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

Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR-raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin-like growth factor 1 resistance in peripheral insulin-responsive tissues and in the beta-cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism's response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of beta-cell function and mass in the diabetic environment.
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PMID:The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. 1883 43

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor molecules that function as signaling intermediates downstream of activated cell surface receptors. Based on data implicating IRS-2 but not IRS-1 in breast cancer invasion, survival, and metastasis, we assessed the contribution of IRS-1 and IRS-2 to aerobic glycolysis, which is known to impact tumor growth and progression. For this purpose, we used tumor cell lines derived from transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and that are wild-type (WT) or null for either Irs-1 (Irs-1-/-) or Irs-2 (Irs-2-/-). Aerobic glycolysis, as assessed by the rate of lactic acid production and glucose consumption, was diminished significantly in Irs-2-/- cells when compared with WT and Irs-1-/- cells. Expression of exogenous Irs-2 in Irs-2-/- cells restored the rate of glycolysis to that observed in WT cells. The transcription factor FoxO1 does not appear to be involved in Irs-2-mediated glycolysis. However, Irs-2 does regulate the surface expression of glucose transporter 1 (Glut1) as assessed by flow cytometry using a Glut1-specific ligand. Suppression of Glut1 expression inhibits Irs-2-dependent invasion, which links glycolysis to mammary tumor progression. Irs-2 was shown to be important for mammalian target of rapamycin (mTor) activation, and Irs-2-dependent regulation of Glut1 surface expression is rapamycin-sensitive. Collectively, our data indicate that Irs-2, but not Irs-1, promotes invasion by sustaining the aerobic glycolysis of mouse mammary tumor cells and that it does so by regulating the mTor-dependent surface expression of Glut1.
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PMID:Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1. 1905 42

Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Recently, it has been shown by several groups as well as ours that insulin-like growth factor-I receptor (IGF-IR) overexpression is related to higher proliferation, survival, angiogenesis, and highly invasive pancreatic tumors. Several studies have been carried out to understand the pathways that lead to growth factor-mediated signaling, but the molecular mechanism of receptor overexpression remains mostly unknown. Treatment with neutralizing antibodies or a specific kinase inhibitor against IGF-IR could block the receptor expression in PCA cells. Furthermore, we also showed that insulin receptor substrate (IRS)-2, but not IRS-1, is involved in regulation of IGF-IR expression, which is most likely not transcriptional control. By blocking mammalian target of rapamycin (mTOR) pathway with rapamycin as well as other biochemical analysis, we defined a unique regulation of IGF-IR expression mediated by protein kinase Cdelta (PKCdelta) and mTOR pathway. Moreover, we showed that the down-regulation of IGF-IR expression due to IRS-2 small interfering RNA can be compensated by overexpression of dominant-active mutant of PKCdelta, suggesting that PKCdelta is downstream of IGF-IR/IRS-2 axis. Overall, these findings suggest a novel regulatory role of IRS-2 on the expression of IGF-IR through PKCdelta and mTOR in pancreatic cancer cells.
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PMID:Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. 1919 Mar 47

Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr(705), a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser(473) or phospho-p70S6K-Thr(389), markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.
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PMID:The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling. 1943 52

New-onset diabetes mellitus after transplantation (NODAT) is a serious complication in organ transplantation; not only does it enhance the risk of graft dysfunction, it also increases cardiovascular morbidity and mortality. The mammalian target of rapamycin (mTOR) is regulated independently by insulin, amino acids, and energy sufficiency. It integrates signal from growth factors, hormones, nutrients, and cellular energy levels to regulate protein translation and cell growth, proliferation, and survival. In addition, mTOR generates an inhibitory feedback loop on insulin receptor substrate (IRS) proteins. Therefore, it was suggested that mTOR might link nutrient excess with both obesity and insulin resistance. In this review, we summarize the role of mTOR and its inhibitor sirolimus (SRL) on chronic hyperglycemia and insulin resistance in beta cells, adipose tissue, liver, and muscle. We further hypothesize, based on data from the literature and generated in our laboratory, that SRL could counteract the development of NODAT in stable glucose homeostasis due to its positive effects on insulin-stimulated glucose uptake, whereas in conditions that require an adaptive beta cell proliferation (such as pregnancy and weight increase), the administration of SRL might have effects that would promote the development of NODAT. Therefore, it seems crucial for patient outcome to consider these potentially contrasting effects of SRL.
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PMID:Mammalian target of rapamycin and diabetes: what does the current evidence tell us? 1965 Dec 94

Pluripotent embryonic stem (ES) cells are a potential source of all types of cells for regenerative medicine. ES cells maintain pluripotency through a complex interplay of different signaling pathways and transcription factors, including leukemia inhibitory factor (LIF), Nanog, Sox2, and Oct3/4. Nanog, however, plays a key role in maintaining the pluripotency of mouse and human ES cells. Phosphoinositde 3-kinase (PI3K) signaling pathway which is activated in response to growth factors and cytokines also plays a critical role in promoting the survival and proliferation of ES cells. Our earlier studies revealed that retinol, the alcohol form of vitamin A, enhances the expression of Nanog and prevents differentiation of ES cells in long-term cultures. Normally vitamin A/retinol is associated with cell differentiation via its potent metabolite, retinoic acid. Thus far, no direct function has been ascribed to retinol itself. In this study, we demonstrate for the first time that retinol directly activates phosphoinositide three (PI3) kinase signaling pathway through IGF-1 receptor/insulin receptor substrate one (IRS-1) by engaging Akt/PKB-mTORC1 mammalian target of rapamycin-2 (mammalian target of rapamycin complex 2), indicating a growth factor-like function of vitamin A. Furthermore, ES cells do not express enzymes to metabolize retinol into retinoic acid and lack receptors for retinol transport into the cytoplasm, indicating that retinol signaling is independent of retinoic acid. This study presents a novel system to investigate how extracellular signals control the self renewal of ES cells which will be important for high-quality ES cells for regenerative medicine.
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PMID:A novel signaling by vitamin A/retinol promotes self renewal of mouse embryonic stem cells by activating PI3K/Akt signaling pathway via insulin-like growth factor-1 receptor. 1989 Sep 80

Insulin resistance can occur in response to many different external insults, including chronic exposure to insulin itself as well as other agonists such as dexamethasone. It is generally thought that such defects arise due to a defect(s) at an early stage in the insulin signaling cascade. One model suggests that this involves activation of the mammalian target of rapamycin/S6 kinase pathway, which inactivates insulin receptor substrate via Ser/Thr phosphorylation. However, we have recently shown that insulin receptor substrate is not a major node for insulin resistance defects. To explore the mechanism of insulin resistance, we have developed a novel system to activate Akt independently of its upstream effectors as well as other insulin-responsive pathways such as mitogen-activated protein kinase. 3T3-L1 adipocytes were rendered insulin-resistant either with chronic insulin or dexamethasone treatment, but conditional activation of Akt2 stimulated hemagglutinin-tagged glucose transporter 4 translocation to the same extent in these insulin-resistant and control cells. However, addition of insulin to cells in which Akt was conditionally activated resulted in a reversion to the insulin-resistant state, indicating a feedforward inhibitory mechanism activated by insulin itself. This effect was overcome with wortmannin, implicating a role for phosphatidylinositol 3-kinase in this inhibitory process. We conclude that in chronic insulin- and dexamethasone-treated cells, acute activation with insulin itself is required to activate a feedforward inhibitory pathway likely emanating from phosphatidylinositol 3-kinase that converges on a target downstream of Akt to cause insulin resistance.
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PMID:Dissecting the mechanism of insulin resistance using a novel heterodimerization strategy to activate Akt. 2002 50

This perspective on the report by McCampbell et al. in this issue of the journal (beginning on page 290) addresses the role of insulin receptor substrate (IRS) proteins in cancer progression. The IRS proteins link many cell-surface receptors to signal transduction pathways. Activation of the phosphoinositide-3 kinase/Akt/mammalian target of rapamycin axis normally results in serine phosphorylation and subsequent downregulation of these adaptor proteins. The authors show that changes in the negative feedback regulation of IRS proteins is associated with the progression of endometrial epithelial cells to hyperplasia and cancer. Therefore, understanding the function of adaptor proteins could provide additional strategies for cancer prevention and treatment.
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PMID:Adaptor proteins as targets for cancer prevention. 2017 97

The mammalian target of rapamycin complex 1 (mTORC)1 pathway has emerged as a critical signaling component in the modulation of insulin's metabolic action. This effect is triggered by a nutrient- and insulin-mediated negative feedback loop in which mTOR and S6 kinase (S6K)1 phosphorylate insulin receptor substrate (IRS)-1 on serine residues, which blunts phosphatidylinositol 3-kinase (PI3K) activation. Acute inhibition of mTORC1/S6K1 by rapamycin increases insulin signaling and glucose uptake in myocytes and adipocytes, but whether these effects can be maintained under chronic inhibition of mTORC1 or S6K1 remains unclear. Here, we analyzed the effect of chronic rapamycin inhibition or small interfering RNA-based down-regulation of specific elements of the mTORC1/S6K1 pathway on insulin signaling and glucose transport in adipocytes. Both chronic inhibition of mTORC1 by rapamycin or knockdown of either mTOR, raptor, or S6K1 reduced inhibitory serine phosphorylation of IRS-1, while increasing its insulin-stimulated tyrosine phosphorylation and associated PI3K activity. However, knockdown of either mTOR or raptor selectively blunted IRS-1 phosphorylation on Ser636/639, whereas only S6K1 knockdown was found to reduce phosphorylation of IRS-1 on Ser1101. Unexpectedly, insulin-induced activation of Akt2 and glucose transporter 4 expression were reduced after chronic disruption of the mTORC1/S6K1 pathway, impairing insulin-mediated glucose uptake despite increased PI3K activation. In conclusion, these data indicate that both mTORC1 and S6K1 are key elements of the negative feedback loop but inhibit insulin-induced PI3K activity through phosphorylation of specific serine residues in IRS-1. However, this study also shows that chronic inhibition of the mTORC1/S6K1 pathway uncouples IRS-1/PI3K signaling from insulin-induced glucose transport due to impaired activation of Akt2 and blunted glucose transporter 4 expression.
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PMID:Chronic inhibition of the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. 2020 2

Obesity morbidity is associated with excess visceral adiposity, whereas sc adipose tissue is much less metabolically hazardous. Human abdominal sc preadipocytes have greater capacity for proliferation, differentiation, and survival than omental preadipocytes. IGF-I is a critical mediator of preadipocyte proliferation, differentiation, and survival through multiple signaling pathways. We investigated IGF-I action in primary cultures of human preadipocytes isolated from sc and omental adipose tissue of obese subjects. IGF-I-stimulated DNA synthesis was significantly lower in omental compared with sc preadipocytes. IGF-I phosphorylation of the IGF-I receptor and the ERK pathway was comparable in sc and omental cells. However, omental preadipocytes had decreased insulin receptor substrate (IRS)-1 protein associated with increased IRS-1-serine(636/639) phosphorylation and degradation. IGF-I-stimulated phosphorylation of AKT on serine(473) but not threonine(308) was decreased in omental cells, and activation of downstream targets, including S6Kinase, glycogen synthase kinase-3, and Forkhead box O1 was also impaired. CyclinD1 abundance was decreased in omental cells due to increased degradation. Over-expression of IRS-1 by lentivirus in omental preadipocytes increased IGF-I-stimulated AKT-serine(473) phosphorylation. The mammalian target of rapamycin (mTOR)-Rictor complex regulates phosphorylation of AKT-serine(473) in 3T3-L1 adipocytes, but knockdown of Rictor by lentivirus-delivered short hairpin RNA in sc preadipocytes did not affect AKT-serine(473) phosphorylation by IGF-I. These data reveal an intrinsic defect in IGF-I activation of the AKT pathway in omental preadipocytes from obese subjects that involves IRS-1 but probably not mTOR-Rictor complex. We conclude that impaired cell cycle regulation by AKT contributes to the distinct growth phenotype of preadipocytes in visceral fat of obese subjects.
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PMID:IGF-I activation of the AKT pathway is impaired in visceral but not subcutaneous preadipocytes from obese subjects. 2055 32


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