Gene interactions and pathways from curated databases and text-mining

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Pathways - manually collected, often from reviews:

Protein-Protein interactions - manually collected from original source literature:

Studies that report less than 10 interactions are marked with *

Text-mined interactions from Literome

Zhang et al., Cancer Biol Ther 2009 : PIM1 protein kinase overexpression reduced the association of PRAS40 with mTOR, and increased the mTOR directed phosphorylation of 4EBP1 and p70S6Kinase
Chen et al., Lab Invest 2010 : Here, we show that hydrogen peroxide ( H ( 2 ) O ( 2 ) ), a major oxidant generated when oxidative stress occurs, induced apoptosis of neuronal cells ( PC12 cells and primary murine neurons ), by inhibiting the mammalian target of rapamycin (mTOR) mediated phosphorylation of ribosomal p70 S6 kinase ( S6K1 ) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 ( 4E-BP1 )
Shen et al., International journal of clinical and experimental pathology 2010 (Carcinoma, Endometrioid...) : mTORC1 and mTORC2 phosphorylatively regulate their respective downstream effectors p70S6K/4EBP1 , and Akt ... mTORC1 and mTORC2 phosphorylatively regulate their respective downstream effectors p70S6K/4EBP1 , and Akt
Herbert et al., J Biol Chem 2002 : In conclusion, the Erk pathway, via mechanisms also requiring mTOR , regulates the phosphorylation of multiple sites in 4E-BP1 in vivo and this is sufficient for the release of 4E-BP1 from eIF4E
Kuehn et al., J Biol Chem 2011 : In mouse bone marrow derived mast cells, PGE ( 2 ) was found to induce activation of mTORC1 ( mTOR complexed to raptor ) as indicated by increased p70S6K and 4E-BP1 phosphorylation, and activation of mTORC2 ( mTOR complexed to rictor ), as indicated by increased phosphorylation of AKT at position Ser ( 473 )
Han et al., Cancer Res 2006 (Carcinoma, Non-Small-Cell Lung...) : Rapamycin, an inhibitor of mTOR , blocked the fibronectin induced phosphorylation of p70S6K and 4E-BP1
Dunlop et al., Cell Signal 2009 : Interestingly, we show that a point mutation in the highly conserved Raptor RNC domain still allows binding to mTOR but prevents Raptor association and mTOR dependent phosphorylation of 4E-BP1 , indicating that this Raptor domain facilitates substrate recognition by mTORC1
Chotechuang et al., Am J Physiol Endocrinol Metab 2009 : As expected, branched-chain AAs ( BCAA ) or leucine stimulated the phosphorylation of mTOR , but both insulin and BCAA or leucine are required for 4E-BP1 phosphorylation
Mita et al., Cancer Biol Ther 2003 (Neoplasms) : Since mTOR activates both the 40S ribosomal protein S6 kinase ( ( p)70(s6k ) ) and the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) , RAP blocks activation of these downstream signaling elements, which results in cell cycle arrest in the G1 arrest
Rhein et al., Ann Hematol 2011 (Leukemia, Experimental) : However, Rapamycin did not completely inhibit mTORC1 dependent phosphorylation of 4E-BP1
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
Akcakanat et al., Biochem Biophys Res Commun 2007 : mTORC1 is rapamycin-sensitive, and results in phosphorylation of 4E-BP1 and S6K1
Galbaugh et al., BMC cell biology 2006 : But lower levels of PI-3-K and mTOR inhibitors were required to block insulin induced phosphorylation of RPS6 than EGF induced phosphorylation, and insulin induced phosphorylation of elF4E and 4E-BP1 was not completely mTOR dependent suggesting some diversity of signaling for EGF and insulin
Oh et al., J Virol 2006 (Uterine Cervical Neoplasms) : The mTOR kinase inhibitor rapamycin blocked phosphorylation of 4E-BP1 and significantly decreased the level of E7 protein in Caski cells, suggesting that phosphorylation of 4E-BP1 is linked to E7 expression
Chuluunbaatar et al., Genes Dev 2010 (Herpes Simplex) : Viruses producing methyl-7 ( m7 ) GTP capped mRNAs, like Herpes Simplex Virus-1 ( HSV-1 ), stimulate cap dependent translation by activating mTORC1 to inhibit the translational repressor 4E-binding protein 1 (4E-BP1)
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
Wong et al., Biochem Biophys Res Commun 2013 : Thus, we found that inhibiting mTORC1 dependent 4E-BP1 phosphorylation mimics the effect of hypoxia on TXNIP expression
Riemenschneider et al., Cancer Res 2006 (Glioblastoma) : mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression ( i.e., phosphorylation ) of 4E-BP1 , leading to cell cycle progression and inhibition of apoptosis
Liu et al., J Biol Chem 2013 : Although it has been demonstrated previously that the phosphorylation of 4E-BP1 is controlled by mammalian target of rapamycin in the mammalian target of rapamycin complex 1, the mechanism underlying the dephosphorylation of 4E-BP1 remains elusive
Pourdehnad et al., Proc Natl Acad Sci U S A 2013 (Cell Transformation, Neoplastic) : Using a pharmacogenetic approach, we find that mTOR dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc dependent tumor initiation and maintenance ... We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers
Martín et al., Biochem J 2000 (Anoxia...) : Rapamycin, the inhibitor of mammalian target of rapamycin ('mTOR') , but not PD98059, the inhibitor of extracellular signal regulated protein kinases ( ` ERK1/2 ' ), induced similar effects on 4E-BP1 phosphorylation to ischaemia ; nevertheless, 4E-BP1-eIF4E complex levels were higher in ischaemia than in rapamycin treated cells
Hara et al., J Biol Chem 1997 : We show herein that such mTOR mutants also protect eIF-4E BP1 against rapamycin induced dephosphorylation, and for both p70 S6 kinase and eIF-4E BP1 , such protection requires that the rapamycin-resistant mTOR variant retains an active catalytic domain
Yip et al., Mol Cell 2010 : Extended incubation with FKBP12-rapamycin compromises the structural integrity of mTORC1 in a stepwise manner, leading us to propose a model in which rapamycin inhibits mTORC1 mediated phosphorylation of 4E-BP1 and S6K1 through different mechanisms
Beugnet et al., J Biol Chem 2003 : The RAIP motif thus promotes the mTOR dependent phosphorylation of multiple sites in 4E-BP1 independently of the 4E-BP1/raptor interaction
Dunlop et al., Autophagy 2011 : Despite this evidence for heightened mTORC1 kinase activity following ULK1 overexpresssion, mTORC1 mediated phosphorylation of S6K1 and 4E-BP1 is significantly inhibited
Montero et al., Mol Cancer Ther 2012 (Ovarian Neoplasms) : Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive
Kakigi et al., J Physiol Sci 2011 (MAP Kinase Signaling System) : HS significantly increased the phosphorylation of Akt/PKB, mTOR , and ribosomal protein S6 at 1 h after exercise ( P < 0.05 ), and the 4E-BP1 phosphorylation level, which had initially decreased with exercise, had recovered by 1 h after exercise with HS
Kuang et al., Biochem Biophys Res Commun 2009 (Lymphoma...) : Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes
Kam et al., FASEB J 2004 : Mitogens activate protein translation through phosphorylation of p7S6 kinase ( p70 ( S6K ) ) and eIF4E binding protein 1 ( 4E-BP1 ) mediated by the mammalian target of rapamycin (mTOR) or phosphoinositide 3-kinase (PI3K)
Argadine et al., Am J Physiol Cell Physiol 2011 : Phosphorylation of their downstream effector mTOR ( Ser2481 ) did not change at any time point after DNV, and phosphorylated p70S6K and eIF4E binding protein 1 ( 4EBP1 ) increased only by DNV-5D
Prabhu et al., Oncogene 2007 (Leukemia, Myelogenous, Chronic, BCR-ABL Positive) : In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation ( inactivation ) of 4E-BP1 , an inhibitor of the eIF4E translation initiation factor
Wang et al., J Biol Chem 2006 : The stimulatory effects of insulin on both 4EBP1 kinase activity and binding occurred rapidly and at physiological concentrations of insulin, and both effects required an intact mTORC1
Tomiya et al., Biochem Biophys Res Commun 2007 : Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) , suppressed leucine induced activation of p70 S6 kinase and 4E-BP1 and negated the stimulatory effect of leucine on HGF production
Southgate et al., J Biol Chem 2007 : FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle
Tinton et al., FEBS Lett 1999 : This enhanced association of 4E-BP1 with eIF-4E might be mediated by mTOR
Schalm et al., Curr Biol 2002 : The molecular basis of mTOR regulation of S6K1 and 4E-BP1 remains controversial
Gibbons et al., Semin Oncol 2009 (Neoplasms) : Activated mTORC1 regulates protein synthesis by directly phosphorylating 4E-binding protein 1 (4E-BP1) and p70S6K ( S6K ), translation initiation factors that are important to cap dependent mRNA translation, which increases the level of many proteins that are needed for cell cycle progression, proliferation, angiogenesis, and survival pathways
Gingras et al., Genes Dev 1998 : Furthermore, phosphorylation of 4E-BP1 by Akt requires the activity of FRAP/mTOR
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
Jaramillo et al., Cell Host Microbe 2011 (Leishmaniasis, Cutaneous) : mTOR cleavage results in the inhibition of mTOR complex 1 (mTORC1) and concomitant activation of 4E-BP1 to promote Leishmania proliferation
Fingar et al., Mol Cell Biol 2004 : Here we demonstrate that restoration of mTOR signaling ( by using a rapamycin-resistant mutant of mTOR ) rescues rapamycin inhibited G ( 1 ) -phase progression, and restoration of signaling along the mTOR dependent S6K1 or 4E-BP1/eukaryotic translation initiation factor 4E ( eIF4E ) pathways provides partial rescue
Hara et al., J Biol Chem 1998 : Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism
Chen et al., J Am Soc Nephrol 2005 (Hypertrophy) : The highly specific mTOR inhibitor rapamycin blocked UNX increased phosphorylation of both rpS6 and 4E-BP1
Marzec et al., PloS one 2011 (Lymphoma, T-Cell, Cutaneous) : mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein 1 (4E-BP1)
Davies et al., J Biol Chem 2004 (MAP Kinase Signaling System) : In addition, CD40 ligation was found to mediate a PI3K- and mammalian target of rapamycin (mTOR) dependent phosphorylation of 4E-BP1 and its subsequent dissociation from the mRNA cap binding protein eIF4E as well as an ERK dependent phosphorylation of eIF4E, thus promoting translation initiation
Hara et al., Cell 2002 : The binding of raptor to mTOR is necessary for the mTOR catalyzed phosphorylation of 4EBP1 in vitro, and it strongly enhances the mTOR kinase activity toward p70alpha
Vary et al., Mol Cell Biochem 2005 : Activation of the potential upstream regulators of 4E-BP1 and S6K1 phosphorylation via PKB and mTOR was also observed
Ciechomska et al., Oncogene 2013 (Brain Neoplasms...) : Decrease of phosphorylation of 4E-BP1 , p70S6K1 and its downstream target S6 ribosomal protein demonstrate inhibition of mTOR signaling by CsA
Kleijn et al., FEBS Lett 1996 : Apparently, PHAS-I was phosphorylated in a PI-3 kinase-, PKC-, and FRAP dependent manner after EGF or NGF stimulation ... Only PI-3 kinase and FRAP are involved in the regulation of the basal level of PHAS-I phosphorylation
Lee et al., J Biol Chem 2005 : We also show that insulin stimulated the phosphorylation of 4E-binding protein 1 (4E-BP1) and p70S6 kinase (p70S6K) in a mTOR dependent manner
Choo et al., Proc Natl Acad Sci U S A 2008 : This reemerged 4E-BP1 phosphorylation is rapamycin-resistant but still requires mTOR , Raptor, and mTORC1 's activity
Zindy et al., Cancer Res 2011 (Breast Neoplasms) : mTOR dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A
Ikenoue et al., Methods Enzymol 2009 : In turn, mTORC1 regulates the activity of the translational machinery by modulating S6 kinase ( S6K ) activity and eIF4E binding protein 1 ( 4E-BP1 ) through direct phosphorylation