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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study an overview is presented of the mTOR signaling pathway and its regulation by amino acids, particularly L-leucine. Our laboratory is studying amino acid regulation of mTOR in adipocytes. Potential roles for mTOR in adipocytes that were previously posited include hypertrophic growth, leptin secretion, protein synthesis and adipose tissue morphogenesis. A current area of interest in the field is how amino acids regulate mTOR and which amino acids are regulatory. Revelations concerning mechanism and recognition are emerging from different laboratories that examined the structural requirements for stimulation and inhibition of the mTOR signaling pathway by leucine and amino acid analogs. In adipocytes and some other cell types, leucine appears to be the main regulatory amino acid. However, this is not uniformly the case. In those cells where mTOR is regulated by several amino acids, there is evidence that the mechanism of mTOR activation may be different from cells where mainly leucine is regulatory. Furthermore, in tissues where leucine regulates mTOR, the possible existence of different tissue-specific leucine recognition sites may be indicated.
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PMID:Role of leucine in the regulation of mTOR by amino acids: revelations from structure-activity studies. 1123 75

Recent findings have demonstrated that the branched-chain amino acid leucine can activate the translational regulators, phosphorylated heat- and acid-stable protein regulated by insulin (PHAS-I) and p70 S6 kinase (p70S6k), in an insulin-independent and rapamycin-sensitive manner through mammalian target of rapamycin (mTOR), although the mechanism for this activation is undefined. It has been previously established that leucine-induced insulin secretion by beta-cells involves increased mitochondrial metabolism by oxidative decarboxylation and allosteric activation of glutamate dehydrogenase (GDH). We now show that these same intramitochondrial events that generate signals for leucine-induced insulin exocytosis are required to activate the mTOR mitogenic signaling pathway by beta-cells. Thus, a minimal model consisting of leucine and glutamine as substrates for oxidative decarboxylation and an activator of GDH, respectively, confirmed the requirement for these two metabolic components and mimicked closely the synergistic interactions achieved by a complete complement of amino acids to activate p70s6k in a rapamycin-sensitive manner. Studies using various leucine analogs also confirmed the close association of mitochondrial metabolism and the ability of leucine analogs to activate p70s6k. Furthermore, selective inhibitors of mitochondrial function blocked this activation in a reversible manner, which was not associated with a global reduction in ATP levels. These findings indicate that leucine at physiological concentrations stimulates p70s6k phosphorylation via the mTOR pathway, in part, by serving both as a mitochondrial fuel and an allosteric activator of GDH. Leucine-mediated activation of protein translation through mTOR may contribute to enhanced beta-cell function by stimulating growth-related protein synthesis and proliferation associated with the maintenance of beta-cell mass.
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PMID:Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. 1127 47

Protein synthesis in mammalian cells is regulated through alterations in the states of phosphorylation of eukaryotic initiation factors and elongation factors (eIFs and eEFs respectively) and of other regulatory proteins. This modulates their activities or their abilities to interact with one another. Insulin activates several of these proteins including the following: the guanine-nucleotide exchange factor eIF2B; the eIF4F complex, which (through eIF4E) interacts with the cap of the mRNA; p70 S6 kinase; and elongation factor eEF2, which mediates the translocation step of elongation. Control of the last three of these is linked to mTOR (mammalian target of rapamycin). In Chinese hamster ovary cells, regulation of all these proteins by insulin is modulated by the presence of amino acids and/or glucose in the medium. For example, p70 S6 kinase activity declines in the absence of amino acids and cannot be stimulated by insulin under this condition. The readdition of amino acids, especially leucine, restores activity and sensitivity to insulin. With eIF2B and eEF2, both amino acids and glucose must be provided for insulin to regulate their activities. In contrast, insulin-stimulation of the formation of eIF4F complexes requires glucose but not amino acids. Glucose metabolism is required for this permissive effect. Our recent studies have also identified the mechanism by which mTOR signalling regulates the phosphorylation of eEF2. eEF2 kinase is phosphorylated by p70 S6 kinase at Ser-366; this results in the inactivation of eEF2 kinase, especially at low (micromolar) Ca concentrations.
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PMID:Interplay between insulin and nutrients in the regulation of translation factors. 1149 25

The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
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PMID:8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways. 1168 2

Control of protein synthesis by amino acid availability is an active and centrally important area of research that has produced several recent advances in our understanding of how these substrates serve not only as precursors but also as signaling molecules. One particularly noteworthy advance is the identification of the unique specificity of leucine in signaling to stimulate protein synthesis in skeletal muscle. Leucine mediated signaling results in a stimulation of initiation of mRNA translation and involves increases in the phosphorylation status of the translational repression 4E-BP1 and the ribosomal protein S6 kinase S6K1. It requires sustained activation of the mammalian target of rapamycin protein kinase. Leucine, however, also signals to stimulate protein synthesis in skeletal muscle by a mammalian target of rapamycin protein kinase independent (i.e. rapamycin insensitive) pathway, suggesting that the amino acid may signal through multiple pathways. Furthermore, leucine signaling in skeletal muscle differs from that in liver, suggesting that various responses may be tissue specific. Finally, there continues to be active research on the beneficial effects of glutamine as a unique supplement in catabolic circumstances. In this case, however, the signaling properties and mechanism of action of glutamine remain as an unsolved mystery.
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PMID:Control of protein synthesis by amino acid availability. 1179 Sep 48

RAFT1/FRAP/mTOR is a key regulator of cell growth and division and the mammalian target of rapamycin, an immunosuppressive and anticancer drug. Rapamycin deprivation and nutrient deprivation have similar effects on the activity of S6 kinase 1 (S6K1) and 4E-BP1, two downstream effectors of RAFT1, but the relationship between nutrient- and rapamycin-sensitive pathways is unknown. Using transcriptional profiling, we show that, in human BJAB B-lymphoma cells and murine CTLL-2 T lymphocytes, rapamycin treatment affects the expression of many genes involved in nutrient and protein metabolism. The rapamycin-induced transcriptional profile is distinct from those induced by glucose, glutamine, or leucine deprivation but is most similar to that induced by amino acid deprivation. In particular, rapamycin treatment and amino acid deprivation up-regulate genes involved in nutrient catabolism and energy production and down-regulate genes participating in lipid and nucleotide synthesis and in protein synthesis, turnover, and folding. Surprisingly, however, rapamycin had effects opposite from those of amino acid starvation on the expression of a large group of genes involved in the synthesis, transport, and use of amino acids. Supported by measurements of nutrient use, the data suggest that RAFT1 is an energy and nutrient sensor and that rapamycin mimics a signal generated by the starvation of amino acids but that the signal is unlikely to be the absence of amino acids themselves. These observations underscore the importance of metabolism in controlling lymphocyte proliferation and offer a novel explanation for immunosuppression by rapamycin.
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PMID:The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. 1210 Dec 49

In freshly isolated rat adipocytes, leucine or its analog norleucine activates the mammalian target of rapamycin (mTOR)-signaling pathway. This results in phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), two proteins involved in the initiation phase of protein synthesis. The purpose of the studies reported herein was to address the question of whether or not these in vitro effects of leucine and norleucine on adipocytes could be extended to the intact animal and to other tissues. To accomplish this, food-deprived (18 h) male Sprague-Dawley rats were orally administered solutions (2.5 ml/100 g body wt) containing normal saline (0.9% NaCl), a carbohydrate mixture (26.2% D-glucose and 26.2% sucrose), leucine (5.4%), or norleucine (5.4%). The protein synthetic responses of adipose tissue were measured and compared with those of other tissues. In addition, S6K1 and 4E-BP1 phosphorylation was measured, as was the plasma concentration of insulin and tissue ATP concentrations. Leucine administration stimulated protein synthesis in adipose tissue, gastrocnemius, and kidney but not in liver and heart. Norleucine stimulated protein synthesis in all of the tissues tested but, in contrast to leucine, without affecting plasma insulin concentrations. The carbohydrate meal had no effect on protein synthesis in any tissue tested but elicited a robust increase in plasma insulin. These findings provide support for a role of leucine as a direct-acting nutrient signal for stimulation of protein synthesis in adipose tissue as well as other select tissues. In adipose tissue, the effects of the different treatment conditions on the acute regulation of protein synthesis closely correlated with changes in phosphorylation of S6K1 and 4E-BP1; however, this correlation did not exist in all tissues examined. This result implies that leucine or norleucine may acutely stimulate protein synthesis, at least in some tissues, by a mechanism that is independent of both S6K1 and 4E-BP1 phosphorylation.
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PMID:Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. 1216 44

Acute administration of leucine and norleucine activates the mammalian target of rapamycin (mTOR) cell-signaling pathway and increases rates of protein synthesis in a number of tissues in fasted rats. Although persistent stimulation of mTOR signaling is thought to increase protein synthetic capacity, little information is available concerning the effects of chronic administration of these agonists on protein synthesis, mTOR signal transduction, or leucine metabolism. Hence, we developed a model of chronic leucine/norleucine supplementation via drinking water and examined the effects of chronic (12 days) supplementation on protein synthesis in adipose tissue, kidney, heart, liver, and skeletal muscle from ad libitum-fed rats. The relative concentration of proteins involved in mTOR signaling and the two initial steps in leucine oxidation were also examined. Leucine or norleucine supplementation was accompanied by increased rates of protein synthesis in adipose tissue, liver, and skeletal muscle, but not in heart or kidney. Supplementation was not associated with increases in the anabolic hormones insulin or insulin-like growth factor I. Chronic supplementation did not cause apparent adaptation in either components of the mTOR cell-signaling pathway that respond to leucine (mTOR, ribosomal protein S6 kinase, and eukaryotic initiation factor 4E-binding protein-1) or the first two steps in leucine metabolism (the mitochondrial isoform of branched-chain amino acid transaminase, branched-chain keto acid dehydrogenase, and branched-chain keto acid dehydrogenase kinase), which may be involved in terminating the signal from leucine. These results suggest that provision of leucine or norleucine supplementation via the drinking water results in stimulation of postprandial protein synthesis in adipose tissue, skeletal muscle, and liver without notable adaptive changes in signaling proteins or metabolic enzymes.
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PMID:Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. 1221 1

Mammalian target of rapamycin (mTOR) is a serine and threonine protein kinase that regulates numerous cellular functions, in particular, the initiation of protein translation. mTOR-mediated phosphorylation of both the translational repressor eukaryotic initiation factor 4E binding protein-1 and p70 S6 kinase are early events that control the translation initiation process. Rapamycin, an inhibitor of mTOR, is a potent immunosuppressant due, in part, to its ability to interfere with T-cell activation at the level of translation, and it has gained a prominent role in preventing the development and progression of rejection in pancreatic islet transplant recipients. The characterization of the insulin signaling cascade that modulates mTOR in insulin-sensitive tissues has been a major focus of investigation. Recently, the ability of nutrients, in particular the branched-chain amino acid leucine, to activate mTOR independent of insulin by a process designated as nutrient signaling has been identified. The beta-cell expresses components of the insulin signaling cascade and utilizes the metabolism of nutrients to affect insulin secretion. These combined transduction processes make the beta-cell an unique cell to study metabolic and autocrine regulation of mTOR signaling. Our studies have described the ability of insulin and IGFs in concert with the nutrients leucine, glutamine, and glucose to modulate protein translation through mTOR in beta-cells. These findings suggest that mitochondria-derived factors, ATP in particular, may be responsible for nutrient signaling. The significance of these findings is that the optimization of mitochondrial function is not only important for insulin secretion but may significantly impact the growth and proliferation of beta-cells through these mTOR signaling pathways.
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PMID:Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. 1235 22

Leptin biosynthesis in adipose cells in vivo is increased by food intake and decreased by food deprivation. However, the mechanism that couples leptin production to food intake remains unknown. We found that addition of leucine to isolated rat adipocytes significantly increased leptin production by these cells, suggesting that postprandial leptin levels may be directly regulated by dietary leucine. The effect of leucine was inhibited by rapamycin and not by actinomycin D. Besides, leucine administration did not increase the amount of leptin mRNA in adipocytes. Therefore, we concluded that leucine activates leptin expression in adipose cells at the level of translation via a mammalian target of rapamycin (mTOR)-mediated pathway. Because leptin is a secreted protein, its biosynthesis is compartmentalized on the endoplasmic reticulum. To analyze mTOR signaling in this subcellular fraction, we separated adipose cells by centrifugation into a heavy membrane fraction that includes virtually all endoplasmic reticulum and the cytosolic extract. Phosphorylation of the major mTOR targets, the ribosomal protein S6 and the translational inhibitor 4E-binding protein (BP)/phosphorylated heat- and acid-stable protein (PHAS)-1, was stimulated by leucine in the cytosolic extract, whereas, in the heavy fraction, S6 was constitutively phosphorylated and leucine only induced phosphorylation of 4E-BP/PHAS-1. We also found that 60-70% of leptin mRNA was stably associated with the heavy fraction, and leucine administration did not change the ratio between compartmentalized and free cytoplasmic leptin mRNA. We suggest that, in adipose cells, a predominant part of leptin mRNA is compartmentalized on the endoplasmic reticulum, and leucine activates translation of these messages via the mTOR/4E-BP/PHAS-1-mediated signaling pathway.
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PMID:Nutrient-sensing mTOR-mediated pathway regulates leptin production in isolated rat adipocytes. 1238 66


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