basal activity of PLD. Consistent with a TSC-Rheb-PLD signaling cascade, AMPK and PI3K, both established regulators of TSC2, appear to lie upstream of PLD as revealed by the effects of pharmacological inhibitors, and serum activation of PLD is also dependent on amino acid sufficiency. Finally, Rheb binds and activates PLD1 in vitro in a GTP-dependent manner, strongly suggesting that PLD1 is a bona fide effector for Rheb. Hence, our findings reveal an unexpected interaction between two cascades in the mTOR signaling pathways and open up additional possibilities for targeting this important growth-regulating network for the development of anticancer drugs.
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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.