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

The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
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PMID:Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. 1546 18

Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.
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PMID:Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. 1671 28

Mammalian target of rapamycin (mTOR) controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. Phosphorylation at Ser473, along with Thr308 of its activation loop, is deemed necessary for Akt function, although the regulatory mechanisms and physiological importance of each phosphorylation site remain to be fully understood. Here, we report that SIN1/MIP1 is an essential TORC2/PDK2 subunit. Genetic ablation of sin1 abolished Akt-Ser473 phosphorylation and disrupted rictor-mTOR interaction but maintained Thr308 phosphorylation. Surprisingly, defective Ser473 phosphorylation affected only a subset of Akt targets in vivo, including FoxO1/3a, while other Akt targets, TSC2 and GSK3, and the TORC1 effectors, S6K and 4E-BP1, were unaffected. Our findings reveal that the SIN1-rictor-mTOR function in Akt-Ser473 phosphorylation is required for TORC2 function in cell survival but is dispensable for TORC1 function.
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PMID:SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. 1696 53

Recent work has shown that the mTOR (mammalian target of rapamycin) pathway is an integral cell growth regulator. The mTOR pathway involves two functional complexes, TORC1 and TORC2, which have been defined by both their association with raptor or rictor, respectively, and their sensitivity to short-term rapamycin inhibition. Loss of tumor suppressors TSC1 or TSC2 leads to aberrant activation of TORC1, which has been implicated in the control of cell size. As a result, both physiologic and pathologic tissue hypertrophy are associated with TORC1 activation. Some clinical examples include skeletal and cardiac muscle hypertrophy, vascular restenosis, and compensatory nephrotic hypertrophy. Clarification of the mTOR pathway may lead to increased understanding of both the etiology and consequences of aberrant cell size regulation. This review covers some of the biochemical regulation of the mTOR pathway that may be important to the regulation of cell size, and it will present several potential clinical applications where the control of cell size may be biologically significant.
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PMID:mTOR pathway as a target in tissue hypertrophy. 1696 13

Target of rapamycin (TOR) is an evolutionally conserved protein kinase in eukaryotes and a central cell growth controller. TOR exists in two distinct complexes, termed TORC1 and TORC2. Mammalian TORC2 has recently been shown to possess kinase activity toward the C-terminal hydrophobic site of Akt/PKB. Here, we report that Sin1 is an essential component of TORC2 but not of TORC1, and functions similarly to Rictor, the defining member of TORC2, in complex formation and kinase activity. Knockdown of Sin1decreases Akt phosphorylation in both Drosophila and mammalian cells and diminishes Akt function in vivo. It also disrupts the interaction between Rictor and mTOR. Furthermore, Sin1 is required for TORC2 kinase activity in vitro. Disruption of the Rictor gene in mice results in embryonic lethality and ablates Akt phosphorylation. These data demonstrate that Sin1 together with Rictor are key components of mTORC2 and play an essential role in Akt phosphorylation and signaling.
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PMID:Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. 1704 9

Phosphorylation of eukaryotic initiation factor 4G (eIF4G) is hypothesized to be an important contributor to the stimulation of protein synthesis in skeletal muscle following meal feeding. The experiments reported herein examined the potential role for a rapamycin-sensitive signaling pathway in mediating the meal feeding-induced elevations in phosphorylation of eIF4G. Gastrocnemius from male Sprague-Dawley rats trained to consume a meal consisting of rat chow was sampled prior to and following 3 h of having the meal provided in the presence or absence of treatment with rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Pretreatment with rapamycin prevented the feeding-induced phosphorylation of mTOR, eIF4G, and S6K1 but only partially attenuated the shift in 4E-BP1 into the gamma-form. In contrast, the feeding-induced increase in phosphorylation of PKCepsilon was not reduced by rapamycin. Rapamycin also prevented the augmented association of eIF4G with eIF4E and the decreased association of eIF4E with 4E-BP1. Similar findings were observed in gastrocnemius from animals after oral administration of leucine. Perfusion of gastrocnemius with medium containing rapamycin partially prevented the leucine-induced increase in phosphorylation of eIF4G. Thus, rapamycin attenuated a feeding- or leucine-induced phosphorylation of eIF4G in skeletal muscle both in vivo and in situ. The latter observation implies that the effects observed with rapamycin were the result of modulation of skeletal muscle signaling mechanisms responsible for eIF4G phosphorylation.
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PMID:Rapamycin blunts nutrient stimulation of eIF4G, but not PKCepsilon phosphorylation, in skeletal muscle. 1738 11

The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors, insulin, and Akt-dependent signaling associated with oncoprotein expression or loss of the tumor-suppressor PTEN. In this regard, mTOR activity is associated with cancer cell growth and survival. Here, we have explored an involvement of the I kappa B kinase (IKK) pathway, associated with nuclear factor-kappaB activation, in controlling mTOR activity. The experiments show that IKK alpha controls mTOR kinase activity in Akt-active, PTEN-null prostate cancer cells, with less involvement by IKK beta. In these cells, IKK alpha associates with mTOR, as part of the TORC1 complex, in an Akt-dependent manner. Additionally, IKKalpha is required for efficient induction of mTOR activity downstream of constitutively active Akt expression. The results indicate a novel role for IKK alpha in controlling mTOR function in cancer cells with constitutive Akt activity.
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PMID:Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha. 1761 84

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.
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PMID:The selectivity of protein kinase inhibitors: a further update. 1785 Feb 14

Nutrients act both directly and indirectly to modulate muscle protein accretion through changes in protein synthesis and degradation. For example, glucose, amino acids and fatty acids can all be metabolized to produce energy in the form of ATP that can be utilized for protein synthesis. In addition, amino acids are used directly for the synthesis of new proteins. Nutrients also regulate protein synthesis through activation of a signalling pathway involving the protein kinase, mTOR [mammalian TOR (target of rapamycin)]. Together with several regulatory proteins, mTOR forms a complex referred to as TORC1 (TOR complex 1). Because of its central role in controlling cell growth, TORC1 is an integral component of the mechanism through which nutrients modulate protein synthesis. Herein, the mechanism(s) through which nutrients, and in particular amino acids, regulate signalling through TORC1 will be discussed. In addition, downstream effectors of TORC1 action on mRNA translation will be briefly presented. Finally, a previously unrecognized effector of TORC1 signalling in regulating protein synthesis will be described.
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PMID:The role of nutrition in stimulating muscle protein accretion at the molecular level. 1795 35

Transforming growth factor-beta (TGFbeta) stimulates pathological renal cell hypertrophy for which increased protein synthesis is critical. The mechanism of TGFbeta-induced protein synthesis is not known, but PI 3 kinase-dependent Akt kinase activity is necessary. We investigated the contribution of downstream effectors of Akt in TGFbeta-stimulated protein synthesis. TGFbeta increased inactivating phosphorylation of Akt substrate tuberin in a PI 3 kinase/Akt dependent manner, resulting in activation of mTOR kinase. mTOR activity increased phosphorylation of S6 kinase and the translation repressor 4EBP-1, which were sensitive to inhibition of both PI 3 kinase and Akt. mTOR inhibitor rapamycin and a dominant negative mutant of mTOR suppressed TGFbeta-induced phosphorylation of S6 kinase and 4EBP-1. PI 3 kinase/Akt and mTOR regulated dissociation of 4EBP-1 from eIF4E to make the latter available for binding to eIF4G. mTOR and 4EBP-1 modulated TGFbeta-induced protein synthesis. mTOR is present in two multi protein complexes, mTORC1 and mTORC2. Raptor and rictor are part of mTORC1 and mTORC2, respectively. shRNA-mediated downregulation of raptor inhibited TGFbeta-stimulated mTOR kinase activity, resulting in inhibition of phosphorylation of S6 kinase and 4EBP-1. Raptor shRNA also prevented protein synthesis in response to TGFbeta. Downregulation of rictor inhibited serine 473 phosphorylation of Akt without any effect on phosphorylation of its substrate, tuberin. Furthermore, rictor shRNA increased phosphorylation of S6 kinase and 4EBP-1 in TGFbeta-independent manner, resulting in increased protein synthesis. Thus mTORC1 function is essential for TGFbeta-induced protein synthesis. Our data also provide novel evidence that rictor negatively regulates TORC1 activity to control basal protein synthesis, thus conferring tight control on cellular hypertrophy.
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PMID:Raptor-rictor axis in TGFbeta-induced protein synthesis. 1806 36


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