The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Sancak, Yasemin; Peterson, Timothy R.; Shaul, Yoav D.; Lindquist, Robert A.; Thoreen, Carson C.; Bar-Peled, Liron; Sabatini, David M.

doi:10.1126/science.1157535

Cited by 2,294 publications

(2,806 citation statements)

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“…Therefore, under our experimental conditions, our results would support the idea that HMB acts mainly via the class I PI3K/Akt pathway,19 whereas it is described that L‐Leu exerts its action via the class III PI3K2, 31 that could mediate the activation of mTOR. In fact, it has been described that branched amino acids stimulate directly mTOR through a mechanism involving Rag GTPases 45. This alternate pathway has been described under amino acid deprivation,45 but during our experimental conditions without leucine starvation, there was no increase in protein synthesis nor in mTOR phosphorylation.…”

Section: Discussionsupporting

confidence: 52%

“…In fact, it has been described that branched amino acids stimulate directly mTOR through a mechanism involving Rag GTPases 45. This alternate pathway has been described under amino acid deprivation,45 but during our experimental conditions without leucine starvation, there was no increase in protein synthesis nor in mTOR phosphorylation. Up to this point, under non‐amino‐acid deprivation, our results indicated HMB as a more active inductor of protein synthesis.…”

Section: Discussionsupporting

confidence: 52%

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Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundL‐Leu and its metabolite β‐hydroxy‐β‐methylbutyrate (HMB) stimulate muscle protein synthesis enhancing the phosphorylation of proteins that regulate anabolic signalling pathways. Alterations in these pathways are observed in many catabolic diseases, and HMB and L‐Leu have proven their anabolic effects in in vivo and in vitro models. The aim of this study was to compare the anabolic effects of L‐Leu and HMB in myotubes grown in the absence of any catabolic stimuli.MethodsStudies were conducted in vitro using rat L6 myotubes under normal growth conditions (non‐involving L‐Leu‐deprived conditions). Protein synthesis and mechanistic target of rapamycin signalling pathway were determined.ResultsOnly HMB was able to increase protein synthesis through a mechanism that involves the phosphorylation of the mechanistic target of rapamycin as well as its downstream elements, pS6 kinase, 4E binding protein‐1, and eIF4E. HMB was significantly more effective than L‐Leu in promoting these effects through an activation of protein kinase B/Akt. Because the conversion of L‐Leu to HMB is limited in muscle, L6 cells were transfected with a plasmid that codes for α‐keto isocaproate dioxygenase, the key enzyme involved in the catabolic conversion of α‐keto isocaproate into HMB. In these transfected cells, L‐Leu was able to promote protein synthesis and mechanistic target of rapamycin regulated pathway activation equally to HMB. Additionally, these effects of leucine were reverted to a normal state by mesotrione, a specific inhibitor of α‐keto isocaproate dioxygenase.ConclusionOur results suggest that HMB is an active L‐Leu metabolite able to maximize protein synthesis in skeletal muscle under conditions, in which no amino acid deprivation occurred. It may be proposed that supplementation with HMB may be very useful to stimulate protein synthesis in wasting conditions associated with chronic diseases, such as cancer or chronic heart failure.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionsupporting

confidence: 52%

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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“…Accordingly, expression of a constitutively active (GTP-bound) Gtr1 GTP , which interacted strongly with TORC1, rendered TORC1 partially resistant to leucine deprivation, while expression of a growth inhibitory GDP-bound Gtr1 GDP caused constitutively low TORC1 activity. In line with this proposed model in yeast, two complementary studies in Drosophila and mammalian cells have also reported that the conserved Rag GTPases act as upstream regulators of TORC1 and play important roles in coupling amino acid-derived signals to TORC1 (Kim et al 2008;Sancak et al 2008).…”

Section: How Is Tor Signalling Regulated?mentioning

confidence: 60%

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

et al. 2010

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Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G 0 ) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.

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“…Amino acid levels are linked to mTOR through a mechanism that is dependent, at least to some extent, on p62/ SQSTM1 (Duran et al 2011): mTORC1 associates with the amino acid sensing Rag family of small GTPases (Kim et al 2008;Sancak et al 2008) on the surface of lysosomes (Sancak et al 2010). p62/SQSTM1 mediates this process by associating with Raptor, a subunit of the mTORC1 complex, and the Rag GTPases, thereby forming a high molecular weight complex that relays the signal from amino acids to the mTORC1 pathway (Duran et al 2011).…”

Section: Amino Acid Sensing: Mtormentioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

120

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Cited by 2,294 publications

References 29 publications

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

p62/SQSTM1 at the interface of aging, autophagy, and disease

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