Rapid Mitogenic Regulation of the mTORC1 Inhibitor, DEPTOR, by Phosphatidic Acid

Yoon, Mee Sup; Rosenberger, Christina L.; Wu, Cong; Truong, Nga; Sweedler, Jonathan V.; Chen, Jiawen

doi:10.1016/j.molcel.2015.03.028

Cited by 87 publications

(86 citation statements)

References 41 publications

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“…Under one plausible model, rdgA ’s main link to body mass and nutrient response could be in the control of taste preference and/or feeding behavior. Alternatively, rdgA ’s metabolic role could involve its known link to TOR signaling [60, 65, 71], plausibly via regulation of macroautophagy in the fat body [72] or global regulation of translation in response to stress [73]. The latter would be consistent with our finding that rdgA mutants are only long-lived when on a restricted diet.…”

Section: Discussionsupporting

confidence: 77%

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

et al. 2016

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BackgroundObesity-related diseases are major contributors to morbidity and mortality in the developed world. Molecular diagnostics and targets of therapies to combat nutritional imbalance are urgently needed in the clinic. Invertebrate animals have been a cornerstone of basic research efforts to dissect the genetics of metabolism and nutrient response. We set out to use fruit flies reared on restricted and nutrient-rich diets to identify genes associated with starvation resistance, body mass and composition, in a survey of genetic variation across the Drosophila Genetic Reference Panel (DGRP).ResultsWe measured starvation resistance, body weight and composition in DGRP lines on each of two diets and used several association mapping strategies to harness this panel of phenotypes for molecular insights. We tested DNA sequence variants for a relationship with single metabolic traits and with multiple traits at once, using a scheme for cross-phenotype association mapping; we focused our association tests on homologs of human disease genes and common polymorphisms; and we tested for gene-by-diet interactions. The results revealed gene and gene-by-diet associations between 17 variants and body mass, whole-body triglyceride and glucose content, or starvation resistance. Focused molecular experiments validated the role in body mass of an uncharacterized gene, CG43921 (which we rename heavyweight), and previously unknown functions for the diacylglycerol kinase rdgA, the huntingtin homolog htt, and the ceramide synthase schlank in nutrient-dependent body mass, starvation resistance, and lifespan.ConclusionsOur findings implicate a wealth of gene candidates in fly metabolism and nutrient response, and ascribe novel functions to htt, rdgA, hwt and schlank.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3137-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

et al. 2016

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“…Our data thus suggest a new signaling axis from priming amino acids to mTORC1 in addition to the recognized pathways from growth factors through PI3K-TSC and from Leu through RAGs. We do not yet know the mechanism of priming, but it may involve modification of mTORC1 subunits or their interactions, similar to what has been shown for mitogens (8,9). Priming amino acids may also aid in Leu uptake from the medium, as demonstrated for Gln (20), although the prolonged time course of the primed state (2 h; Fig.…”

Section: Discussionmentioning

confidence: 67%

“…mTORC1 is composed of the protein kinase mTOR and several associated proteins: Raptor (regulatory associated protein of mTOR), mLST8 (mammalian lethal with Sec13 protein 8, also known as GBL), PRAS40 (proline-rich AKT substrate 40 kDa), and Deptor (DEP domain-containing mTOR-interacting protein) (4). Deptor binds and inhibits mTOR in the absence of stimuli; upon stimulation Deptor quickly dissociates from mTOR and is subsequently degraded (5)(6)(7)(8). In contrast, Raptor activates mTOR within the complex when it is phosphorylated in response to stimuli (9).…”

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confidence: 99%

Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism

Dyachok

Earnest²,

Iturraran

et al. 2016

Journal of Biological Chemistry

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The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes L-asparagine, L-glutamine, L-threonine, L-arginine, L-glycine, L-proline, L-serine, L-alanine, and L-glutamic acid. The group of activating amino acids is dominated by L-leucine but also includes L-methionine, L-isoleucine, and L-valine. L-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation.

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“…However, studies in Drosophila still lend support to the role of PIPKII in cell growth and Akt/mTORC1 signaling ([41]. Additionally, phosphatidic acid which activates different isoforms of PIPKI inhibits endogenous inhibitor of mTORC1, suggesting that PIPKI provide another level of mechanism in regulating the PI3K/Akt/mTORC1 signaling in cancer [42, 43]. …”

Section: Pipki/pipkii Control Of Pi3k/akt Activation In Cancermentioning

confidence: 99%

The Hidden Conundrum of Phosphoinositide Signaling in Cancer

et al. 2016

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Phosphoinositide 3-kinase (PI3K) generation of PI(3,4,5)P3 from PI(4,5)P2 and the subsequent activation of Akt and its downstream signaling cascades (e.g. mTORC1) dominates the landscape of phosphoinositide signaling axis in cancer research. However, PI(4,5)P2 is breaking its boundary as merely a substrate for PI3K and phospholipase C (PLC), and is now an established lipid messenger pivotal for different cellular events in cancer. Here, we review the phosphoinositide signaling axis in cancer, giving due weight to PI(4,5)P2 and its generating enzymes, the phosphatidylinositol phosphate (PIP) kinases (PIPKs). We highlighted how PI(4,5)P2 and PIP kinases serve as a proximal node in phosphoinositide signaling axis and how its interaction with cytoskeletal proteins regulates migratory and invasive nexus of metastasizing tumor cells.

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Rapid Mitogenic Regulation of the mTORC1 Inhibitor, DEPTOR, by Phosphatidic Acid

Cited by 87 publications

References 41 publications

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism

The Hidden Conundrum of Phosphoinositide Signaling in Cancer

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