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)

Insulin signaling through phosphatidylinositol 3-kinase (PI 3-kinase) activates the protein kinase Akt through phosphorylation of its threonine 308 and serine 473 residues by the PDK1 protein kinase and the Rictor-mammalian target of rapamycin complex (mTORC2), respectively. Remarkably, we show here that the Rictor protein is also present in cultured adipocytes in complexes containing Myo1c, a molecular motor that promotes cortical actin remodeling. Interestingly, the Rictor-Myo1c complex is biochemically distinct from the previously reported mTORC2 and can be immunoprecipitated independently of mTORC2. Furthermore, while RNA interference-directed silencing of Rictor results in the expected attenuation of Akt phosphorylation at serine 473, depletion of Myo1c is without effect. In contrast, loss of either Rictor or Myo1c inhibits phosphorylation of the actin filament regulatory protein paxillin at tyrosine 118. Furthermore, Myo1c-induced membrane ruffling of 3T3-L1 adipocytes is also compromised following Rictor knockdown. Interestingly, neither the mTORC2 inhibitor rapamycin nor the PI 3-kinase inhibitor wortmannin affects paxillin tyrosine 118 phosphorylation. Taken together, our findings suggest that the Rictor-Myo1c complex is distinct from mTORC2 and that Myo1c, in conjunction with Rictor, participates in cortical actin remodeling events.
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PMID:A Rictor-Myo1c complex participates in dynamic cortical actin events in 3T3-L1 adipocytes. 1842 11

AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
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PMID:AMPK phosphorylation of raptor mediates a metabolic checkpoint. 1847 72

mTORC2 is a multiprotein kinase composed of mTOR, mLST8, PRR5, mSIN1 and Rictor. The complex is insensitive to rapamycin and has demonstrated functions controlling cell growth, motility, invasion and cytoskeletal assembly. mTORC2 is the major hydrophobic domain kinase which renders Akt fully active via phosphorylation on serine 473. We isolated Hsp70 as a putative Rictor interacting protein in a yeast two-hybrid assay and confirmed this interaction via co-immunoprecipitation and colocalization experiments. In cells expressing an antisense RNA targeting Hsp70, mTORC2 formation and activity were impaired. Moreover, in cells lacking Hsp70 expression, mTORC2 activity was inhibited following heat shock while controls demonstrated increased mTORC2 activity. These differential effects on mTORC2 activity were specific, in that mTORC1 did not demonstrate Hsp70-dependent alterations under these conditions. These data suggest that Hsp70 is a component of mTORC2 and is required for proper assembly and activity of the kinase both constitutively and following heat shock.
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PMID:Hsp70 associates with Rictor and is required for mTORC2 formation and activity. 1850 77

Immunosuppressive drugs modulate cellular and humoral immune response in the acute allograft rejection. The panel of drugs, which has been recently extended, allowed a significant progress for immunosuppressive treatment. These drugs help us to improve our knowledge of lymphocyte activation pathways. Corticoids, the oldest immunosuppresive drugs, inhibit many cytokines such as interleukin 2 (IL2) and interleukin 6. They represent the treatment of acute rejection. The other immunosuppressive drugs are used for preventing acute rejection. After binding to a specific immunophillin, cyclosporin and tacrolimus inhibit calcineurine, a serine/threonine phosphatase which plays a major role in cytokines transcription notably IL2 after T-cell activation. Anti-IL2 receptor monoclonal antibodies block IL2 activity following T-cell activation. Protein mammalian target of rapamycin inhibitors avoid the transcription of different mRNA involved in the regulation of the cellular cycle. These new agents are rapamycin or sirolimus and everolimus. The inhibitors of pyrimidic and puric bases synthesis, mycophenolic acid and azathioprin, inhibit T- and B-cell proliferation. The wide variety of immunosuppressive drugs permits the use of combinations, which aims at decreasing the immunologic risk and their own toxicities, notably nephrotoxicity. Before transplant, the pharmacist plays an important role in the prevention of initial pathologies and in the politic of organ donation. After transplant, the pharmacist has a role in the pharmacological and biological monitoring of immunosuppressive drugs. But the pharmacist must be involved in the optimization of therapeutics and in the education of transplant patients.
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PMID:[Today in molecular mechanisms of immunosuppressive drugs actions: roles of pharmacist]. 1857 Sep 9

Renal carcinogenesis is promoted by overexpression of the activated serine/ threonine kinase Akt (p-Akt) and supposedly a concomitant reduction in phosphatase and tensin homologue deleted on chromosome 10 tumour suppressor gene (PTEN), which normally inhibits the activation of Akt. Because promising anti-cancer therapies increasingly focus on pathways involving p-Akt and PTEN, the present study evaluated the expression of p-Akt in renal cell carcinomas and compared it with prognosis. P-Akt and PTEN expression were analysed in a tissue microarray (TMA) from renal cell carcinoma (n = 386) and adjacent uninvolved renal tissue (n = 32) specimens. Increased p-Akt was found more often in the nucleus than in the cytoplasm, and PTEN was concomitantly reduced in about 50% of cases. Neither tumour grade nor stage influenced p-Akt expression, whereas the clear cell and papillary subtypes showed increased p-Akt more often than did the chromophobe or sarcomatoid types. Increased cytoplasmic and nuclear p-Akt levels were independent prognostic factors for diminishing patient survival. The present study found significantly increased nuclear but also cytoplasmic p-Akt expression in renal cell carcinoma subtypes. Increased nuclear and cytoplasmic p-Akt was an independent prognostic factor for diminishing patient survival. The considerable number of high-grade and high-stage RCC showing increased p-Akt and reduced PTEN would justify further evaluation of therapeutic concepts based on inhibitors of the PI3K/p-Akt/mTOR pathway.
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PMID:Increased activated Akt expression in renal cell carcinomas and prognosis. 1877 62

Ribosomal protein S6 kinase plays a critical role in the regulation of cell growth and energy metabolism. S6K belongs to the AGC family of serine/threonine kinases and is a downstream effector of the mTOR and PI3K signalling pathways. The activity and subcellular localisation of S6K are tightly controlled by phosphorylation/dephosphorylation events. We have recently demonstrated that steady-state levels of S6K isoforms, S6K1 and S6K2, are regulated by ubiquitination-mediated proteasomal degradation. In this study, we report for the first time that the ubiquitination status of S6K isoforms is coordinated by signalling pathways induced by mitogenic stimuli and extracellular stresses. The induction of signal transduction by serum and growth factors significantly increases the level of S6K ubiquitination, while the treatment of cells with UV and staurosporine has the opposite effect. Furthermore, we found that the phosphorylation/activation of S6Ks does not correlate directly with the induction of their ubiquitination in response to diverse cellular stimuli. This study suggests that the ubiquitination and subsequent proteasomal degradation of S6K are controlled by signalling pathways, which could possibly facilitate their association with the components of the ubiquitination machinery.
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PMID:The ubiquitination of ribosomal S6 kinases is independent from the mitogen-induced phosphorylation/activation of the kinase. 1878 49

Preclinical studies have implicated the mammalian target of rapamycin (mTOR) pathway in the cell cycle progression and growth of prostate cancer cells. Downstream signaling from PI3'-K/Akt leads to phosphorylation (p) of mTOR at serine 2448 and to activation of its substrate, p70S6Kinase (p70S6K), phosphorylated on threonine 389. This promotes translation and cell cycle progression. Morphoproteomic analysis, that combines both the application of phosphospecific probes directed against putative sites of activation on protein analytes and cellular compartmentalization [1] was carried out on tissue microarray (TMA) slides from 64 cases of primary, previously untreated adenocarcinomas of the prostate. Gleason scores ranged from 6 to 10. High grade prostatic intraepithelial neoplasia (HGPIN), which accompanied the invasive cancer in 20 cases, and 15 non-neoplastic controls from benign prostatic hypertrophy specimens in a separate TMA were also included. Ninety-three percent (93%) of tumors exhibited moderate to strong cytoplasmic/plasmalemmal expression of p-mTOR and eighty-five percent (85%) showed similar staining intensity for p-p70S6K. HGPIN demonstrated comparable and occasionally, stronger expression levels for these protein analytes. Quantitative digital imaging revealed an overall increase in the mean expression levels in HGPIN, reaching statistical significance for p-mTOR (Ser 2448) at p<0.05. Morphoproteomic analysis confirms the constitutive activation of the mTOR pathway in prostate cancer and HGPIN, with relative overexpression of p-mTOR in HGPIN. These findings coincide with preclinical studies in supporting a role for the mTOR pathway in the biology and development of prostate cancer through its putative precursor lesion, HGPIN and in suggesting a potential therapeutic target.
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PMID:Morphoproteomic confirmation of a constitutively activated mTOR pathway in high grade prostatic intraepithelial neoplasia and prostate cancer. 1878 12

Eukaryotic translation initiation factor 4B (eIF4B) plays a critical role during the initiation of protein synthesis and its activity can be regulated by multiple phosphorylation events. In a search for novel protein kinase B (PKB/c-akt) substrates, we identified eIF4B as a potential target. Using an in vitro kinase assay, we found that PKB can directly phosphorylate eIF4B on serine 422 (ser422). Activation of a conditional PKB mutant, interleukin-3 (IL-3) or insulin stimulation resulted in PKB-dependent phosphorylation of this residue in vivo. This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or pharmacological inhibition of PKB. Pretreatment of cells with rapamycin, inhibiting mTOR or U0126 to inhibit MEK, had little effect on eIF4B ser422 phosphorylation. In contrast, following amino-acid refeeding, eIF4B ser422 phosphorylation was found to be mammalian target of rapamycin (mTOR)-dependent. We further identified eIF4B ser406 as a novel mitogen-regulated phosphorylation site. Insulin-induced phosphorylation of eIF4B ser406 was dependent on both MEK and mTOR activity. Utilizing a novel translational control luciferase assay, we could further demonstrate that phosphorylation of ser406 or ser422 is essential for optimal translational activity of eIF4B. These data provide novel insights into complex multikinase regulation of eIF4B phosphorylation and reveal an important mechanism by which PKB can regulate translation, potentially critical for the transforming capacity of this AGC kinase family member.
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PMID:AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. 1883 82

SGK1 (serum- and glucocorticoid-induced protein kinase 1) is a member of the AGC (protein kinase A/protein kinase G/protein kinase C) family of protein kinases and is activated by agonists including growth factors. SGK1 regulates diverse effects of extracellular agonists by phosphorylating regulatory proteins that control cellular processes such as ion transport and growth. Like other AGC family kinases, activation of SGK1 is triggered by phosphorylation of a threonine residue within the T-loop of the kinase domain and a serine residue lying within the C-terminal hydrophobic motif (Ser(422) in SGK1). PDK1 (phosphoinositide-dependent kinase 1) phosphorylates the T-loop of SGK1. The identity of the hydrophobic motif kinase is unclear. Recent work has established that mTORC1 [mTOR (mammalian target of rapamycin) complex 1] phosphorylates the hydrophobic motif of S6K (S6 kinase), whereas mTORC2 (mTOR complex 2) phosphorylates the hydrophobic motif of Akt (also known as protein kinase B). In the present study we demonstrate that SGK1 hydrophobic motif phosphorylation and activity is ablated in knockout fibroblasts possessing mTORC1 activity, but lacking the mTORC2 subunits rictor (rapamycin-insensitive companion of mTOR), Sin1 (stress-activated-protein-kinase-interacting protein 1) or mLST8 (mammalian lethal with SEC13 protein 8). Furthermore, phosphorylation of NDRG1 (N-myc downstream regulated gene 1), a physiological substrate of SGK1, was also abolished in rictor-, Sin1- or mLST8-deficient fibroblasts. mTORC2 immunoprecipitated from wild-type, but not from mLST8- or rictor-knockout cells, phosphorylated SGK1 at Ser(422). Consistent with mTORC1 not regulating SGK1, immunoprecipitated mTORC1 failed to phosphorylate SGK1 at Ser(422), under conditions which it phosphorylated the hydrophobic motif of S6K. Moreover, rapamycin treatment of HEK (human embryonic kidney)-293, MCF-7 or HeLa cells suppressed phosphorylation of S6K, without affecting SGK1 phosphorylation or activation. The findings of the present study indicate that mTORC2, but not mTORC1, plays a vital role in controlling the hydrophobic motif phosphorylation and activity of SGK1. Our findings may explain why in previous studies phosphorylation of substrates, such as FOXO (forkhead box O), that could be regulated by SGK, are reduced in mTORC2-deficient cells. The results of the present study indicate that NDRG1 phosphorylation represents an excellent biomarker for mTORC2 activity.
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PMID:mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). 1902 18

Transduction of the insulin signal is mediated by multisite Tyr and Ser/Thr phosphorylation of the insulin receptor substrates (IRSs). Previous studies on the function of single-site phosphorylation, particularly phosphorylation of Ser-302, -307, and -318 of IRS-1, showed attenuating as well as enhancing effects on insulin action. In this study we investigated a possible cross talk of these opposedly acting serine residues in insulin-stimulated skeletal muscle cells by monitoring phosphorylation kinetics, and applying loss of function, gain of function, and combination mutants of IRS-1. The phosphorylation at Ser-302 was rapid and transient, followed first by Ser-318 phosphorylation and later by phosphorylation of Ser-307, which remained elevated for 120 min. Mutation of Ser-302 to alanine clearly reduced the subsequent protein kinase C-zeta-mediated Ser-318 phosphorylation. The Ser-307 phosphorylation was independent of Ser-302 and/or Ser-318 phosphorylation status. The functional consequences of these phosphorylation patterns were studied by the expression of IRS-1 mutants. The E302A307E318 mutant simulating the early phosphorylation pattern resulted in a significant increase in Akt and glycogen synthase kinase 3 phosphorylation. Furthermore, glucose uptake was enhanced. Because the down-regulation of the insulin signal was not affected, this phosphorylation pattern seems to be involved in the enhancement but not in the termination of the insulin signal. This enhancing effect was completely absent when Ser-302 was unphosphorylated and Ser-307 was phosphorylated as simulated by the A302E307E318 mutant. Phospho-Ser-318, sequentially phosphorylated at least by protein kinase C-zeta and a mammalian target of rapamycin/raptor-dependent kinase, was part of the positive as well as of the subsequent negative phosphorylation pattern. Thus we conclude that insulin stimulation temporally generates different phosphorylation statuses of the same residues that exert different functions in insulin signaling.
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PMID:Interplay and effects of temporal changes in the phosphorylation state of serine-302, -307, and -318 of insulin receptor substrate-1 on insulin action in skeletal muscle cells. 1892 38


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