An Emerging Role of mTOR in Lipid Biosynthesis

Laplante, Mathieu; Sabatini, David M.

doi:10.1016/j.cub.2009.09.058

Cited by 527 publications

(414 citation statements)

References 48 publications

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“…Thus, myelinating cells seem to possess specific mechanisms to regulate SREBPs and the expression of enzymes for lipid synthesis, with the additional twist that these mechanisms are probably different between SCs and OLs. Although overshadowed by the role of mTORC1, also mTORC2 has been implicated in lipid metabolism (Laplante & Sabatini, 2009). This could partially explain the stronger defects observed in OLs‐Raptor/Rictor double mutants (Lebrun‐Julien et al, 2014).…”

Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

128

104

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

128

104

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“…It suggests that excess NEFA taken up by the liver may favour lipogenesis and hepatic steatosis by activating mTORC1. Hence, oleate should be added to the list of nutrients whose availability is sensed by mTOR to adapt cell metabolism accordingly, notably in lipid biosynthesis [29].…”

Section: Discussionmentioning

confidence: 99%

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

2011

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Aims/hypothesis A high-fat diet and obesity are associated with increased risk of liver cancer. Because increased delivery of NEFA to the liver occurs in these conditions, we investigated the involvement of the unsaturated fatty acid oleate in hepatocarcinoma cell proliferation using humanderived hepatocarcinoma cell lines as model systems. Methods Western blotting, FACS analysis and [ 3 H]thymidine incorporation were used to study the signalling pathways and the proliferation of cells cultured for up to 72 h with or without a concentration of oleate considered to be relevant to human pathophysiology (50 μmol/l) or a concentration considered elevated (1 mmol/l). Results In HepG2 cells, proliferation was increased in the presence of 50 μmol/l oleate, but was decreased at 1 mmol/ l. This differential effect was correlated with the activation of the mammalian target of rapamycin complex 1 (mTORC1) and with increased translation of cell cycle regulators. Oleate-mediated mTORC1 activation required phospholipase D activation, which produces phosphatidic acid and is known to render mTORC1 rapamycin resistant.Remarkably, rapamycin resistance was found to affect specifically the mTORC1/eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) branch of the mTORC1 pathway in the presence of 50 μmol/l oleate. Furthermore, inhibition of phosphatidic acid production abolished oleateinduced increases in mTORC1 activity and cyclin A production. Importantly, the same differential effects of oleate on mTORC1 activation, cell cycle regulators and rapamycin resistance were found in SK-Hep1 cells. Conclusions/interpretation Oleate stimulates mTORC1 activation and rapamycin resistance. We propose that rapamycin-derived mTOR inhibitors are likely to be of limited therapeutic use to restrain hepatic tumour growth, particularly in the context of associated obesity.

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“…At the cellular level, mTORC1 promotes cellular anabolic processes, including ribosome biogenesis, protein and lipid synthesis, cell growth (increase in cell mass and size), and cell cycle progression, which drives cell proliferation (17,22,42,45). During growth factor and nutrient sufficiency, mTORC1 phosphorylates the translational regulators p70 ribosomal S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4EBP1) to coordinately upregulate protein synthesis (35,45).…”

mentioning

confidence: 99%

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

Ekim

Magnuson

Acosta-Jaquez

et al. 2011

Molecular and Cellular Biology

107

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The mammalian target of rapamycin complex 1 (mTORC1) functions as an environmental sensor to promote critical cellular processes such as protein synthesis, cell growth, and cell proliferation in response to growth factors and nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which mTORC1 senses and responds to these signals remain poorly defined. Here we investigated the role of mTOR phosphorylation in mTORC1 function. By employing mass spectrometry and phospho-specific antibodies, we demonstrated novel phosphorylation on S2159 and T2164 within the mTOR kinase domain. Mutational analysis of these phosphorylation sites indicates that dual S2159/T2164 phosphorylation cooperatively promotes mTORC1 signaling to S6K1 and 4EBP1. Mechanistically, S2159/T2164 phosphorylation modulates the mTOR-raptor and raptor-PRAS40 interactions and augments mTORC1-associated mTOR S2481 autophosphorylation. Moreover, mTOR S2159/T2164 phosphorylation promotes cell growth and cell cycle progression. We propose a model whereby mTOR kinase domain phosphorylation modulates the interaction of mTOR with regulatory partner proteins and augments intrinsic mTORC1 kinase activity to promote biochemical signaling, cell growth, and cell cycle progression.

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An Emerging Role of mTOR in Lipid Biosynthesis

Cited by 527 publications

References 48 publications

Myelination and mTOR

Myelination and mTOR

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

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