Phosphatidic acid and lipid-sensing by mTOR

Foster, David A.

doi:10.1016/j.tem.2013.02.003

Cited by 95 publications

(84 citation statements)

References 73 publications

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“…It could also indicate sufficient glucose and glutamine, which are key nutrients that are incorporated into PA (50). We have proposed that the PA requirement of mTOR evolved as a means to sense the presence of sufficient materials for membrane synthesis to complement the ability to sense amino acids (50,51). Consistent with this hypothesis, the enzymes involved in the de novo synthesis of PA stimulate mTOR (52,53), indicating that the PA requirement of mTOR is related to the ability to synthesis membrane phospholipids.…”

Section: Discussionmentioning

confidence: 83%

Reciprocal Regulation of AMP-activated Protein Kinase and Phospholipase D

Mukhopadhyay

Saqcena²,

Chatterjee

et al. 2015

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 83%

Reciprocal Regulation of AMP-activated Protein Kinase and Phospholipase D

Mukhopadhyay

Saqcena²,

Chatterjee

et al. 2015

Journal of Biological Chemistry

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“…We previously proposed that the responsiveness of mTOR to PA evolved as a means for sensing the sufficiency of lipid precursors for membrane phospholipid biosynthesis (28). This was based on the central position of PA in the anabolic synthesis of membrane phospholipids (Fig.…”

Section: The Role For Pa In Cell Cycle Progressionmentioning

confidence: 99%

“…However, very little is known about the dependence of mTOR on glucose, another critical nutrient sensed by mTOR. Although the PA dependence of mTOR that has been proposed represents a means for sensing sufficient lipids for cell growth (17,28), it is plausible that PA represents a broader indicator of nutrient sufficiency. In dividing cells and cancer cells, there is a metabolic reprograming that shifts from the catabolic generation of reducing power (NADH) that drives mitochondrial ATP generation to anabolic synthetic reactions that generate the biological molecules needed for doubling the cell mass prior to cell division (43).…”

Section: Pa As a Broader Indicator Of Nutrient Sufficiencymentioning

confidence: 99%

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Foster

Salloum

Menon

et al. 2014

Journal of Biological Chemistry

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107

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Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival.

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“…mTORC1 stimulates protein and lipid synthesis, ribosome biogenesis, energy metabolism, and lysosome biogenesis (Foster 2013), whereas the mTORC2 pathway in adipocytes for the body is very important for the energy balance (Kumar et al 2010). mTORC1 is known to be strongly inhibited by rapa mycin (Kim et al 2002, Sarbassov et al 2004, but the sensitivity of mTORC2 to rapamycin varies among cell lines and tissue types.…”

Section: Introductionmentioning

confidence: 99%

Effects of rapamycin on life span and on expression of TOR and S6K in Brachionus calyciflorus (Rotifera)

Xu¹,

Liu²,

Su³

et al. 2017

Aquat. Biol.

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The mechanistic target of rapamycin (mTOR) coordinates a complex signal pathway from translation to autophagy that is a key regulator of not only growth and proliferation but also metabolism and aging. mTOR is sensitive to many environmental and endocrine stimuli. We investigated the influence of TOR signaling on aging and reproduction of the rotifer Brachionus calyciflorus using rapamycin as an exogenous inhibitor. We found that 2 and 4 µM rapamycin extended B. calyciflorus life span by 15 and 22%, respectively compared with controls (p < 0.05). The reproductive peak was significantly delayed by rapamycin at 2 and 4 µM (p < 0.01), but the pre-and post-reproduction periods were not significantly different from controls (p > 0.05). Partial cDNAs coding 375 bp for TOR and 951 bp for S6 kinase (S6K ) were obtained from B. calyciflorus expressed sequence tags. The identities of the deduced amino acid sequences of B. calyciflorus cDNAs to their human orthologs were 58% for TOR and 68% for S6K. TOR and S6K mRNA expression were up-or down-regulated by different rapamycin concentrations (0.5, 1, 2, 4, 8, and 16 µM) and treatment intervals (control, 12, 24, 36, and 48 h). The results indicated that TOR inhibition acted additively to extend rotifer life span, with up-and down-regulation simultaneously impacting reproduction and gene expression.

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Phosphatidic acid and lipid-sensing by mTOR

Cited by 95 publications

References 73 publications

Reciprocal Regulation of AMP-activated Protein Kinase and Phospholipase D

Reciprocal Regulation of AMP-activated Protein Kinase and Phospholipase D

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Effects of rapamycin on life span and on expression of TOR and S6K in Brachionus calyciflorus (Rotifera)

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