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

Kimura et al., Genes Cells 2003 : The insensitivity of the rapamycin-resistant p70 S6k variant to AICAR treatment suggests that the inhibition of p70 S6k is mediated through a common effector, supporting a model whereby mTOR and its downstream effector are controlled by AMPK
Horman et al., J Biol Chem 2003 (Anoxia...) : Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), did not mimic the effect of oxygen deprivation to inhibit protein synthesis in cardiomyocytes or lead to eEF2 phosphorylation in perfused hearts, suggesting that AMPK activation did not inhibit mTOR/p70 ribosomal protein S6 kinase (p70S6K) signaling
Brugarolas et al., Genes Dev 2004 (Anoxia) : In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1
Kimball et al., Med Sci Sports Exerc 2006 : The focus of the present review is to briefly summarize current knowledge concerning the regulation of mTOR signaling by AMPK
Nader et al., Med Sci Sports Exerc 2006 : That is, activation of AMPK by endurance exercise may inhibit signaling to the protein-synthesis machinery by inhibiting the activity of mTOR and its downstream targets
Du et al., J Anim Sci 2007 : Applying 5-aminoimidazole-4-carbox-amide 1-beta-d-ribonucleoside, an activator of AMPK, abolished the stimulation of mTOR signaling by leucine, showing that AMPK negatively controls mTOR signaling ... To further show the role of AMPK in mTOR signaling , myoblasts expressing a dominant negative AMPKalpha subunit were employed ... The activation of mTOR induced by leucine in these cells was abated, showing that AMPK contributed to mTOR activation
Guo et al., Circ Res 2007 : Constitutively active and dominant negative mutants of AMPK and Akt were used to elucidate further the positive effect of Akt and negative role of AMPK in mediating mTOR ( mammalian target of rapamycin ) and its target p70S6 kinase ( S6K ) in response to laminar and oscillatory flows
Høyer-Hansen et al., Autophagy 2007 (Calcium Signaling) : The present study suggests hat AMPK inhibits mTORC1 and autophagy also in nonstarved cells
Canabal et al., Am J Physiol Regul Integr Comp Physiol 2007 (Acute Disease...) : Glucose- and insulin regulated NO production was restored in the presence of the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside or the mTOR inhibitor rapamycin
Baumann et al., Exp Cell Res 2007 (Multiple Myeloma) : Activation of AMPK inhibited basal extracellular signal regulated kinase ( ERK ), mammalian target of rapamycin (mTOR) and P70S6 kinase ( P70S6K ) as well as AKT phosphorylation, and blocked IL-6, IGF-1, and HS-5 stromal cell conditioned medium induced increase of cell growth
Dowling et al., Cancer Res 2007 (Breast Neoplasms) : These results show that metformin mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth
Barb et al., Endocr Relat Cancer 2007 (Prostatic Neoplasms) : Previous studies have shown that adiponectin can activate AMP activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR)
Kim et al., Mol Cell Biol 2008 : The antiapoptotic effect of GIP in beta cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK dependent regulation of CREB/TORC2 activity
McGee et al., J Physiol 2008 (Hypertrophy) : The activation of the AMP activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin complex 1 ( mTORC1 ) is hypothesized to underlie the fact that muscle growth following resistance exercise is decreased by concurrent endurance exercise
Deshmukh et al., Mol Endocrinol 2008 : We hypothesized that AMPK mediated inhibitory effects on mTOR signaling depend on catalytic alpha2 and regulatory gamma3 subunits ... However, in WT mice, preincubation with AICAR completely inhibited insulin induced phosphorylation of mTOR targets, suggesting mTOR signaling is blocked by prior AMPK activation
Gwinn et al., Mol Cell 2008 : AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1 ; however, TSC2-deficient cells remain responsive to energy stress
Mariño et al., Hum Mol Genet 2008 (Aging, Premature...) : These Zmpste24 ( -/- ) mice metabolic alterations are also linked to substantial changes in circulating blood parameters, such as leptin, glucose, insulin or adiponectin which in turn lead to peripheral LKB1-AMPK activation and mTOR inhibition
Budanov et al., Cell 2008 : We now demonstrate that the products of two p53 target genes, Sestrin1 and Sestrin2, activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTOR
Shaw et al., Acta Physiol (Oxf) 2009 (Neoplasms) : Many details of the molecular mechanism by which AMPK inhibits mTORC1 signalling have also been decoded in the past 5 years ... Here we explore the molecular connections between AMPK and mTOR signalling pathways and examine the physiological processes in which AMPK regulation of mTOR is critical for growth or metabolic control
Racanelli et al., Cancer Res 2009 (Carcinoma, Non-Small-Cell Lung...) : Therapeutics by cytotoxic metabolite accumulation : pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition
Tong et al., J Cell Biochem 2009 : In addition, AMPK inhibition of mTOR may provide an additional explanation for the enhancement of UL expression by AMPK
Fujimoto et al., Free radical research 2010 : To further confirm the role of mTOR in gAd stimulation, the effect of the activators of AMP activated protein kinase (AMPK) on gAd induced mTOR phosphorylation was examined
Wong et al., J Biol Chem 2010 : Inhibition of AMPK prevented translation repression by cordycepin and abolished 4EBP1 dephosphorylation, indicating that the effect of cordycepin on mTOR signaling and protein synthesis is mediated by AMPK activation
Dere et al., PloS one 2010 (Polycystic Kidney, Autosomal Dominant) : Interestingly, while membrane tethering of CP1 was required to activate TSC2 and repress mTOR, the ability of CP1 to inhibit mTOR signaling did not require primary cilia and was independent of AMPK activation
Hou et al., Endocrinology 2010 : In contrast, activation of AMPK inhibited LH-stimulated MTOR/S6K1 signaling and progesterone secretion
Habib et al., Eur J Cancer 2010 (Kidney Neoplasms) : Novel mechanism of reducing tumourigenesis : upregulation of the DNA repair enzyme OGG1 by rapamycin mediated AMPK activation and mTOR inhibition ... Our data show that inhibition of mTOR can activate AMPK and lead to upregulation of DNA repair enzyme OGG1
Jalving et al., Eur J Cancer 2010 (Diabetes Mellitus, Type 2...) : The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR) , a downstream effector of growth factor signalling
Kim et al., J Lipid Res 2010 : The lipogenic effects of GIP in the presence of insulin are therefore at least partially mediated by upregulation of adipocyte LPL gene transcription through a pathway involving PI3-K/PKB/AMPK dependent CREB/TORC2 activation
Ma et al., Eur Heart J 2011 (Myocardial Infarction...) : ALDH2 significantly promoted autophagy during ischaemia, which was accompanied by AMPK activation and mammalian target of rapamycin (mTOR) inhibition
Ji et al., Oncogene 2010 (Neoplasms) : Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin induced apoptosis by promoting AMPK activation and mTORC1 inhibition
Memmott et al., Cancer prevention research (Philadelphia, Pa.) 2010 (Carcinoma...) : In liver tissue, metformin activated AMPK and inhibited mTOR ... In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor ( IGF-1R/IR ), Akt, extracellular signal regulated kinase ( ERK ), and mTOR
Leclerc et al., Journal of molecular signaling 2010 : We found that AICAR induced AMPK activation resulted in up-regulation of P-Akt ( Ser473 and Thr308 ) and decrease of P-mTOR ( Ser2448 ) expression and downstream signaling
Zhang et al., J Biol Chem 2010 (Glioblastoma) : Activation of AMPK by TMZ also inhibits mTOR complex 1 (mTORC1) signaling and promotes anti-apoptosis protein Bcl-2 down-regulation, which together mediate TMZ induced pro-cell apoptosis effects
Rothbart et al., Cancer Res 2010 : Whereas AMPK activation resulted in marked inhibition of mTORC1 , other targets of AMPK were phosphorylated that were not mTORC1 dependent
Chao et al., J Agric Food Chem 2011 (Glioblastoma) : Activation of AMPK induces a-mangostin mediated phosphorylation of raptor, which subsequently associates with 14-3-3? and results in the loss of mTORC1 activity
Micic et al., Hormones (Athens) 2011 (Neoplasms) : Moreover, by activating AMPK , metformin inhibits the mammalian target of rapamycin complex 1 ( mTORC1 ) resulting in decreased cancer cell proliferation
Wolff et al., Mol Cell Biol 2011 (Anoxia) : AMPK activation ( using 5-aminoimidazole-4-carboxamide riboside [ AICAR ] ) induces raptor phosphorylation and inhibits mTORC1 in both mouse embryo fibroblasts ( MEFs ) and hepatocytes, but whereas mTORC1 inhibition is Tsc1/Tsc2 dependent in MEFs, it is independent in hepatocytes
Padmasekar et al., Stem Cells Dev 2011 : Inhibition of AMPK by Comp C resulted in phosphorylation of mTOR and generation of NO ... NO generation was likewise achieved when AMPK was either activated by AICAr or mTOR was inhibited by rapamycin, suggesting that NO generation occurred by two mutually active parallel signaling pathways, one being AMPK dependent and mTOR independent ( AICAr pathway ) and the other being AMPK independent and mTOR dependent ( Comp C pathway )
Layne et al., J Clin Endocrinol Metab 2011 (Insulin Resistance...) : Failure of resistance training to improve insulin responsiveness in MS subjects was coincident with diminished phosphorylation of muscle AMPK , but increased phosphorylation of mTOR , suggesting activation of the mTOR pathway could be involved in inhibition of exercise training related increases in AMPK and its activation and downstream events
Tong et al., Mol Carcinog 2012 : Although AMPK is traditionally thought to play a major role in the regulation of cellular lipid and protein metabolism, recent discoveries reveal that AMPK inhibits mammalian target of rapamycin (mTOR) signaling and connects with several tumor suppressors such as liver kinase B1 (LKB1), p53, and tuberous sclerosis complex 2 (TSC2), indicating that AMPK may be a potential target for cancer prevention and treatment ... Although AMPK is traditionally thought to play a major role in the regulation of cellular lipid and protein metabolism, recent discoveries reveal that AMPK inhibits mammalian target of rapamycin (mTOR) signaling and connects with several tumor suppressors such as liver kinase B1 (LKB1), p53, and tuberous sclerosis complex 2 (TSC2), indicating that AMPK may be a potential target for cancer prevention and treatment ... Apigenin induced AMPK activation inhibited mTOR signaling and further induced autophagy in human keratinocytes
Liu et al., Urol Oncol 2013 (Carcinoma, Renal Cell...) : Further study revealed metformin induced the activation of AMP activated protein kinase (AMPK) , and inhibited mammalian target of rapamycin (mTOR) , which is a central regulator of protein synthesis and cell growth, and negatively regulated by AMPK
Zannella et al., Radiother Oncol 2011 (Colorectal Neoplasms) : These data reveal novel functional roles for AMPK in regulating mTOR signaling , cell cycle, survival and metabolic responses to IR
Zhao et al., Anat Rec (Hoboken) 2011 (Nasopharyngeal Neoplasms) : AMPK mediated inhibition of mTORC1 signaling may be involved in this process
Lee et al., J Biol Chem 2011 (Breast Neoplasms) : Beyond AMPK mediated effects on mammalian target of rapamycin signaling and lipogenesis, OSU-53 also targeted multiple AMPK downstream pathways
Ng et al., Cell Death Differ 2012 : However, AMPK activation represses the mTOR complex-1 (mTORC1) pathway only in transformed cells, suggesting a key role for AMPK mediated mTORC1 inhibition in the suppression of anoikis ... Our data implicate AMPK mediated mTORC1 inhibition and suppression of protein synthesis as a means for bioenergetic conservation during detachment, thus promoting anoikis resistance
Tillu et al., Molecular pain 2012 (Acute Pain...) : We reasoned that activators of AMP activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision induced pain because AMPK activators inhibit ERK and mTOR signaling , two important pathways involved in the sensitization of peripheral nociceptors ... Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity
Stevanovic et al., Neuroendocrinology 2012 : Metformin could reduce food intake by preventing ghrelin induced AMPK signalling and mTOR inhibition in the hypotalamus
Zheng et al., Biochem Biophys Res Commun 2012 (Urinary Bladder Neoplasms) : Further, activation of AMPK by UA promoted c-Jun N-terminal kinase (JNK) activation, but inhibited mTOR complex 1 (mTORC1) signaling to cause survivin down-regulation
Klubo-Gwiezdzinska et al., Endocr Relat Cancer 2012 (Thyroid Neoplasms) : Recent studies showed that the antidiabetic agent metformin decreases proliferation of cancer cells through 5'-AMP activated protein kinase (AMPK) dependent inhibition of mTOR
Hong-Brown et al., Am J Physiol Cell Physiol 2012 : Rag GTPases and AMPK/TSC2/Rheb mediate the differential regulation of mTORC1 signaling in response to alcohol and leucine
Watterson et al., Neurosignals 2013 (Anorexia) : Insulin and leptin increase mTORC1 activity in a phosphoinositide-3-kinase (PI3K)- and protein kinase B (PKB) dependent manner, compared to vehicle controls, whereas increasing AMPK activity inhibits mTORC1 activity and blocks the actions of the anorexigenic hormones ... Ghrelin mediates an AMPK dependent decrease in mTORC1 activity and increases hypothalamic AgRP mRNA levels, the latter effect being prevented by insulin in an mTORC1 dependent manner
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
Guo et al., International journal of molecular sciences 2012 : Furthermore, our data indicate that the increase of autophagy in senescent cells is linked to the activation of transcription factor FoxO3A, which blocks ATP generation by transcriptionally up-regulating the expression of PDK4, an inhibitor of pyruvate dehydrogenase complex, thus leading to AMPK activation and mTOR inhibition
Yuan et al., CNS Neurosci Ther 2012 (Glioblastoma) : Subsequently, activated AMPK inhibited mTOR signaling and downregulated antiapoptosis protein Bcl-2, which was contributed to the additive antiproliferation effects of combination treatment
Jin et al., Cell death & disease 2012 (Carcinoma, Non-Small-Cell Lung...) : Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK activated mTOR inhibition ... Silencing of Twist1 triggered ATP depletion, leading to AMP activated protein kinase (AMPK) activated mammalian target of rapamycin (mTOR) inhibition in NSCLC cells ... AMPK induced mTOR inhibition, in turn, resulted in downregulation of ribosome protein S6 kinase 1 (S6K1) activity ... In conclusion, silencing of Twist1 sensitizes lung cancer cells to cisplatin via stimulating AMPK induced mTOR inhibition, leading to a reduction in Mcl-1 protein
Wu et al., PloS one 2012 : Further mechanistic investigation revealed that H ( 2 ) S stimulated the phosphorylation of AMP activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and S6 kinase
Cook et al., Cancer Res 2012 : Mechanistically, GRP78 integrated multiple cellular signaling pathways to inhibit apoptosis and stimulate prosurvival autophagy, which was dependent on TSC2/AMPK mediated mTOR inhibition but not on beclin-1
Jung et al., J Toxicol Sci 2012 : In conclusion, OA increases the proliferation and decreases the starvation induced apoptosis of SK-Hep1 cells via mTORC1 activation mediated by negative regulation of AMPK
Hofmann et al., Mol Biol Cell 2012 : In addition, cold shock leads to reduced mitochondrial function, energy depletion, concomitant activation of AMP activated protein kinase (AMPK) , and inhibition of mTOR signaling
Burgos et al., Horm Metab Res 2013 : The inhibitory effects of AMPK activation on mTORC1 signaling were associated with a marked increase in Ser792 phosphorylation on raptor
Zhang et al., Breast Cancer Res Treat 2012 (Breast Neoplasms) : Although NDGA stimulated AMP activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2) signaling, which negatively regulates mTORC1, AMPK and TSC2 deletion could not diminish the inhibition of mTORC1 by NDGA ... Disruption of mTOR-Raptor complex and activation of AMPK/TSC signaling may contribute to inhibitory effects of NDGA against mTORC1
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
White et al., Mol Cell Endocrinol 2013 : Muscle AMPK and raptor phosphorylation, mTOR inhibitors , were not altered by low testosterone
Dong et al., Acta Pharmacol Sin 2013 (Carcinoma, Non-Small-Cell Lung...) : Negative regulation of mTOR activity by LKB1-AMPK signaling in non-small cell lung cancer cells ... In non-small cell lung cancer cells, LKB1/AMPK signaling negatively regulates mTOR activity and contributes to cell growth inhibition in response to energy stress
Sviripa et al., Bioorg Med Chem Lett 2013 : AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and regulates mTOR signaling by activating TSC2
Demeulder et al., Biochim Biophys Acta 2013 (Myocardial Ischemia) : This challenges the accepted notion that mTOR-p70S6K is inhibited by myocardial ischemia mainly via an AMPK dependent mechanism
White et al., Am J Physiol Endocrinol Metab 2013 (Cachexia...) : Muscle mTORC1 suppression by IL-6 during cancer cachexia : a role for AMPK ... IL-6 suppression of mTOR activity was dependent on AMPK activation and independent of STAT signaling in myotubes
Huang et al., Int J Oncol 2013 : In SK-HEP-1 cells, kaempferol increased the protein levels of p-AMPK , LC3-II, Atg 5, Atg 7, Atg 12 and beclin 1 as well as inhibited the protein levels of CDK1, cyclin B , p-AKT and p-mTOR
Chen et al., Cell Signal 2013 : Further, after plumbagin treatment, activated AMPK directly phosphorylates Raptor to inhibit mTOR complex 1 (mTORC1) activation and Bcl-2 expression in colon cancer cells
Pung et al., Arterioscler Thromb Vasc Biol 2013 (Body Weight...) : We conclude that activation of AMPK-a during mitochondrial oxidative stress inhibits mammalian target of rapamycin signaling, which impairs phenotypic switching necessary for the growth of blood vessels
Fumarola et al., Breast Cancer Res Treat 2013 (Breast Neoplasms) : The key role of AMPK dependent inhibition of mTORC1 in sorafenib mechanisms of action was confirmed by AMPKa1 silencing, which restored mTORC1 activity conferring a significant protection from cell death