AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control

González, Asier; Hall, Michael N.; Lin, Sheng-Cai; Hardie, D. Grahame

doi:10.1016/j.cmet.2020.01.015

Cited by 491 publications

(470 citation statements)

References 257 publications

(322 reference statements)

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“…AMPK, a master regulator of cell energy homeostasis, is activated when there is a lack of energy or nutrients [115]. AMPK downregulates mTORC1 in two ways.…”

Section: Ampk Activates Mtorc2mentioning

confidence: 99%

Regulation of mTORC2 Signaling

Hall

2020

Genes

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145

130

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Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 appears to exist in functionally distinct pools, but few mTORC2 effectors/substrates have been identified. Here, we review recent advances in our understanding of mTORC2 signaling, with particular emphasis on factors that control mTORC2 activity.

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“…AMPK, a master regulator of cell energy homeostasis, is activated when there is a lack of energy or nutrients [115]. AMPK downregulates mTORC1 in two ways.…”

Section: Ampk Activates Mtorc2mentioning

confidence: 99%

Regulation of mTORC2 Signaling

Hall

2020

Genes

Self Cite

145

130

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“…This may indicate that pheromones in the CM activate more than one pathway and that they have to act in combination to elicit the full effect. Our findings that several energy-sensing pathways are involved in this process in A. freiburgensis, and that AMPK, insulin and TOR pathways are cross-regulated, are indicative of this hypothesis (González et al, 2020, Ruderman et al, 2010, Banerjee et al, 2016.…”

Section: Discussionmentioning

confidence: 56%

Chromatin-associated effectors of energy-sensing pathways mediate intergenerational effects

Silva¹,

Robles²,

Zuco³

et al. 2020

Preprint

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Environmental stimuli experienced by the parental generation influence the phenotype of subsequent generations. The effects of these stimuli on the parental generation may be passed through the germline, but the mechanisms of this non-Mendelian type of inheritance are poorly known. Here we show that modulation of nutrient-sensing pathways in the parental generation of a nematode (Auanema freiburgensis) regulates phenotypic plasticity of its offspring. In response to pheromones, AMP-activated protein kinase (AMPK), mechanistic target of rapamycin complex 1 (mTORC1) and insulin signaling regulate stress resistance and sex determination across a generation. The effectors of these pathways are closely associated with the chromatin and their regulation affects the acetylation chromatin status in the germline. These results suggest that highly conserved metabolic sensors regulate phenotypic plasticity by changing the epigenetic status of the germline.

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“…Key metabolic signaling pathways in macrophage activation include the mammalian target of rapamycin (mTOR), adenosine monophosphate (AMP) kinase (AMPK) and HIF-1a pathways. 64 There is increasing evidence that these pathways play important roles in regulating Leishmania granuloma formation as well as the polarization of macrophages within these tissues to form both permissive and nonpermissive niches within these tissues as outlined in the following sections.…”

Section: Role Of Macrophage Metabolic Signaling Pathways In Leishmanimentioning

confidence: 99%

“…Activation of murine macrophages with antiinflammatory cytokines, such as IL-4 or IL-13, promotes mTORC1 activation through the PI3K/protein kinase B (Akt) pathway, leading to increased protein synthesis and a switch to anabolic metabolism that is needed to sustain the energy-demanding functions of cell migration, cytokine production and tissue repair. 51,64 Infection of murine macrophages with L. donovani also leads to the activation of mTOR and polarization toward a permissive M2 phenotype, while inhibition of mTORC1 (via rapamycin treatment) limits parasite growth in ex vivo infected macrophages and granuloma development in mice. [67][68][69] Other studies have shown that mTORC1 activates a number of key downstream targets and transcription factors, including HIF-1a, peroxisome proliferator-activated receptor gamma coactivator 1-a, sterol regulatory element-binding protein-1 and PPAR-c, that lead to transcriptional upregulation of proteins involved in glucose uptake, glycolysis, mitochondrial biogenesis, oxidative phosphorylation, and fatty acid and cholesterol biosynthesis that individually or collectively may promote intracellular Leishmania growth.…”

Section: Mtor Signaling and Regulation Of Leishmania Growthmentioning

confidence: 99%

Immunometabolism of Leishmania granulomas

Saunders

McConville

2020

Immunol Cell Biol

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Leishmania are parasitic protists that cause a spectrum of diseases in humans characterized by the formation of granulomatous lesions in the skin or other tissues, such as liver and spleen. The extent to which Leishmania granulomas constrain or promote parasite growth is critically dependent on the host Thelper type 1/T-helper type 2 immune response and the localized functional polarization of infected and noninfected macrophages toward a classically (M1) or alternatively (M2) activated phenotype. Recent studies have shown that metabolic reprograming of M1 and M2 macrophages underpins the capacity of these cells to act as permissive or nonpermissive host reservoirs, respectively. In this review, we highlight the metabolic requirements of Leishmania amastigotes and the evidence that these parasites induce and/or exploit metabolic reprogramming of macrophage metabolism. We also focus on recent studies highlighting the role of key macrophage metabolic signaling pathways, such as mechanistic target of rapamycin, adenosine monophosphate-activated protein kinase and peroxisome proliferator receptor gamma in regulating the pathological progression of Leishmania granulomas. These studies highlight the intimate connectivity between Leishmania and host cell metabolism, the need to investigate these interactions in vivo and the potential to exploit host cell metabolic signaling pathways in developing new host-directed therapies.

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AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control

Cited by 491 publications

References 257 publications

Regulation of mTORC2 Signaling

Regulation of mTORC2 Signaling

Chromatin-associated effectors of energy-sensing pathways mediate intergenerational effects

Immunometabolism of Leishmania granulomas

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