Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p70S6 kinase is a multipotent kinase that phosphorylates substrates in response to extracellular stimuli. This kinase activity inhibits apoptosis, regulates cell size and controls translation. In the CNS, p70S6K also participates in synaptic plasticity. In this study, we report that leucine, a branched-chain amino acid, induces phosphorylation and activation of p70S6 kinase in cortical neurons. Leucine also induces phosphorylation of S6 protein, a substrate of p70S6K. These effects of leucine are completely inhibited by rapamycin, consistent with mammalian target of rapamycin mediating p70S6 phosphorylation. Finally, we demonstrate that the action of leucine on cortical neurons is mediated by the system L amino acid transporter. Neurons express components of system L amino acid transporter LAT1, LAT2, and CD98. Leucine uptake and its effect on p70S6 kinase are both inhibited by a specific inhibitor of system L amino acid transporter. We propose that leucine plays important roles in regulating signaling by p70S6 kinase by acting as an intercellular communicator in the CNS.
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PMID:Leucine induces phosphorylation and activation of p70S6K in cortical neurons via the system L amino acid transporter. 1843 29

The effect of amino acid on muscle protein degradation remains unclear. Recent studies have elucidated that proteolysis in catabolic conditions occurs through ubiquitin-proteasome proteolysis pathway and that muscle-specific ubiquitin ligases (atrogin-1 and MuRF1) play an important role in protein degradation. In the present study, we examined the direct effect of 5 mM amino acids (leucine, isoleucine, valine, glutamine and arginine) on atrogin-1 and MuRF1 levels in C2C12 muscle cells and the involved intracellular signal transduction pathway. Leucine, isoleucine and valine suppressed atrogin-1 and MuRF1 mRNA levels (approximately equal to 50%) at 6 and 24 h stimulations. Arginine showed a similar effect except at 24 h-treatment for atrogin-1 mRNA. However, glutamine failed to reduce atrogin-1 and MuRF1 mRNA levels. The inhibitory effect of leucine, isoleucine or arginine on atrogin-1 mRNA level was reversed by rapamycin, although wortmannin did not reverse the effect. PD98059 and HA89 reduced basal atrogin-1 level without influencing the inhibitory effects of those amino acids. The inhibitory effect of leucine, isoleucine or arginine on MuRF1 mRNA levels was not reversed by rapamycin. Taken together, these findings indicated that leucine, isoleucine and arginine decreased atrogin-1 mRNA levels via mTOR and that different pathways were involved in the effect of those amino acids on MuRF1 mRNA levels.
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PMID:Branched-chain amino acids and arginine suppress MaFbx/atrogin-1 mRNA expression via mTOR pathway in C2C12 cell line. 1861 83

Signaling through mammalian target of rapamycin complex 1 (mTORC1) is stimulated by amino acids and insulin. Insulin inactivates TSC1/2, the GTPase-activator complex for Rheb, and Rheb.GTP activates mTORC1. It is not clear how amino acids regulate mTORC1. FKBP38 (immunophilin FK506-binding protein, 38 kDa), was recently reported to exert a negative effect on mTORC1 function that is relieved by its binding to Rheb.GTP. We confirm that Rheb binds wild type FKBP38, but inactive Rheb mutants showed contrasting abilities to bind FKBP38. We were unable to observe any regulation of FKBP38/mTOR binding by amino acids or insulin. Furthermore, FKBP38 did not inhibit mTORC1 signaling. The translationally controlled tumor protein (TCTP) in Drosophila was recently reported to act as the guanine nucleotide-exchange factor for Rheb. We have studied the role of TCTP in mammalian TORC1 signaling and its control by amino acids. Reducing TCTP levels did not reproducibly affect mTORC1 signaling in amino acid-replete/insulin-stimulated cells. Moreover, overexpressing TCTP did not rescue mTORC1 signaling in amino acid-starved cells. In addition, we were unable to see any stable interaction between TCTP and Rheb or mTORC1. Accumulation of uncharged tRNA has been previously proposed to be involved in the inhibition of mTORC1 signaling during amino acid starvation. To test this hypothesis, we used a Chinese hamster ovary cell line containing a temperature-sensitive mutation in leucyl-tRNA synthetase. Leucine deprivation markedly inhibited mTORC1 signaling in these cells, but shifting the cells to the nonpermissive temperature for the synthetase did not. These data indicate that uncharged tRNA(Leu) does not switch off mTORC1 signaling and suggest that mTORC1 is controlled by a distinct pathway that senses the availability of amino acids. Our data also indicate that, in the mammalian cell lines tested here, neither TCTP nor FKBP38 regulates mTORC1 signaling.
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PMID:Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. 1867 70

As obesity rates continue to climb, there is a pressing need for novel weight loss techniques. However, the energy-restricted diets recommended for weight loss typically result in significant amounts of lean tissue loss, in addition to the desired body fat loss. Leucine, a supported anticatabolic agent, has shown promise in research at many levels. First, leucine is known to stimulate the mammalian target of rapamycin pathway, which initiates translation and protein synthesis in muscle cells. Furthermore, leucine may help to regulate blood glucose levels by promoting gluconeogenesis. Finally, several recent studies provide evidence that leucine aids in the retention of lean mass in a hypocaloric state. The aim of this paper is to review relevant leucine research in the three areas described and assess its potential as supplement for obese individuals.
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PMID:Leucine for retention of lean mass on a hypocaloric diet. 1905 49

During ageing, a progressive loss of muscle mass has been well described in both man and rodents. This loss of proteins results from an imbalance between protein synthesis and degradation rates. Although some authors have shown a decrease of myofibrillar protein synthesis rates in human volunteers, this imbalance is not clearly apparent when basal rates of protein turnover are measured. A decrease in muscle protein synthesis stimulation was detected nevertheless in ageing rats during the postprandial period, suggesting that the 'meal signal' was altered during ageing. Many results now suggest that aged muscle is less sensitive to the stimulatory effect of amino acids at physiological concentrations but is still able to respond if the increase in aminoacidaemia is sufficiently large. Indeed amino acids play an important role in regulating muscle protein turnover both in vitro and in vivo. At the molecular level, amino acids modulate gene expression. Amino acid response elements have been characterised in the promoter of transcriptional factor CCAAT-enhancer binding protein homologous protein and asparagine synthetase genes. Among amino acids, leucine seems to play the major role in regulating the metabolic function. It inhibits proteolysis and stimulates muscle protein synthesis independently of insulin. Leucine has been shown to act as a real mediator by modulating specifically the activities of intracellular kinases linked to the translation of proteins such as phosphatidylinosinol 3' kinase and mammalian target of rapamycin-70 kDa ribosomal protein S6 (p70S6K) kinases. We recently demonstrated in vitro that protein synthesis of ageing rat muscles becomes resistant to the stimulatory effect of leucine in its physiological concentration range. However, when leucine concentration was increased greatly above its postprandial level, protein synthesis was stimulated normally. Moreover, we studied the effect of meal leucine supplementation on in vivo protein synthesis in adult and ageing rats. Leucine supplementation had no additional effect on muscle protein synthesis in adults but totally restored its stimulation in ageing rats. Whether chronic oral leucine supplementation would be beneficial for maintaining muscle protein mass in elderly men and women remains to be studied.
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PMID:Leucine: a key amino acid in ageing-associated sarcopenia? 1907 37

Linear growth in children is sensitive to nutritional status. Amino acids, in particular leucine, have been shown to regulate cell growth, proliferation, and differentiation through the mammalian target of rapamycin (mTOR), a nutrient-sensing protein kinase. Having recently demonstrated a role for mTOR in chondrogenesis, we hypothesized that leucine restriction, acting through mTOR, would inhibit growth plate chondrocyte proliferation and differentiation. The effect of leucine restriction was compared with that of the specific mTOR inhibitor, rapamycin. Leucine restriction produced a dose-dependent inhibition of fetal rat metatarsal explant growth. This was accounted by reduced cell proliferation and hypertrophy but not apoptosis. mTOR activity, as reflected by ribosomal protein S6 phosphorylation, was only partially inhibited by leucine restriction, whereas rapamycin abolished S6 phosphorylation. In chondrogenic ATDC5 cells, leucine restriction inhibited cell number, proteoglycan accumulation, and collagen X expression despite minimal inhibition of mTOR. Microarray analysis demonstrated that the effect of leucine restriction on ATDC5 cell gene expression differed from that of rapamycin. Out of 1,571 genes affected by leucine restriction and 535 genes affected by rapamycin, only 176 genes were affected by both. These findings indicate that the decreased chondrocyte growth and differentiation associated with leucine restriction is only partly attributable to inhibition of mTOR signaling. Thus nutrient restriction appears to directly modulate bone growth through unidentified mTOR-independent mechanisms in addition to the well-characterized mTOR nutrient-sensing pathway.
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PMID:Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. 1940 55

Dietary protein and amino acids, including glutamate, generate signals involved in the control of gastric and intestinal motility, pancreatic secretion, and food intake. They include postprandial meal-induced visceral and metabolic signals and associated nutrients (eg, amino acids and glucose), gut neuropeptides, and hormonal signals. Protein reduces gastric motility and stimulates pancreatic secretions. Protein and amino acids are also more potent than carbohydrate and fat in inducing short-term satiety in animals and humans. High-protein diets lead to activation of the noradrenergic-adrenergic neuronal pathway in the brainstem nucleus of the solitary tract and in melanocortin neurons of the hypothalamic arcuate nucleus. Moreover, some evidence indicates that circulating concentrations of certain amino acids could influence food intake. Leucine modulates the activity of energy and nutrient sensor pathways controlled by AMP-activated protein kinase and mammalian target of rapamycin in the hypothalamus. At the brain level, 2 afferent pathways are involved in protein and amino acid monitoring: the indirect neural (mainly vagus-mediated) and the direct humoral pathways. The neural pathways transfer preabsorptive and visceral information through the vagus nerve that innervates part of the orosensory zone (stomach, duodenum, and liver). Localized in the brainstem, the nucleus of the solitary tract is the main projection site of the vagus nerve and integrates sensory information of oropharyngeal, intestinal, and visceral origins. Ingestion of protein also activates satiety pathways in the arcuate nucleus, which is characterized by an up-regulation of the melanocortin pathway (alpha-melanocyte-stimulating, hormone-containing neurons) and a down-regulation of the neuropeptide Y pathway.
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PMID:Protein, amino acids, vagus nerve signaling, and the brain. 1964 Sep 48

Leucine has profound effects on glucose metabolism in muscle; however, the effects of leucine on glucose transport in muscle have not been well documented. We investigated the effects of leucine on contraction- and insulin-stimulated glucose transport in isolated rat epitrochlearis muscle in vitro. In the absence of insulin, tetanic contraction increased 3-O-methyl-D-glucose (3-MG) transport and Thr(172) phosphorylation of the catalytic alpha-subunit of 5'-AMP-activated protein kinase (AMPK), a signaling intermediary leading to insulin-independent glucose transport. Leucine (2 mM, 30 min) significantly enhanced contraction-stimulated 3-MG transport and AMPK phosphorylation, accompanied by increased phosphorylation of p70 S6 kinase (p70S6K) Thr(389). The stimulatory effects of leucine on 3-MG transport and AMPK phosphorylation were canceled by STO-609 blockade of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) or rapamycin blockade of p70S6K. On the other hand, leucine blunted insulin-stimulated 3-MG transport and reduced insulin-stimulated Akt Thr(473) phosphorylation. Leucine increased insulin-stimulated p70S6K Thr(389) phosphorylation and enhanced the inhibitory phosphorylation of the insulin receptor substrate 1 (IRS1) Ser(636/639). Furthermore, the effects of leucine on insulin-stimulated 3-MG transport and IRS phosphorylation were abolished by rapamycin. These results indicate that leucine activates contraction-stimulated glucose transport and inhibits insulin-stimulated glucose transport in skeletal muscle by activating mammalian target of rapamycin (mTOR)/p70S6K signaling. Enhanced increases in contraction-stimulated AMPK Thr(172) phosphorylation and insulin-stimulated IRS1 Ser(636/639) phosphorylation might be responsible for these opposing effects of leucine, respectively.
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PMID:Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle. 1994 Jan

The postprandial rise in amino acids, particularly leucine, stimulates muscle protein synthesis in neonates. Previously, we showed that a 1-h infusion of leucine increased protein synthesis, but this response was not sustained for 2 h unless the leucine-induced decrease in amino acids was prevented. To determine whether a parenteral leucine infusion can stimulate protein synthesis for a more prolonged, clinically relevant period if baseline amino acid concentrations are maintained, overnight food-deprived neonatal pigs were infused for 24 h with saline, leucine (400 mumol.kg(-1). h(-1)), or leucine with replacement amino acids. Amino acid replacement prevented the leucine-induced decrease in amino acids. Muscle protein synthesis was increased by leucine but only when other amino acids were supplied to maintain euaminoacidemia. Leucine did not affect activators of mammalian target of rapamycin (mTOR), i.e. protein kinase B, AMP-activated protein kinase, tuberous sclerosis complex 2, or eukaryotic elongation factor 2. There was no effect of treatment on the association of mTOR with regulatory associated protein of mammalian target of rapamycin (raptor), G-protein beta subunit-like protein, or rictor or the phosphorylation of raptor or proline-rich Akt substrate of 40 kDa. Phosphorylation of mTOR and its downstream targets, eukaryotic initiation factor (eIF) 4E binding protein and ribosomal protein S6 kinase, and the eIF4E . eIF4G association were increased and eIF2alpha phosphorylation was reduced by leucine and was not further altered by correcting for the leucine-induced hypoaminoacidemia. Thus, prolonged parenteral infusion of leucine activates mTOR and its downstream targets in neonatal skeletal muscle, but the stimulation of protein synthesis also is dependent upon amino acid availability.
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PMID:Stimulation of muscle protein synthesis by prolonged parenteral infusion of leucine is dependent on amino acid availability in neonatal pigs. 2003 89

Like insulin, leucine stimulates the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70(S6K)) axis in various organs. Insulin proceeds via the canonical association of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent protein kinase-1 (PDK1), and protein kinase B (PKB/Akt). The signaling involved in leucine effect, although known to implicate a PI3K mechanism independent of PKB/Akt, is more poorly understood. In this study, we investigated whether PDK1 could also participate in the events leading to mTOR/p70(S6K) activation in response to leucine in the heart. In wild-type hearts, both leucine and insulin increased p70(S6K) activity whereas, in contrast to insulin, leucine was unable to activate PKB/Akt. The changes in p70(S6K) activity induced by insulin and leucine correlated with changes in phosphorylation of Thr(389), the mTOR phosphorylation site on p70(S6K), and of Ser(2448) on mTOR, both related to mTOR activity. Leucine also triggered phosphorylation of the proline-rich Akt/PKB substrate of 40 kDa (PRAS40), a new pivotal mTOR regulator. In PDK1 knockout hearts, leucine, similarly to insulin, failed to induce the phosphorylation of mTOR and p70(S6K), leading to the absence of p70(S6K) activation. The loss of leucine effect in absence of PDK1 correlated with the lack of PRAS40 phosphorylation. Moreover, the introduction in PDK1 of the L155E mutation, which is known to preserve the insulin-induced and PKB/Akt-dependent phosphorylation of mTOR/p70(S6K), suppressed all leucine effects, including phosphorylation of mTOR, PRAS40, and p70(S6K). We conclude that the leucine-induced stimulation of the cardiac PRAS40/mTOR/p70(S6K) pathway requires PDK1 in a way that differs from that of insulin.
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PMID:Activation of the cardiac mTOR/p70(S6K) pathway by leucine requires PDK1 and correlates with PRAS40 phosphorylation. 2005 28


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