Gene interactions and pathways from curated databases and text-mining

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AKT2 — MTOR

Pathways - manually collected, often from reviews:

Text-mined interactions from Literome

Gangoiti et al., Biochimie 2012 : The mitogenic action of C1P also involved activation of phosphatidylinositol 3-kinase/Akt , ERK1/2 and the mammalian target of rapamycin
Evren et al., Prostate 2010 (Adenocarcinoma...) : mTOR is activated by AKT phosphorylation ( p-mTOR )
Xue et al., Arterioscler Thromb Vasc Biol 2009 (Neovascularization, Pathologic) : Rapamycin ( 0.5 mg/kg/d ) effectively inhibited mTOR and downstream S6K1 signaling and partially inhibited Akt signaling, likely through effects on TORC2
Hahn-Windgassen et al., J Biol Chem 2005 : Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity ... However, the mechanism by which Akt activates mTOR is not fully understood ... The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR ... Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR ... Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2 ... We propose that the activation of mTOR by Akt mediated cellular energy and inhibition of AMPK is the predominant pathway by which Akt activates mTOR in vivo
Villa-Cuesta et al., PloS one 2011 (Carcinoma, Hepatocellular...) : The effects on mTOR signaling were independent of effects on AMP activated kinase or AKT
Sunavala-Dossabhoy et al., BMC molecular biology 2004 : The activation of mTOR was likely due to the rapid activation of Akt following radiation
Sini et al., Autophagy 2010 (Neoplasms) : mTORC2 activates AKT directly by phosphorylating Serine 473
Wang et al., Science signaling 2009 (Cardiovascular Diseases...) : Rapamycin treatment of diet induced obese mice or of transgenic mice with long-term activation of endothelial Akt inhibits activation of mammalian target of rapamycin (mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke ... Rapamycin treatment of diet induced obese mice or of transgenic mice with long-term activation of endothelial Akt inhibits activation of mammalian target of rapamycin (mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke
Edinger et al., Cancer Res 2003 : Whereas kinase-inactive mTOR did not enhance the decreases in cell size and glycolysis induced by rapamycin, expression of this mTOR mutant significantly enhanced the inhibitory effects of rapamycin on cell proliferation, 4EBP1 phosphorylation, and Akt activity
Magri et al., Cell stem cell 2011 (Epilepsy...) : Notably, mTORC1 dependent Akt inhibition and STAT3 activation were involved in the reduced self-renewal and earlier neuronal and astroglial differentiation of mutant NSCs
Saba et al., J Investig Med 2012 (Acquired Immunodeficiency Syndrome...) : Protein kinase C-beta-selective inhibition was observed not to affect AKT phosphorylation but to induce a rapid and sustained reduction in the phosphorylation of glycogen synthase kinase-3 beta, ribosomal protein S6, and mammalian target of rapamycin in sensitive cell lines
Misra et al., J Cell Biochem 2012 (Prostatic Neoplasms) : We measured mTORC2 dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells ... These studies represent the first report that Epac1 mediates mTORC2 dependent phosphorylation of Akt ( S473 )
Melnik et al., Exp Dermatol 2013 : Antiandrogens may attenuate mTORC1 by suppressing mTORC2 mediated Akt/TSC2 signalling
Roudier et al., Mol Cancer Ther 2006 (Carcinoma, Hepatocellular...) : Statins induce mammalian target of rapamycin (mTOR) mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs ... It was found that insulin- and cytostatic drug induced Akt phosphorylation and nuclear translocation was inhibited by pravastatin and atorvastatin in HepG2, A549, and H1299 cells in an mTOR dependent manner ... Taken together, these data suggest that a mTOR dependent , statin induced inhibition of Akt phosphorylation and nuclear translocation sensitizes cells to cytostatic drugs
Lodeiro et al., PloS one 2009 : This beta-arrestin scaffolded complex leads to full activation of Akt through PDK1 and mTORC2 , which are not associated to the complex
Masri et al., Cancer Res 2007 (Brain Neoplasms...) : mTORC2 has recently been shown to phosphorylate and activate Akt
Ma et al., Breast Cancer Res Treat 2013 (Breast Neoplasms...) : In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor ( IGF-1R )
Pang et al., World J Gastroenterol 2013 : Furthermore, TM treatment also activated mTORC1 , and in turn reduced Akt phosphorylation, which suggested the PI3K/Akt/mTOR signal pathway was involved in the TM-induced autophagic response in EC109 cells
Park et al., Haematologica 2010 (Leukemia, Myeloid, Acute) : However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells ... However, as mTORC1 activation is independent of PI3K/AKT in acute myeloid leukemia, dual PI3K and mTOR inhibitors may induce apoptosis in blast cells
Facchinetti et al., EMBO J 2008 : Here, we demonstrate that mTOR , SIN1 and rictor, components of mammalian ( m)TORC2, are required for phosphorylation of Akt and conventional protein kinase C ( PKC ) at the turn motif ( TM ) site
Jung et al., J Nutr Biochem 2013 : The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt dependent manner
Harston et al., Am J Physiol Heart Circ Physiol 2011 (Hypertrophy) : Another molecular keystone involved in the hypertrophic growth process is the mammalian target of rapamycin (mTOR), which forms two distinct functional complexes : mTORC1 that activates p70S6 kinase-1 to enhance protein synthesis and mTORC2 that activates Akt to promote cell survival
Murata et al., J Biol Chem 2011 (Neuroblastoma...) : A new cytosolic pathway from a Parkinson disease associated kinase, BRPK/PINK1 : activation of AKT via mTORC2 ... Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 ( mTORC2 ) by PINK1
Murayama et al., Br J Cancer 2009 (Adenocarcinoma...) : We evaluated the correlation of mTOR expression with clinicopathological features, outcomes, and the expression of Akt , an upstream regulator of mTOR , in gastric cancer
Dunaway et al., Mol Cell Biol 2011 : Slit2 stimulates angiogenesis through mTORC2 dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1
Dan et al., J Immunol 2008 : mTOR is negatively controlled by the tuberous sclerosis complex 1/2 (TSC1/2), and activation of Akt induces phosphorylation of TSC2, which blocks the repressive TSC1/2 activity ... Insulin activation of mTOR requires Akt in a manner that involves IKKalpha, preferentially to IKKbeta, and TSC2 phosphorylation ... In MCF7 cells, TNF does not activate Akt and requires IKKbeta to activate mTOR
Faghiri et al., Exp Eye Res 2010 : Inhibition of PI3K or mTOR/p70S6K by wortmannin and rapamycin, respectively, increased apoptosis and inhibited phosphorylation of Akt and p70S6K induced by single-dose oxidative stress
Lee et al., Carcinogenesis 2010 (Colonic Neoplasms) : Suppression of mTOR via Akt dependent and -independent mechanisms in selenium treated colon cancer cells : involvement of AMPKalpha1 ... In contrast, the Akt dependent mTORC1 inhibition by selenium did not require AMPKalpha ( 1 )
Kim et al., Stem Cells 2008 : E ( 2 ) -injected TIS21 ( -/- ) male mice also increased LSK cells in BM. Taken together, expansion of hematopoietic progenitors in TIS21 ( -/- ) female mice might be through inhibition of Akt activation, and constitutive activation of mTOR via preferential binding of TIS21 to E ( 2 ) -induced p-Erk1/2, compared with that of Akt
Wieman et al., Mol Biol Cell 2007 : Although Akt did not require mTOR/RAPTOR to maintain surface Glut1 levels, inhibition of mTOR/RAPTOR by rapamycin greatly diminished glucose uptake, suggesting Akt stimulated mTOR/RAPTOR may promote Glut1 transporter activity
Balasubramanian et al., Cardiovasc Hematol Agents Med Chem 2009 (Cardiomegaly) : mTORC2 regulates the actin cytoskeleton in addition to activating Akt ( Protein kinase B ) for the subsequent removal of proapoptotic factors via the UPS for cell survival
Finlay et al., J Exp Med 2012 : The present study now demonstrates that mTORC1 activity in CD8 ( + ) T cells is not dependent on PI3K or Akt but is critical to sustain glucose uptake and glycolysis in CD8 ( + ) T cells
Chang et al., Eur J Immunol 2012 : Sin1 deficiency blocks the mTORC2 dependent Akt phosphorylation in T cells during development and activation
Asnaghi et al., Oncogene 2004 : Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt
Wenner , J Cell Physiol 2012 (Neoplasms) : In addition, chemotherapeutic approaches based on Akt activated mTORC1 are described, and their relationship to the role of aerobic glycolysis in this protection
Berdichevsky et al., J Neurosci 2013 : Inhibition of PI3K and Akt prevented activation of mTOR , and was as effective as inhibition of mTOR in reducing ictal activity and cell death
Woo et al., J Biol Chem 2007 (Breast Neoplasms...) : Despite no significant effect of PRR5 on mTORC2 mediated Akt phosphorylation, PRR5 silencing inhibits Akt and S6K1 phosphorylation and reduces cell proliferation rates, a result consistent with PRR5 roles in cell growth and tumorigenesis
Majumder et al., Nat Med 2004 (Prostatic Neoplasms) : Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition
Yang et al., Cell cycle (Georgetown, Tex.) 2010 (Neoplasms) : Akt activity is well-known regulated through its phosphorylation at T308 and S473 by PDK1 and mTOrC2 , respectively
Floc'h et al., Cancer Res 2012 (Disease Models, Animal...) : In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus ( MK-8669 ) are due in part to limiting the mTORC2 feedback activation of Akt
Zitzmann et al., Cancer Lett 2010 (MAP Kinase Signaling System...) : Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual targeted therapy approaches in neuroendocrine tumor disease
Hietakangas et al., Genes Dev 2007 : Here we analyze the role of TORC2 mediated AKT phosphorylation in Drosophila
Jeon et al., Biochim Biophys Acta 2013 (Breast Neoplasms...) : Activation of Akt is enhanced by activating the mammalian target of rapamycin complex 2 ( mTORC2 ) ... When SelW was down-regulated, mTORC2 dependent phosphorylation of Akt at Ser473 was decreased
Loehberg et al., Biochem Pharmacol 2012 (Breast Neoplasms...) : The anticancer drug RAD001 ( everolimus ) is a known mTOR-inhibitor, but mTOR-inhibition leads to phosphorylation of Akt inducing resistance against RAD001 treatment
Julien et al., Mol Cell Biol 2010 : While mTOR complex 1 (mTORC1) regulates mRNA translation and ribosome biogenesis, mTORC2 plays an important role in the phosphorylation and subsequent activation of Akt ... Interestingly, mTORC1 negatively regulates Akt activation, but whether mTORC1 signaling directly targets mTORC2 remains unknown ... However, cells expressing a Rictor T1135A mutant were found to have increased mTORC2 dependent phosphorylation of Akt
Guo et al., Arterioscler Thromb Vasc Biol 2011 : According to Western blot analysis and immunoprecipitation results, rHDL promoted mTOR phosphorylation, mTOR-rictor complex formation, and mTOR-rictor dependent Akt activation, which were accompanied by increased nuclear translocation of human telomerase reverse transcriptase and enhanced nuclear telomerase activity
Zhu et al., Mol Endocrinol 2013 : One potential mechanism is PI3K- and Akt mediated activation of mechanistic target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K), which may impair insulin mediated activation of insulin receptor substrate (IRS)1/2 via inhibitory serine phosphorylation or proteasomal degradation
Vassiliadis et al., J Am Soc Nephrol 2011 : Furthermore, activation of Akt through mTOR had a direct role on glomerular barrier integrity, and activation of calcium channels mediated this process, likely independent of phosphoinositide 3-kinase
Lazorchak et al., Protein & cell 2011 (Cell Transformation, Neoplastic) : We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability
Memmott et al., Cancer prevention research (Philadelphia, Pa.) 2010 (Carcinoma...) : This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR
Bhaskar et al., Molecular neurodegeneration 2009 : Finally, our results also demonstrate that Abeta oligomer treated neurons exhibit elevated levels of activated Akt and mTOR ( mammalian Target Of Rapamycin ) and that PI3K, Akt or mTOR inhibitors blocked Abeta oligomer induced neuronal CCEs
Gulhati et al., Carcinogenesis 2012 (Colorectal Neoplasms...) : In this study, we show that inhibition of mTORC1 with rapamycin leads to feedback activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and possible contribution to rapamycin resistance
Nölting et al., J Mol Endocrinol 2012 : Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling
Wang et al., Cancer Biol Ther 2008 (Carcinoma, Renal Cell...) : However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors ' anticancer efficacy
Li et al., Int J Biochem Cell Biol 2005 (MAP Kinase Signaling System) : Here we tested the hypothesis that PI3K/Akt mediated inactivation of GSK-3beta and activation of mTOR contribute to the anabolic effects of IGF-I in dexamethasone treated myotubes ... Our results suggest that PI3K/Akt mediated inactivation of GSK-3beta and activation of mTOR contribute to the anabolic effects of IGF-I in dexamethasone treated myotubes
Cai et al., Biochem Pharmacol 2008 : It is unknown whether Akt activation can counteract AMPK mediated apoptosis, nor whether mTOR activation downstream of Akt mediates any survival signal in these conditions
Zeng et al., Blood 2007 (Leukemia, Myeloid, Acute) : Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML
Meric-Bernstam et al., Clin Cancer Res 2012 (Breast Neoplasms...) : Cancer cell lines were tested for rapamycin sensitivity, Akt phosphorylation, and mTOR target inhibition
Rodrik-Outmezguine et al., Cancer Discov 2011 : mTOR kinase inhibition causes feedback dependent biphasic regulation of AKT signaling ... mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin ... Inhibition of mTORC2 leads to AKT serine 473 ( S473 ) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling
Cleveland-Donovan et al., Endocrinology 2010 (Obesity) : 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 ... 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
Dhingra et al., Circ Heart Fail 2013 : Akt activates the kinase mammalian target of rapamycin (mTOR) , which mediates important processes such as cardiac hypertrophy
Dan et al., Genes Dev 2008 (Prostatic Neoplasms) : Akt dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK
Faried et al., Oncol Rep 2006 (Neoplasm Metastasis...) : Activation of Akt was detected in the cytoplasm and nucleus of the cancer cells in 12 patients ( 48 % ), whereas p-mTOR was detected in the cytoplasm and membrane of the cancer cells in 13 patients ( 52 % )
Sanchez Canedo et al., Am J Physiol Endocrinol Metab 2010 : Moreover, the introduction in PDK1 of the L155E mutation, which is known to preserve the insulin induced and PKB/Akt dependent phosphorylation of mTOR/p70 ( S6K ), suppressed all leucine effects, including phosphorylation of mTOR, PRAS40, and p70 ( S6K )
Matheny et al., Growth Factors 2012 : Enhanced Akt phosphorylation and myogenic differentiation in PI3K p110ß-deficient myoblasts is mediated by PI3K p110a and mTORC2
Moore et al., J Biol Chem 2011 (MAP Kinase Signaling System) : In this study, we investigated the role of the mammalian target of rapamycin complex ( mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1
Hong et al., Mol Cell 2008 (Melanoma) : mTOR overexpression activated both Akt and SGK1, causing TGF-beta resistance through impaired nuclear import and cytoplasmic accumulation of p27
Fischer et al., Lung Cancer 2012 (Mesothelioma...) : The PI3K/mTOR inhibitor NVP-BEZ235 and PI3K inhibitor wortmannin reduced the phosphorylation of downstream target AKT , S6 and 4EBP1 and decreased the SP fraction
Li et al., Cancer Immunol Immunother 2011 : Rapamycin inhibited these phosphorylation events without impacting Akt or Erk activation, even though specific inhibition of Akt or Erk in turn reduced the activation of mTOR
Aoki et al., Nat Genet 2003 (Chromosomal Instability...) : Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells
Wolin , Cancer Lett 2013 (Neuroendocrine Tumors...) : The mTOR inhibitor everolimus has been approved by the FDA for the treatment of pNET, but its efficacy may be limited by its inability to prevent mTORC2 mediated activation of Akt
Zhang et al., Translational oncology 2012 : Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer
McDonald et al., Cancer Res 2008 (Breast Neoplasms...) : Depletion of ILK and rictor in breast and prostate cancer cell lines resulted in inhibition of Akt Ser ( 473 ) phosphorylation and induction of apoptosis, whereas, in several cell lines, depletion of mTOR increased Akt phosphorylation
Pearce et al., Biochem J 2011 : Both complexes phosphorylate the hydrophobic motifs of AGC kinase family members : mTORC1 phosphorylates S6K ( S6 kinase ), whereas mTORC2 regulates phosphorylation of Akt , PKCa ( protein kinase Ca ) and SGK1 ( serum- and glucocorticoid induced protein kinase 1 )
Zhang et al., Proc Natl Acad Sci U S A 2012 : GPAT1 overexpression impaired insulin stimulated phosphorylation of Akt-S473 and -T308, diminished insulin-suppression of glucose production, significantly inhibited mTOR complex 2 (mTORC2) activity and decreased the association of mTOR and rictor
Matheny et al., Biochem Biophys Res Commun 2009 : Our results collectively suggest that mTOR/p70S6K is activated in a PI3K/Akt dependent manner, but that in the absence of p110alpha or Akt, alternate pathway ( s ) may mediate activation of mTOR/p70S6K in C2C12 myoblasts
Kato et al., Cell Death Differ 2012 (MAP Kinase Signaling System) : Activation of mTORC1 reduced Akt phosphorylation, which was an event upstream of IRE-JNK signaling and consequent apoptosis ... These results disclosed that, under ER stress conditions, mTORC1 causes apoptosis through suppression of Akt and consequent induction of the IRE1-JNK pathway
Naing et al., Clin Cancer Res 2011 (Neoplasms) : Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type 1 insulin-like growth factor receptor ( IGF-1R ) -dependent mechanism
Breuleux et al., Mol Cancer Ther 2009 (Neoplasms) : Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition
Feldman et al., PLoS Biol 2009 : Unlike rapamycin, these TORKinibs ( PP242 and PP30 ) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation
Brito et al., Atherosclerosis 2009 (Atherosclerosis) : The activation of mTOR signaling by oxLDL, requires the upstream activation of PI3K and Akt , as assessed by the inhibitory effect of the PI3K inhibitor Ly294002 on mTOR activation and DNA synthesis
Giménez-Xavier et al., Int J Mol Med 2008 (Neuroblastoma) : While the PI3K-mTOR pathway was inhibited by serum deprivation, dopamine increased the phosphorylation of Akt but inhibited mTOR activity in a similar way to rapamycin
Riaz et al., PloS one 2012 : RICTOR-mTOR was required also for LPA induced AKT Ser473 phosphorylation in MCF7 cells, but, interestingly, not in HeLa cells
Mazzoletti et al., Cancer Res 2011 : At the molecular level, combined inhibition of mTOR prevented the rebound activation of Akt that is seen after treatment with rapamycin and its analogues and caused more sustained inhibition of Akt phosphorylation
Wang et al., Cancer Res 2008 (Lung Neoplasms) : It has been shown that mammalian target of rapamycin (mTOR) inhibitors activate Akt while inhibiting mTOR signaling ... Collectively, we conclude that inhibition of the mTOR/raptor complex initiates Akt activation independent of mTOR/rictor
Wu et al., Urol Oncol 2012 (Carcinoma, Transitional Cell...) : The present findings also suggest rictor dependent AKT activation as a consequence of mTORC1 inhibition
Riaz et al., J Biol Chem 2013 : Protein suppression using specific siRNAs revealed that heparanase induced phosphorylation of AKT at Ser-473 was RICTOR-mTOR dependent , whereas ILK and PAK1/2 were dispensable
Castillo-Pichardo et al., Nutr Cancer 2012 (Breast Neoplasms) : RQC was found to reduce Akt activity, induce the activation of AMPK, and inhibit mTOR signaling in breast cancer cells
Razmara et al., Cell communication and signaling : CCS 2013 : Platelet derived growth factor induced Akt phosphorylation requires mTOR/Rictor and phospholipase C-?1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D ... mTORC1 is activated in a PLD dependent manner and promotes phosphorylation of the S6 protein, whereas mTORC2 , in concert with PLC? signaling, promotes Akt phosphorylation
Law et al., BMC complementary and alternative medicine 2012 (Anoxia...) : Among the Akt/mTOR signal transduction molecules being examined, AST caused PTEN upregulation, reduction in Akt phosphorylation and subsequent activation of mTOR
Li et al., J Endocrinol 2005 : Rapamycin significantly enhanced Akt phosphorylation whereas it inhibited mTOR phosphorylation
Hwang et al., BMB Rep 2011 (Ischemia) : The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt ... The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt ... From Drosophila to humans, mTOR is necessary for Ser473 phosphorylation of Akt , and the regulation of Akt-mTOR signaling pathways may have a potential role in ischemic disease
Koh et al., Endocr Relat Cancer 2012 (Carcinoma...) : Cells treated with everolimus demonstrated activation of Akt and Ret via TORC2 complex dependent and TORC2 complex independent mechanisms respectively
Riesterer et al., Oncogene 2004 : Inhibition of the VEGF receptor and PKB/Akt-downstream PIK related mTOR-kinase by rapamycin also neutralized the VEGF-protective effect in an PKB/Akt gene expression independent way but results in proteolysis dependent reduction of PKB/Akt protein stability
Parrales et al., Cell Signal 2013 : Since Akt functions as an upstream activator of mechanistic target of rapamycin complex 1 ( mTORC1 ) and is also a downstream target for mTORC2 , the aim of this work was to determine whether mTOR is involved in thrombin induced RPE cell proliferation by regulating cyclin D1 expression in immortalized rat RPE-J cell line
Sekulić et al., Cancer Res 2000 : Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells
Edelstein et al., Neurosci Lett 2012 (Neuroblastoma) : These findings suggested that PP2A inhibition uncouples the regulation of Akt signaling by mTOR and affects cell survival ... We therefore examined the effects of mTOR inhibition on Akt phosphorylation at sites threonine 308 ( T308 ) and serine 473 ( S473 ) and survival in OA treated cells
O'Reilly et al., Cancer Res 2006 : mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt ... We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001
Puli et al., Neurochem Res 2010 (Glioblastoma) : In this study we investigated the effect of combination treatment of rapamycin with isoflavones such as genistein and biochanin A on mTOR pathway and activation of Akt and eIF4E in human glioblastoma ( U87 ) cells
Alam et al., Endocrinology 2009 : These results indicate that FSH stimulated HIF-1 activation leading to up-regulation of targets such as vascular endothelial growth factor requires not only PI3-kinase/AKT mediated activation of mammalian target of rapamycin as well as phosphorylation of FOXO1 and possibly MDM2 but also a protein ( kinase ) activity that is inhibited by the classic ERK kinase inhibitor PD98059 but not ERK1/2 or 5
Lishner et al., Cell Signal 2008 (Multiple Myeloma) : Akt and mTOR afford attractive therapeutic targets in cancer yet, due to pathways ' interactions, inhibitors of mTOR frequently activate Akt and vise versa
Espona-Fiedler et al., Biochem Pharmacol 2012 (Melanoma) : The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308 ... The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308
Banerjee et al., Mol Cancer Ther 2011 (Disease Models, Animal...) : Third, the incomplete suppression of Nf1-deficient glial cell proliferation in vivo following 5 mg/kg/day rapamycin treatment reflects mTOR mediated AKT activation , such that combined 5 mg/kg/day rapamycin and PI3-kinase (PI3K) inhibition or dual PI3K/mTOR inhibition recapitulates the growth suppressive effects of 20 mg/kg/day rapamycin
Vanderweele et al., Mol Cancer Res 2005 : We show that dominant negative mTOR diminishes phosphorylation of endogenous Akt and exogenous myristoylated Akt ( mAkt ), that prolonged exposure to rapamycin also inhibits Akt activation, and that this inhibition is dependent on new protein synthesis
Zha et al., Cancer Lett 2011 (Cell Transformation, Neoplastic) : Aberrant activation of mammalian target of rapamycin complex 1 ( mTORC1 ), caused by loss or inactivation of TSC1/TSC2 protein complex, leads to negative feedback inhibition of Akt
Das et al., J Biol Chem 2012 (Tuberous Sclerosis) : TSC2 deficiency induces constitutive activation of mTOR , leading to a state of insulin resistance due to a negative feedback regulation, resulting in reduced Akt phosphorylation
Liu et al., Mol Cancer Ther 2012 (Lung Neoplasms) : Inhibition of mTOR signaling by rapamycin has been shown to activate extracellular signal regulated kinase 1 or 2 ( ERK1/2 ) and Akt in various types of cancer cells, which contributes to rapamycin resistance
Liu et al., Head Neck 2011 (Carcinoma, Squamous Cell...) : However, mTOR inhibitors also increase Akt activity in SCCHN cell lines, which would promote survival and oncogenesis
Chen et al., Mol Carcinog 2010 (Neoplasms) : In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors ... In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors ... Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin based therapeutic approaches in cancer cells
Holland et al., Cancer Chemother Pharmacol 2012 (Carcinoma, Renal Cell...) : Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition
Kanamori et al., Am J Pathol 2013 (Heart Failure...) : The activities of AMP activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed
Gratia et al., Cardiovasc Res 2012 (Disease Models, Animal...) : Combined inhibition of AMPK and activation of Akt and MAPK lead to activation of growth stimulating mammalian target of rapamycin (mTOR) signalling
Hussain et al., Mol Cell Biol 2013 : Raptor bound mTOR ( mTORC1 ) governs cap dependent mRNA translation, whereas mTOR , rictor, and mSin1 ( mTORC2 ) activate the survival and proliferative kinase Akt
Gayle et al., Anticancer Agents Med Chem 2012 (Breast Neoplasms) : Pharmacologic inhibition of mTOR using rapamycin or ridaforolimus increased lapatinib sensitivity and reduced phospho-Akt levels in cells that showed poor response to single-agent lapatinib, including those transfected with hyperactive Akt
Bentzinger et al., Cell Metab 2008 (Muscular Dystrophies) : Finally, we show that activation of PKB/Akt does not require mTORC2
Dennison et al., Blood 2010 (Lymphoma, Mantle-Cell) : Given that Akt controls the activity of mammalian target of rapamycin (mTOR) , we hypothesized that 8-NH ( 2 ) -Ado would be active in mantle cell lymphoma ( MCL ), a hematological malignancy clinically responsive to mTOR inhibitors
Dibble et al., Mol Cell Biol 2009 : Although this phosphorylation event does not affect mTORC2 integrity or in vitro kinase activity, expression of a phosphorylation site mutant of Rictor ( T1135A ) in either wild-type or Rictor null cells causes an increase in the mTORC2 dependent phosphorylation of Akt on S473
Bhagwat et al., Curr Opin Investig Drugs 2010 (Neoplasms) : The discovery of the involvement of rapamycin-insensitive mTOR complex 2 (mTORC2) in the activation of Akt , combined with the limited clinical antitumor activity of mTOR complex 1 (mTORC1) directed rapamycin analogs, have led to the discovery of ATP-competitive selective inhibitors of the mTOR kinase that inhibit the function of both mTORC1 and mTORC2
Wlodarski et al., Cancer Res 2005 (Burkitt Lymphoma...) : Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt , mitogen activated protein kinase/extracellular signal regulated kinase kinase, insulin growth factor-I, and serum
Lamouille et al., J Cell Biol 2007 : This translational regulation results from activation by TGF-beta of mammalian target of rapamycin (mTOR) through phosphatidylinositol 3-kinase and Akt , leading to the phosphorylation of S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1, which are direct regulators of translation initiation
Kaur et al., Proc Natl Acad Sci U S A 2012 : We provide evidence that mTORC2 complexes control IFN induced phosphorylation of AKT on serine 473 and their function is ultimately required for IFN dependent gene transcription via interferon stimulated response elements
Najafov et al., Biochem J 2012 (Neoplasms) : Akt is activated by phosphorylation of its T-loop residue ( Thr ( 308 ) ) by PDK1 ( 3-phosphoinositide dependent kinase-1 ) and its C-terminal hydrophobic motif ( Ser ( 473 ) ) by mTORC2 [ mTOR ( mammalian target of rapamycin ) complex 2 ] ... Consistent with this, we find combing PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of all of the cell lines tested
Timmerman et al., J Clin Endocrinol Metab 2010 : During insulin infusion, blood flow and capillary recruitment increased in the control ( P < 0.05 ) group only ; Akt phosphorylation and glucose uptake increased in both groups ( P < 0.05 ), with no group differences ; and mTORC1 signaling increased more in control ( P < 0.05 ) than in L-NMMA
Cheng et al., Transplant Proc 2008 : Recently, it has been shown that Akt phosphorylation activates mammalian target of rapamycin (m-TOR) and inhibits programmed cell death including apoptosis and autophagy
Lee et al., Genes Dev 2010 : Collectively, these findings establish mTOR/rictor mediated Akt activation as a key driver of NSC proliferation and gliogenesis, and identify a unique mechanism for conferring brain region-specific responses to cancer causing genetic changes
Minhajuddin et al., J Biol Chem 2009 : Stimulation of human vascular endothelial cells with thrombin induced the phosphorylation of mTOR and its downstream target p70 S6 kinase in a PKC-delta- and PI3K/Akt dependent manner
Dormond et al., J Biol Chem 2007 : Recent studies have determined that mTOR mediates the activation of the protein kinase Akt in several cell types, but little is known about the association between mTOR and Akt in vascular endothelial cells
Urbanska et al., J Biol Chem 2012 : We also identified Akt as a downstream effector of mTORC2 needed for proper dendritic arbor morphology, the action of which required mTORC1 and p70S6K1
Tanaka et al., Clin Cancer Res 2011 (Neoplasms) : Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors
Singleton et al., Journal of angiogenesis research 2010 : Inhibition of tyrosine phosphatase activity ( 3,4-dephostatin ) blocked the synergy between MNTX and temsirolimus and increased VEGF induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR Complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR Complex 1 ( rapamycin and temsirolimus target ), while silencing Src, Akt or mTOR complex 2 components blocked VEGF induced angiogenic events
Rosel et al., J Cell Sci 2012 : TORC1 is required for growth in response to growth factors, nutrients and the cellular energy state ; TORC2 regulates AKT signaling, which can modulate cytoskeletal polarization
Bodine , Med Sci Sports Exerc 2006 : Recent work in mammals has suggested that activation of Akt/PKB , a Ser-Thr phosphatidylinositol regulated kinase, and its downstream targets, glycogen synthase kinase-3 ( GSK3 ) and the mammalian target of rapamycin (mTOR) , may be critical regulators of postnatal cell size in multiple organ systems, including skeletal muscle
Sarbassov et al., Mol Cell 2006 : mTORC2 phosphorylates and activates Akt/PKB , a key regulator of cell survival
Vega et al., Cancer Res 2006 (Lymphoma, Large B-Cell, Diffuse) : We also show that AKT activation contributes to mTOR phosphorylation, at least in part, as forced expression of constitutively active AKT by myristoylated AKT adenovirus results in increased phosphorylation of mTOR and its downstream effectors ... Conversely, inhibition of AKT expression or activity results in decreased mTOR phosphorylation
White et al., Mol Cell Endocrinol 2013 : Testosterone ( T ) sensitivity of Akt/mTORC1 signaling was examined in C ( 2 ) C ( 12 ) myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling ... Acute Akt activation in C ( 2 ) C ( 12 ) myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt
Chung et al., J Endocrinol 2013 (MAP Kinase Signaling System) : Our data also suggest that PI3K/Akt mediated inactivation of GSK-3ß and activation of mTOR/p70 ( S6K ) contribute to the proliferative effect of ghrelin
Zhang et al., Mol Cell 2006 : S6K1 regulates GSK3 under conditions of mTOR dependent feedback inhibition of Akt
Wang et al., PloS one 2013 : Western blotting showed that the PP242 inhibition of mTORC2 mediated AKT phosphorylation at Ser 473 ( AKT ( S473 ) ) was transient only in the first few hours of the PP242 treatment
Winter et al., Am J Physiol Cell Physiol 2011 : Previous studies have shown that, in part, Akt and ERK promote mTORC1 signaling through phosphorylation of a GTPase activator protein (GAP), referred to as tuberous sclerosis complex 2 (TSC2), that acts as an upstream inhibitor of mTORC1
Yu et al., Mol Cancer Ther 2008 : Overexpression of constitutively activated Akt or disruption of TSC1-TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin mediated inhibition of Akt/mTOR signaling
Vadlakonda et al., Frontiers in oncology 2013 : We present in this article, a hypothesis that activation of Akt-T308 phosphorylation in the presence of high ATP : AMP ratio promotes the stability of its phosphorylations and activates mTORC1 and the energy consuming biosynthetic processes
Ma et al., Genes Dev 2005 (Cell Transformation, Neoplastic...) : The PTEN and TSC2 tumor suppressors function to antagonize mTOR ( mammalian target of rapamycin ) activation by Akt ; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner
Sun et al., Cancer Res 2005 (Carcinoma, Non-Small-Cell Lung...) : Activation of Akt and eIF4E survival pathways by rapamycin mediated mammalian target of rapamycin inhibition
Meikle et al., J Neurosci 2008 (Disease Models, Animal...) : Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors : effects on mTORC1 and Akt signaling lead to improved survival and function
Moschella et al., Cell Signal 2013 : mTOR complex 2 mediates Akt phosphorylation that requires PKCe in adult cardiac muscle cells ... Since mTORC2 is known to mediate the activation of a prosurvival kinase, Akt, we analyzed whether mTORC2 directly mediates Akt activation or whether it requires the participation of another prosurvival kinase, PKCe ( epsilon isoform of protein kinase-C )
Werzowa et al., Br J Dermatol 2009 (Melanoma...) : Inhibition of mTORC2 led to reduced levels of phosphorylated AKT
Shi et al., Mol Cancer Ther 2005 (Multiple Myeloma) : Thus, mTOR inhibitors activate PI3-K/AKT in multiple myeloma cells ; activation depends on basal IGF-R signaling ; and enhanced IRS-1/IGF-I receptor interactions secondary to inhibited IRS-1 serine phosphorylation may play a role in activation of the cascade
Razeghi et al., Circulation 2003 (Atrophy...) : This activation was independent of Akt , a known upstream regulator of mTOR
Zou et al., Int J Mol Med 2009 (Carcinoma, Non-Small-Cell Lung...) : In the present study, clear antitumor activity was observed with PI-103 treatment in two gefitinib-resistant non-small cell lung cancer ( NSCLC ) cell lines, A549 and H460, by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition
Pollizzi et al., Molecular cancer 2009 (Disease Models, Animal...) : Recent studies indicate that inhibition of mTORC1 with RAD001 ( everolimus ) leads to rebound activation of AKT , which could protect tumors from drug induced cell death
Pantovic et al., Bone 2013 : AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation
Ögmundsdóttir et al., PloS one 2012 : Mammalian Target of Rapamycin Complex 1 ( mTORC1 ) is activated by growth factor regulated phosphoinositide 3-kinase (PI3K)/Akt/Rheb signalling and extracellular amino acids ( AAs ) to promote growth and proliferation
Hiraoka et al., Oncogene 2011 : A well conserved threonine in the turn motif ( TM ) is also constitutively phosphorylated by mTORC2 and contributes to the stability of Akt
Tzatsos , J Biol Chem 2009 : In normal physiological states mTOR phosphorylates and activates Akt ... However, under diabetic mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639 ... The molecular basis for the differential effect of mTOR signaling on Akt is poorly understood ... Overall, these data provide new insights in the molecular mechanisms by which mTORC1 inhibits PI 3-kinase/Akt signaling at the level of IRS-1 and suggest that mTOR signaling toward Akt is scaffold dependent
Li et al., J Biol Chem 2013 : Inhibition of mammalian target of rapamycin complex 1 ( mTORC1 ), for example with rapamycin, increases Akt phosphorylation while inhibiting mTORC1 signaling ... Accordingly, simultaneous inhibition of mTOR and DNA-PK did not stimulate Akt activity and synergistically inhibited the growth of cancer cells both in vitro and in vivo
Tao et al., Journal of molecular signaling 2010 : Our present study demonstrates that AMPK exerts dual effects on the PI3K pathway, stimulating PI3K/Akt and inhibiting mTOR/S6K
Fang et al., J Biol Chem 2012 (Prostatic Neoplasms) : Significantly, androgen increased TORC2 mediated AKT S473 phosphorylation without affecting the PDK1 mediated AKT T308 phosphorylation or TORC1 activity ... This study reveals a pathway linking AR to a selective activation of TORC2 , the subsequent activation of AKT , and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival
Gupta et al., Blood 2012 (Lymphoma) : Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma dependent apoptosis in lymphoid malignancies ... Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma dependent apoptosis in lymphoid malignancies
Hietakangas et al., BMC cancer 2008 (Breast Neoplasms...) : TOR complex 2 (TORC2) activates AKT by phosphorylating it on the ` hydrophobic motif ' site
Willems et al., Leukemia 2012 (Leukemia, Myeloid, Acute) : In addition, the mTORC1 dependent PI3K/Akt feedback activation was fully abrogated in AZD8055 treated AML cells
Sajjad et al., Endocr Pathol 2013 (Growth Hormone-Secreting Pituitary Adenoma...) : mTOR kinase phosphorylation was independent of Erk and Akt in primary cultures
Shortt et al., Blood 2013 (Lymphoma, B-Cell) : Moreover, apoptosis was initiated at drug concentrations insufficient to antagonize PI3K/mTORC2 regulated AKT phosphorylation
Mallon et al., Mol Cancer Ther 2010 : We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt , induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models
Keniry et al., Cancer Discov 2011 : mTOR inhibition with the ATP-competitive kinase inhibitor AZD8055 induces receptor tyrosine kinase dependent feedback activation of AKT
Lee et al., PloS one 2010 (Endotoxemia) : Furthermore, in vitro cellular studies demonstrated that LPS ( lipopolysaccharide ) activation of mTORC1-S6K still occurs in the presence of PI3K-Akt inhibition alone, but can be suppressed by concurrent inhibition of PI3K-Akt and MEK-ERK pathways
Reyes-Gordillo et al., Am J Pathol 2011 (Liver Cirrhosis) : The lack of AKT phosphorylation was not due to the inhibition of PDGF-ßr phosphorylation, the activation of phosphoinositide 3-kinase (PI3K), pyruvate dehydrogenase kinase isozyme 1 ( PDK1 ), and mammalian target of rapamycin (mTOR)
Deeb et al., Prostate 2009 (Prostatic Neoplasms) : Silencing of Akt sensitized the PC-3 cells to CDDO-Me, whereas overexpression of Akt induced resistance to CDDO-Me. Targeted silencing of Akt showed that Akt does not regulate mTOR activation in PC-3 cells, but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition
Kim et al., J Pharmacol Exp Ther 2004 : The phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin and LY294002 [ 2- ( 4-morpholinyl ) -9-phenyl-4H-1-benzopyran-4-one ], dominant negative Akt , or rapamycin, an inhibitor of mTOR ( mammalian target of rapamycin ) and ribosomal p70 S6 kinase (p70S6K) phosphorylation, inhibited the insulin mediated increase in GCLC protein and GSH levels
Liao et al., J Cell Sci 2010 : Chemotactic activation of Dictyostelium AGC-family kinases AKT and PKBR1 requires separate but coordinated functions of PDK1 and TORC2
Boulbés et al., Biochem Biophys Res Commun 2011 : Based on our study we suggest that the mTORC2 dependent phosphorylation of Akt on Ser-473 takes place on the surface of ER
Gallagher et al., Oncogene 2012 (Cell Transformation, Neoplastic...) : We also investigated the effect of targeted PI3K/mTOR inhibition on PI3K/Akt/mTOR and Erk1/2 signaling, and the potential effects on glycemia
Yu et al., Cancer Res 2010 (Neoplasms) : Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT ( S473 ) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT ( T308 ), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells
Wang et al., Mol Cell Biol 2012 (Dermatitis, Seborrheic) : Surprisingly, however, TORC2 does not regulate cell growth via its best characterized target, AKT