Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

The 70 kDa ribosomal S6 kinase (p70S6K) is important for cell growth and survival. Activation of p70S6K requires sequential phosphorylation of multiple serine and threonine sites often triggered by growth factors and hormones. Here, we report that paclitaxel, a microtubule-damaging agent, induces phosphorylation of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration- and time-dependent manner in multiple breast and ovarian cancer cell lines demonstrated by a T421/S424 phospho-p70S6K antibody. Phosphoamino-acid analysis and Western blot analysis by serine-/threonine-specific antibodies further confirms that both serine and threonine residues are phosphorylated in p70S6K following treatment with paclitaxel. Paclitaxel-induced p70S6K(T421/S424) phosphorylation requires both de novo RNA and protein synthesis via multiple signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca(++), PI3K, and mammalian target of rapamycin (mTOR). Despite phosphorylation of p70S6K(T421/S424), paclitaxel inactivates this kinase in a concentration- and time-dependent manner as illustrated by in vitro kinase assay. Inhibitors of mTOR, PI3K, and Ca(++) impair p70S6K activity, whereas inhibitors of JNK and PKC stimulate p70S6K activity. Inhibition of PKC and JNK prevents paclitaxel-induced p70S6K inactivation. Moreover, the paclitaxel-induced phosphorylation and low activity of p70S6K mainly occurs during mitosis. In summary, paclitaxel is able to induce p70S6K(T421/S424) phosphorylation and decrease its activity in mitotic cells via multiple signaling pathways. Our data suggest that paclitaxel-induced p70S6K(T421/S424) phosphorylation and kinase inactivation are differentially regulated. Our data also indicate that paclitaxel may exert its antitumor effect, at least in part, via inhibition of p70S6K.
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PMID:Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis. 1255 62

Ribosomal S6 kinase 2 (S6K2) is a serine/threonine kinase identified as a homologue of p70 ribosomal S6 kinase 1 (S6K1). S6K1 and S6K2 show different cellular localization as well as divergent amino acid sequences in non-catalytic domains, suggesting that their cellular functions and/or regulation may not be identical. Many of the serine/threonine residues that become phosphorylated and contribute to S6K1 activation are conserved in S6K2. In this study we carry out mutational analyses of these serine/threonine residues on S6K2 in order to elucidate the mechanism of S6K2 regulation. We find that Thr-228 and Ser-370 are crucial for S6K2 activity, and the three proline-directed serines in the autoinhibitory domain, Ser-410, Ser-417 and Ser-423, play a role in S6K2 activity regulation in a mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase (MEK)-dependent manner. However, unlike S6K1, changing Thr-388 to glutamic acid in S6K2 renders the kinase fully active. This activity was resistant to the effects of rapamycin or wortmannin, indicating that mammalian target of rapamycin (mTOR) and phosphoinositide 3-kinase (PI3K) regulate S6K2 activity via Thr-388. MEK-dependent phosphorylation of the autoinhibitory serines in S6K2 occurs prior to Thr-388 activation. Combining T388E and T228A mutations inhibited S6K2 activation, and a kinase-inactive phosphoinositide-dependent protein kinase (PDK1) diminished T388E activity, suggesting that the role of Thr-388 is to allow further phosphorylation of Thr-228 by PDK1. Thr-388 fails to become phosphorylated in Ser-370 mutants, suggesting that the role of Ser-370 phosphorylation may be to allow Thr-388 phosphorylation. Finally, using the rapamycin-resistant T388E mutant, we provide evidence that S6K2 can phosphorylate S6 in vivo.
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PMID:Mutational analysis of ribosomal S6 kinase 2 shows differential regulation of its kinase activity from that of ribosomal S6 kinase 1. 1271 46

The Type I IFN receptor-generated signals required for initiation of mRNA translation and, ultimately, induction of protein products that mediate IFN responses, remain unknown. We have previously shown that IFNalpha and IFNbeta induce phosphorylation of insulin receptor substrate proteins and downstream engagement of the phosphatidylinositol (PI) 3'-kinase pathway. In the present study we provide evidence for the existence of a Type I IFN-dependent signaling cascade activated downstream of PI 3'-kinase, involving p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFNalpha or IFNbeta. Such activation of p70 S6K is blocked by pharmacological inhibitors of the PI 3'-kinase or the FKBP 12-rapamycin-associated protein/mammalian target of rapamycin (FRAP/mTOR). Consistent with this, the Type I IFN-dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85alpha and p85beta subunits of the PI 3'-kinase (p85alpha-/-beta-/-). Treatment of sensitive cell lines with IFNalpha or IFNbeta also results in phosphorylation/inactivation of the 4E-BP-1 repressor of mRNA translation. Such 4E-BP1 phosphorylation is also PI3'-kinase-dependent and rapamycin-sensitive, indicating that the Type I IFN-inducible activation of PI3'-kinase and FRAP/mTOR results in dissociation of 4E-BP1 from the eukaryotic initiation factor-4E (eIF4E) complex. Altogether, our data establish that the Type I IFN receptor-activated PI 3'-kinase pathway mediates activation of the p70 S6 kinase and inactivation of 4E-BP1, to regulate mRNA translation and induction of Type I IFN responses.
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PMID:Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons. 1275 54

Rapamycins are macrocyclic lactones that possess immunosuppressive, antifungal and antitumor properties. The parent compound, rapamycin, is approved as an immunosup-pressive agent for preventing rejection in patients receiving organ transplantation. Two analogues, CCI-779 and RAD001 are currently being investigated as anticancer agents. Rapamycins first bind a cyclophilin FKBP12, and this complex binds and inhibits the function of mTOR (mammalian target of rapamycin) a serine/threonine (Ser/Thr) kinase with homology to phosphatidylinositol 3' kinase. Currently, as mTOR is the only identified target, this places rapamycins in a unique position of being the most selective kinase inhibitor known. Consequently these agents have been powerful tools in elucidating the role of mTOR in cellular growth, proliferation, survival and tumorigenesis. Increasing evidence suggests that mTOR acts as a central controller sensing cellular environment (nutritional status or mitogenic stimulation) and regulating translation initiation through the eukaryotic initiation factor 4E, and ribosomal p70 S6 kinase pathways. Here we review the conserved TOR signaling pathways, conceptual basis for tumor selectivity, and the mechanisms of resistance to this class of antitumor agent.
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PMID:Rapamycins: mechanism of action and cellular resistance. 1287 53

Identification of signaling pathways downstream of Abl tyrosine kinase may increase our understanding of the pathogenesis of chronic myelogenous leukemia (CML) and suggest strategies to improve clinical treatment of the disease. By combining the use of a phosphospecific antibody recognizing a substrate motif of serine/threonine kinases with bioinformatics, we found that the translational regulators ribosomal protein S6 and 4E-BP1 are constitutively phosphorylated in CML cells. Experiments with specific inhibitors indicated the phosphorylation is downstream of Bcr-Abl kinase and the mammalian target of rapamycin (mTOR). These results suggest that Bcr-Abl may regulate translation of critical targets in CML cells via mTOR. They also provide a rationale for testing the combination of mTOR inhibitors with the Abl kinase inhibitor imatinib in patients with CML. The mTOR inhibitor rapamycin enhanced imatinib-mediated killing of CML cell lines in vitro, and it overcame imatinib resistance in cells with Bcr-Abl gene amplification.
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PMID:Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. 1452 90

Tuberous sclerosis complex is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, and benign tumors of the brain, skin, heart, and kidneys. Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin. Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle. In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (Thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex. These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle.
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PMID:Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. 1455 Dec 5

In 1321N1 astrocytoma cells, stimulation of the IGF-1 (insulin-like growth factor-1) receptor increased the association of PI3K [phosphoinositide (PI) 3-kinase] activity with IRS-1 (insulin re-ceptor substrate 1), and increased the cellular concentration of PtdIns(3,4,5)P3. Carbachol, acting on M3 muscarinic receptors, inhibited insulin-, but not PDGF (platelet-derived growth factor)-, stimulated responses by approximately 50%. The inhibition of IRS-1-associated PI3K activity by carbachol (i) was rapid (<1 min), persistent (> or =60 min) and potent (half-maximal concentration approximately 1 microM); (ii) was reproduced by stimuli for several phospholipase-C-coupled receptors; (iii) was prevented by the inhibition of protein kinase C, but not by chelation of intracellular Ca2+; and (iv) was not blocked or reproduced by inhibitors or stimuli respectively of mitogen-activated protein kinase, PI3K, protein kinase B or the mammalian target of rapamycin. However, the effects of carbachol were prevented by sodium vanadate, a protein tyrosine phosphatase inhibitor, and were accompanied by reduced insulin-stimulated IRS-1 tyrosine phosphorylation and recruitment of the 85 kDa regulatory subunit of PI3K to IRS-1, but not by reduced IGF-1 receptor kinase activity. The inhibitory effect of carbachol was reproduced by okadaic acid, a protein serine/threonine phosphatase inhibitor, but not by PDGF, yet all three agents stimulated the serine phosphorylation of IRS-1 at residues Ser312, Ser616 and Ser636/639, albeit to different extents. Thus muscarinic receptors may inhibit insulin signalling by promoting IRS-1 tyrosine dephosphorylation and/or by uncoupling IRS-1 from the stimulated IGF-1 receptor by stimulating IRS-1 serine phosphorylation. However, the proportion of IRS-1 molecules phosphorylated at a particular site or the phosphorylation of additional IRS-1 serine residues other than those noted above must be important.
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PMID:Muscarinic-receptor-mediated inhibition of insulin-like growth factor-1 receptor-stimulated phosphoinositide 3-kinase signalling in 1321N1 astrocytoma cells. 1476 30

The tuberous sclerosis gene products Tsc1 and Tsc2 behave as tumor suppressors by restricting cell growth, a function conserved among metazoans. Recent evidence has indicated that hyperactivation of S6 kinase 1 (S6K1) may represent an important biochemical change in the development of tuberous sclerosis-associated lesions. We show here that deletion of either Tsc1 or Tsc2 or expression of the Rheb (Ras homolog enriched in brain) GTPase leads to hyperphosphorylation of S6K1 at a subset of regulatory sites, particularly those of two essential residues functionally conserved among AGC superfamily serine/threonine kinases, i.e. the activation loop (T-loop; Thr-229) and the hydrophobic motif (H-motif; Thr-389). These sites are reciprocally and dose-dependently regulated when S6K1 is coexpressed with the Tsc1-Tsc2 complex. Mutations that render S6K1 mTOR (mammalian target of rapamycin)-resistant also protect S6K1 activity and phosphorylation from down-regulation by Tsc1/2. We demonstrate that two disease-associated mutations in Tsc2 fail to negatively regulate S6K1 activity concomitant with a failure to modify T-loop and H-motif phosphorylation. Finally, we identify one pathological Tsc2 mutation that retains its ability to negatively regulate S6K1, suggesting that, in some cases, tuberous sclerosis may develop independently of S6K1 hyperactivation. These results also highlight the importance of dual control of T-loop and H-motif phosphorylation of S6K1 by the Tsc1-Tsc2 complex.
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PMID:Critical role of T-loop and H-motif phosphorylation in the regulation of S6 kinase 1 by the tuberous sclerosis complex. 1499 19

The signals generated by the IFNgamma receptor to initiate mRNA translation and generation of protein products that mediate IFNgamma responses are largely unknown. In the present study, we provide evidence for the existence of an IFNgamma-dependent signaling cascade activated downstream of the phosphatidylinositol (PI) 3'-kinase, involving the mammalian target of rapamycin (mTOR) and the p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated and activated during engagement of the IFNgamma receptor in sensitive cell lines. Such activation of p70 S6 kinase is blocked by pharmacological inhibitors of the PI 3' kinase and mTOR, and is abrogated in double-knockout mouse embryonic fibroblasts for the alpha and beta isoforms of the p85 regulatory subunit of the PI 3'-kinase. The IFNgamma-activated p70 S6 kinase subsequently phosphorylates the 40S S6 ribosomal protein on serines 235/236, to regulate IFNgamma-dependent mRNA translation. In addition to phosphorylation of 40S ribosomal protein, IFNgamma also induces phosphorylation of the 4E-BP1 repressor of mRNA translation on threonines 37/46, threonine 70, and serine 65, sites whose phosphorylation is required for the inactivation of 4E-BP1 and its dissociation from the eukaryotic initiation factor-4E (eIF4E) complex. Thus, engagement of the PI 3'-kinase and mTOR by the IFNgamma receptor results in the generation of two distinct signals that play roles in the initiation of mRNA translation, suggesting an important role for this pathway in IFNgamma signaling.
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PMID:Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein. 1505


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