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)

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.
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PMID:TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. 1217 53

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

Insulin has long been assigned a key role in the regulation of growth and metabolism during fetal life. Our prior observations indicated that hepatic insulin signaling is attenuated in the late-gestation fetal rat. Therefore, we studied the perinatal ontogeny of hepatic insulin signaling extending from phosphatidylinositol 3-kinase (PI3K) to the ribosome. Initial studies demonstrated markedly decreased insulin-mediated activation of ribosomal protein S6 kinase 1 (S6K1) in the fetus. We found a similar pattern in the regulation of Akt, a kinase upstream from S6K1. Insulin produced minimal activation of insulin receptor substrate (IRS)-1-associated PI3K activity in fetal liver. A modest IRS-2-associated response was seen in the fetus. However, levels of both IRS-1 and IRS-2 were very low in fetal liver relative to adult liver. IRS-1 content and insulin responsiveness of PI3K, Akt, and S6K1 showed a transition to the adult phenotype during the first several postnatal weeks. Examination of downstream insulin signaling to the translational apparatus showed marked attenuation, relative to the adult, of fetal hepatic insulin-mediated phosphorylation of 4E-BP1, the regulatory protein for the eukaryotic initiation factor eIF4E, and ribosomal protein S6. The mammalian target of rapamycin (mTOR), a key integrator of nutritional and metabolic regulation of translation, was present in low amounts, was hypophosphorylated, and was not insulin sensitive in the fetus. Our results indicate that protein synthesis during late-gestation liver development may be mTOR and insulin independent. Reexamination of the role of insulin in fetal liver physiology may be warranted.
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PMID:Insulin signaling during perinatal liver development in the rat. 1221 3

The branched-chain amino acids (BCAA) are committed to catabolism by the activity of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. BCKD activity is regulated through the action of the complex-specific BCKD kinase that phosphorylates two serine residues in the E1alpha subunit. Greater BCKD kinase expression levels result in a lower activity state of BCKD and thus a decreased rate of BCAA catabolism. Activity state varies among tissues and can be altered by diet, exercise, hormones, and disease state. Within individual tissues, the concentration of BCKD kinase reflects the activity state of the BCKD complex. Here we investigated the effects of insulin, an important regulator of hepatic metabolic enzymes, on BCKD kinase expression in Clone 9 rat cells. Insulin effected a twofold increase in message levels and a twofold increase in BCKD kinase protein levels. The response was completely blocked by treatment with LY-294002 and partially blocked by rapamycin, thus demonstrating a dependence on phosphatidylinositol 3-kinase and mTOR function, respectively. These studies suggest that insulin acts to regulate BCAA catabolism through stimulation of BCKD kinase expression.
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PMID:Insulin increases branched-chain alpha-ketoacid dehydrogenase kinase expression in Clone 9 rat cells. 1221 4

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

In differentiated 3T3-L1 adipocytes, insulin stimulated the expression of the mRNA for the genes encoding Fra-1 (>100-fold), which is a component of the AP-1 transcriptional complex, beta-actin (6.0-fold) and hexokinase II (2.4-fold). We have examined the signalling pathways involved in these effects of insulin. Rapamycin, which binds to FRAP/mTOR and completely suppressed the activation of p70S6 kinase by insulin, almost completely blocked the induction of the hexokinase II gene, and caused an approximately 50% inhibition of the induction of the Fra-1 gene. PD98059, which completely blocks MAP kinase activation by insulin, inhibited insulin-induced Fra-1 and beta-actin gene expression by approximately 70% and 40%, respectively. These findings suggest that a FRAP/mTOR-dependent pathway is responsible for the induction of hexokinase II expression, and that MAP kinase is required, at least in part, for the stimulation of beta-actin gene expression. However, the induction of Fra-1 gene expression by insulin requires both the FRAP/mTOR and MAP kinase pathways.
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PMID:Multiple signalling pathways mediate insulin-stimulated gene expression in 3T3-L1 adipocytes. 1239 86

Growth factors are known to favor both proliferation and survival of hepatocytes. In this work, we investigated the role of 2 main signaling pathways, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), in these processes. First, evidence was provided that the PI3K cascade as well as the MEK/ERK cascade is a key transduction pathway controlling hepatocyte proliferation, as ascertained by arrest of DNA synthesis in the presence of LY294002, a specific PI3K inhibitor. Inhibition of FRAP/mTOR by rapamycin also abrogated DNA replication and protein synthesis induced by growth factor. We showed that expression of cyclin D1 at messenger RNA (mRNA) and protein levels was regulated by this pathway. We highlighted that 4E-BP1 phosphorylation was not activated by epidermal growth factor (EGF) but was under an insulin-regulation mechanism through a PI3K-FRAP/mTOR activation that could account for the permissive role of insulin on hepatocyte proliferation. No interference between the MEK/ERK pathway and 4E-BP1 phosphorylation was detected, whereas p70S6K phosphorylation induced by EGF was under a U0126-sensitive regulation. Last, we established that the antiapoptotic function of EGF was dependent on MEK, whereas LY294002 and rapamycin had no direct effect on cell survival. Taken together, these data highlight the regulation and the role of 2 pathways that mediate growth-related response by acting onto distinct steps. In conclusion, hepatocyte progression in late G1 phase induced by EGF generates survival signals depending on MEK activation, whereas PI3K and MEK/ERK cascades are both necessary for hepatocyte replication.
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PMID:PI3K-FRAP/mTOR pathway is critical for hepatocyte proliferation whereas MEK/ERK supports both proliferation and survival. 1239 17

Protein synthesis requires both amino acids, as precursors, and a substantial amount of metabolic energy. It is well established that starvation or lack of nutrients impairs protein synthesis in mammalian cells and tissues. Branched chain amino acids are particularly effective in promoting protein synthesis. Recent work has revealed important new information about the mechanisms involved in these effects. A number of components of the translational machinery are regulated through signalling events that require the mammalian target of rapamycin, mTOR. These include translational repressor proteins (eukaryotic initiation factor 4E-binding proteins, 4E-BPs) and protein kinases that act upon the small ribosomal subunit (S6 kinases). Amino acids, especially leucine, positively regulate mTOR signalling thereby relieving inhibition of translation by 4E-BPs and activating the S6 kinases, which can also regulate translation elongation. However, the molecular mechanisms by which amino acids modulate mTOR signalling remain unclear. Protein synthesis requires a high proportion of the cell's metabolic energy, and recent work has revealed that metabolic energy, or fuels such as glucose, also regulate targets of the mTOR pathway. Amino acids and glucose modulate a further important regulatory step in translation initiation, the activity of the guanine nucleotide-exchange factor eIF2B. eIF2B controls the recruitment of the initiator methionyl-tRNA to the ribosome and is activated by insulin. However, in the absence of glucose or amino acids, insulin no longer activates eIF2B. Since control of eIF2B is independent of mTOR, these data indicate the operation of additional, and so far unknown, regulatory mechanisms that control eIF2B activity.
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PMID:Regulation of mammalian translation factors by nutrients. 1242 31

Cellular sensing of L-amino acids is widespread and controls diverse cellular responses regulating, for example, rates of hormone secretion, amino acid uptake, protein synthesis and protein degradation (autophagy). However, the nature of the sensing mechanisms involved has been elusive. One important sensing mechanism is selective for branched chain amino acids, acts via mTOR (mammalian target of rapamycin) and regulates the rates of insulin and IGF-1 secretion as well as hepatic, and possibly muscle, autophagy. A second sensing mechanism is selective for aromatic L-amino acids and regulates the rate of gastric acid secretion and other responses in the gastro-intestinal tract. Interactions between calcium and protein metabolism, including accelerated urinary calcium excretion in subjects consuming high-protein diets and secondary hyperparathyroidism in subjects consuming low-protein diets, suggest an additional amino acid sensing mechanism linked to the control of urinary calcium excretion and parathyroid hormone (PTH) release. New data demonstrating L-amino acid-dependent activation of the calcium-sensing receptor (CaR), which regulates PTH secretion and urinary calcium excretion, suggests an unexpected explanation for these links between calcium and protein metabolism. Furthermore, expression of the CaR in gastrin-secreting G-cells and acid-secreting parietal cells, together with data indicating that the CaR exhibits selectivity for aromatic amino acids, would appear to provide a molecular explanation for amino acid sensing in the gastrointestinal tract. This review examines what is known about the CaR as a gene, a receptor, a physiological regulator and, now, as an amino acid sensor. Possible new roles for the CaR are also considered.
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PMID:L-amino acid sensing by the calcium-sensing receptor: a general mechanism for coupling protein and calcium metabolism? 1242 72

Soleus muscles isolated from normal rats were incubated to evaluate whether or not leucine promotes glucose uptake under insulin-free conditions, using a labeled 2-deoxyglucose uptake assay. Glucose uptake was promoted by 2mM leucine. A metabolite of leucine, alpha-ketoisocaproic acid (alpha-KIC), also exhibited a similar stimulatory effect, although this was not as potent as leucine. Stimulation of glucose uptake by leucine was completely canceled by pre-treatment with either 10 microM LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), or 6 microM GF109203X, a specific inhibitor of protein kinase C (PKC). No significant change was observed by pre-treatment with 1 microM rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR). These results suggest that leucine stimulates glucose transport in skeletal muscle via PI3-kinase and PKC pathways independently of the mammalian target of mTOR. They also suggest that leucine stimulates glucose transport by an insulin-independent mechanism.
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PMID:Leucine promotes glucose uptake in skeletal muscles of rats. 1247 Jun 33


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